DE10147028A1 - Identifying agents for treatment and diagnosis of diseases, e.g. depression or viral infections, from binding to inorganic phosphate transporters, also new agents - Google Patents

Abstract

Identifying agents (A) for detection or treatment of specified conditions comprises incubating test compound with BNPI or DNPI (brain or differentiation-associated sodium-dependent inorganic phosphate transporter), or related proteins, nucleic acids or cells (and/or cell preparations), then measuring binding of test compound or some functional parameter altered by binding. Identifying agents (A) for detection or treatment of specified conditions comprises incubating test compound with BNPI or DNPI (brain or differentiation-associated sodium-dependent inorganic phosphate transporter), or related proteins, nucleic acids or cells (and/or cell preparations), then measuring binding of test compound or some functional parameter altered by binding. (A) is incubated with one or more of BNPI or DNPI, or 7 specified proteins, all fully disclosed in the specification; proteins with at least 90% similarity; proteins encoded by 7 specified nucleic acid sequences all fully disclosed in the specification, by sequences with at least 90% similarity, by sequences that hybridize to them (or their antisense sequences) under stringent conditions, or fragments of the proteins with at least 10, preferably 20, amino acids. An Independent claim is also included for compounds identified by the new method.

Description

The invention relates to a method for finding pharmaceutical active substances using BNPI and / or DNPI or derived biomolecules and the use of identified ones Compounds, active substances binding to BNPI and / or DNPI, against BNPI and / or DNPI-directed antibodies, from antisense nucleotides against BNPI and / or DNPI, or of BNPI and / or DNPI or partial proteins thereof, or corresponding polynucleotides for the production of Medicines for the treatment of various diseases or Therapy and diagnostics.

Finding the places of attack of pharmaceutical agents, the so-called "targets" is one of the most important tasks of modern Pharmaceutical research. About the affinities to these targets or about which are triggered by an interaction with these targets physiological effects can be assessed using so-called "screening methods" from the variety of known substances, for example from Substance libraries of pharmaceutical research, interesting Filter out substances or classes of substances in the with this Target associated indications are highly likely to be effective are. The most important representatives of these targets include proteins, in general receptors, in particular G protein-coupled receptors, and transport proteins. The discovery of these targets, however, turns out to be sometimes very difficult because the potential selection is very large. to Orientation and identification serve on the one hand to gain knowledge about the (Physiological) function with the (potential) position in signal cascades and metabolic pathways to the other but also localization and Degree of expression in the different tissues. As part of this Invention was given special attention to the central Nervous system where it is not just for general localization but on a very specific and precise distribution in the arrives in different regions.

• a) Inkubation einer zu testenden Substanz unter geeigneten Bedingungen mit mindestens einem Biomolekül aus Gruppe I: dem Protein BNPI und/oder DNPI und/oder einem Protein gemäß einer der Abb. 1b), 1d), 1f), 2b) oder 2d) und/oder einem zu einem dieser vorgenannten Proteine zu mindestens 90% ähnlichen Protein und/oder einem Protein, für das ein Polynukleotid gemäß einer der Abb. 1a), 1c), 1e), 2a) oder 2c) oder ein dazu zu mindestens 90% ähnliches Polynukleotid kodiert, und/oder einem Protein, das durch eine Nukleinsäure kodiert wird, die unter stringenten Bedingungen an ein Polynukleotid gemäß einer der Abb. 1a), 1c), 1e), 2a) oder 2c) oder deren Antisense Polynukleotide bindet, oder einem mindestens 10, vorzugsweise mindestens 15, insbesondere mindestens 20 Aminosäuren langen Teilprotein eines der vorgenannten Proteine und/oder einer Zelle und/oder einer Präparation aus einer solchen Zelle, die mindestens eines der vorgenannten Proteine und Teilproteine, bzw. Biomoleküle, synthetisiert hat,
• b) Messung der Bindung der Testsubstanz an dem oder den von der Zelle synthetisierten Proteinen und/oder Teilproteinen oder Messung mindestens eines der durch die Bindung der Testsubstanz an das oder die Proteine und/oder Teilproteine, bzw. Biomoleküle veränderten funktionellen Parameter.

The object of the invention was therefore to find and identify one or more such targets, in particular with central nervous localization and effectiveness, and to develop a corresponding screening method. The invention therefore relates to a method for the detection of pharmaceutically relevant substances with effectiveness in the indications or for the treatment of
Visual disturbances, retinitis pigmentosa, optic degeneration, hearing disorders, tinitus, M. Meniere, sudden hearing loss, schizophrenia, mania, depression, stroke, brain trauma, paraplegia, amyotrophic lateral sclerosis, neuralgia, weight regulation, obesity, anorexia nervosa, epilepsy, choroidal stress, hemibalism , Parkinson's disease, TIA (transient ischemic attacks), emesis, especially hyperemesis, for example with chemotherapy, dizziness, in any form, cataract, arthritis, hyperactivity, developmental disorders, rabies, virus infections or bacterial infections, flu, malaria, Creutzfeld-Jacob, Inflammatory bowel disease, Crohn's disease, cardiovascular and cardiorespiratory dysfunction, hypertension, disorders of baroafference or chemoafference, toxoplasmosis, asthma, autoimmunity in the central and peripheral nervous system, diabetic neuropathy, autoimmune diabetes, alcoholic neuropathy, HIV-neuroids; Autonomic nervous system disorders, digestive tract nervous system disorders, hyperexcitability, especially glutamate-mediated hyperexcitability, neurodegeneration, especially in Alzheimer's disease, Alzheimer's disease, ischemia; Encephalitis especially viral or bacterial; Prion disease, Rasmussen encephalitis, HIV encephalitis, demyelination, particularly in the case of multiple sclerosis, retinal degeneration, glaucoma, nystagmus, retinal detachment, cerebellar disorders, cerebellar ataxia, disorders of the basal ganglia, diseases of the pallidum, disorders of the hearing organ and / or balance Auditory or vesibular tract, memory disorders, learning disorders, cognitive disorders, Stiff-Man syndrome, restless leg syndrome, anxiety, phobias, sleep disorders; Drug addiction, addiction and withdrawal, especially with alcohol, nicotine, opiates, ecstasy or cocaine; Hepatoencephalopathy with alcohol intoxication, hepatoencephalopathy without alcohol intoxication, neurotoxicological diseases, diseases of the spinal motor neurons, muscle atrophies, muscular dystrophies, diseases of the posterior tract, alcoholic neuropathies, neuroinflammation, sensory disorders with infections or fever, stress, taste disorders, Chinese food, food syndrome, food allergy Paranoia, concussion, neuroendocrine disorders, Tourrette syndrome, cerebrovascular spasms, neuronal apoptosis, neurodegeneration, neuronal necrosis, astrocytosis, burn-out syndrome, sudden infant death (sudden childhood death), heart attack, insomnia, retrograde amnesia, multiple Jet-lag, disorders of sexual function such as impotence or priapism or with effectiveness for promoting microglia activation, learning, cognition or memory, for neuroprotection, for CSF diagnosis of neurostatic diseases or he for adjuvant therapy by electrostimulation of the subthalamic nucleus in Parkinson's with the following procedural steps:

• a) Incubation of a substance to be tested under suitable conditions with at least one biomolecule from Group I: the protein BNPI and / or DNPI and / or a protein according to one of Figs. 1b), 1d), 1f), 2b) or 2d) and / or a protein which is at least 90% similar to one of the abovementioned proteins and / or a protein for which a polynucleotide according to one of Figs. 1a), 1c), 1e), 2a) or 2c) or at least 90% of this encoded a similar polynucleotide, and / or a protein which is encoded by a nucleic acid which, under stringent conditions, binds to a polynucleotide according to one of Figs. 1a), 1c), 1e), 2a) or 2c) or its antisense polynucleotides, or an at least 10, preferably at least 15, in particular at least 20 amino acids long partial protein of one of the aforementioned proteins and / or a cell and / or a preparation from such a cell, the at least one of the aforementioned proteins and partial proteins, or biomolecules, synthesized
• b) measuring the binding of the test substance to the protein and / or partial proteins synthesized by the cell or measuring at least one of the functional parameters changed by the binding of the test substance to the protein and / or partial protein or biomolecule.

This new screening process is based on the fact that there is a potential medical effectiveness of a substance through its interaction with at least one physiologically relevant protein or peptide structure, a target, BNPI and / or DNPI or related structures, can be found. BNPI and DNPI or the ones derived from them Proteins and partial proteins or peptides listed here or for these coding nucleic acids were within the scope of this invention as identified interesting targets. BNPI and DNPI showed one Localization in the most diverse CNS areas, however Surprisingly - despite some of the closest neighborhood - also one Always strictly separate localization, with this strict separation clearly indicates that important DNPI and BNPI physiological processes can be controlled. Since DNPI and BNPI also in therapeutically very interesting areas of the CNS are localized and are therefore of interest for a corresponding number of indications, DNPI and BNPI are accordingly important targets with which Screening method for pharmacologically active compounds can be carried out. Consequently, it is also preferred if in one Screening procedures simultaneously BNPI and DNPI or one of the derived proteins and partial proteins derived from this or Peptides or a nucleic acid coding for them are used, or the result of two separate screening procedures once with BNPI or one of the derived proteins listed here and Partial proteins or peptides or a nucleic acid coding for them and once with DNPI or one of the derived ones listed here Proteins and partial proteins or peptides or one encoding them Nucleic acid can be carried out and in both cases differential comparison of the data optimizes pharmacologically effective Substances are identified.

The terms pharmaceutically relevant or pharmacologically effective on a potentially healing or soothing Influence of the substance on certain clinical pictures. The term substance includes any compound useful as an active pharmaceutical ingredient, in particular so low molecular weight active ingredients, but also others like nucleic acids, Fats, sugars, peptides or proteins such as antibodies.

Incubation under suitable conditions is to be understood here such that the substance to be examined with the cell or the corresponding Preparation in an aqueous medium a defined time before Measurement can react. The aqueous medium can be tempered be, for example between 4 ° C and 40 ° C, preferably at Room temperature or at 37 ° C. The incubation period can be between a few seconds and several hours, depending on the Interaction of the substance with the partial protein or protein. Prefers but are times between 1 min and 60 min. The aqueous medium can contain suitable salts and / or buffer systems, so that the Incubation, for example, a pH between 6 and 8, preferably pH 7.0-7.5 prevails in the medium. The medium can be further suitable Substances such as coenzymes, nutrients etc. can be added. The suitable conditions can be determined by the skilled worker depending on the interaction of the substance to be investigated with the partial protein or Protein due to its experience, literature or less, easier Preliminary tests can easily be set up in order to get one as possible in the procedure to obtain a clear measured value.

A cell that has synthesized a particular sub-protein or protein is a cell that already expresses this partial protein or protein endogenously has or one that has been genetically modified so that it this partial protein or protein is expressed and accordingly before the start of the method according to the invention contains the partial protein or protein. The cells can be cells from possibly immortalized cell lines or native cells derived from and isolated from tissues, whereby the cell structure is mostly dissolved. The preparation from these Cells in particular comprise homogenates from the cells, the cytosol, a membrane fraction of the cells with membrane fragments, a Suspension of isolated cell organelles etc.

Which species these proteins come from is essential for the function of the Process irrelevant, but it is preferred to use the human, mouse or Rat variant to use. BNPI and DNPI are in terms of coding DNA and the amino acid sequence known and also in your general function described. BNPI, the "brain Na + dependent inorganic phosphate cotransporter "is described in WO 96/34288 and the DNPI, the "differentiation-associated Na + dependent inorganic phosphate cotransporter ", was described by Aihara et al. (2000) in J. Neurochem. 74, 2622-2625. In addition to the function as sodium-dependent phosphate transporter also became one for BNPI Function described as a vesicular glutamate transporter and BNPI as VGlutT1 (Bellocchio et al. (2000) Science 189: 957-960; Takamori et al. (2000) Nature 407; 189-194).

The scale by which the method allows the discovery of interesting substances is either the binding to the biomolecule, the protein or partial protein, which, for. B. can be detected by displacement of a known ligand or the extent of bound substance, or the change in a functional parameter by the interaction of the substance with the partial protein or protein. This interaction can be, in particular, regulation, inhibition and / or activation of receptors, ion channels and / or enzymes, and changed functional parameters can be, for example, gene expression, the ionic environment, the pH or the membrane potential, or the change in the enzyme activity or the concentration of the 2 ^nd messenger.

• - Substanz: Damit ist eine chemische Verbindung gemeint. Hier handelt es sich im engeren Sinne um Verbindungen, die potentiell eine Wirkung im Körper entfalten können, niedermolekulare Wirkstoffe, Nukleinsäuren, Fette, Zucker, Peptide oder Proteine, insbesondere hier niedermolekulare Wirkstoffe.
• - pharmazeutisch relevante Substanz: Im Sinne der Erfindung ist eine pharmazeutisch relevante Substanz eine Substanz, die über die Bindung an die Biomoleküle der Gruppen I bis III in wenigstens einer der genannten Indikationen wirksam sein könnte und theoretisch das Potential besitzt, physiologisch die Symptome direkt oder indirekt zu beeinflußen, insbesondere so erscheint, als könne sie therapeutisch, beispielsweise in einem Arzneimittel, eingesetzt werden.
• - schmerzregulierend: Im Sinne der Erfindung heißt schmerzregulierend, daß die Substanz die Wahrnehmung von Schmerz direkt oder indirekt beeinflußt, insbesondere natürlich analgetisch wirkt.
• - Schmerz: Im Sinne der Erfindung bedeutet Schmerz insbesondere ein Schmerzempfinden, präziser akkuter, chronischer, neuropathischer und entzündlicher Schmerz inclusive Migräne, insbesondere ist der Schmerz zugehörig zu folgenden Arten:
  chronischem Schmerz, insbesondere muskuloskelettalem Schmerz; neuropathischem Schmerz, insbesondere allodynischem Schmerz, mechanischer Hyperalgesie oder diabetischer Neuropathie; viszeralem Schmerz, cerebralem Schmerz, peripherem Schmerz oder entzündungsbedingtem Schmerz, insbesondere peripherem Entzündungsschmerz; sowie Migräne, Cluster-Kopfschmerz oder den Schmerz bei Trigeminus Neuralgie.
• - Inkubation: Unter Inkubation ist das Einbringen und Belassen eines biologischen Untersuchungsobjektes, beispielsweise einer Zelle oder eines Proteins, in einem temperierten Medium wie in einem Brutschrank oder auf einem Wasserbad zu verstehen. Dabei heiß hier unter geeigneten Bedingungen eine Inkubation unter physiologischen Bedingungen (z. B. 37°C pH 7,2) oder bei den Bedingungen, bei denen eine optimale Messung im Verfahren möglich wird.
• - Zelle: Die Zelle ist ein sich selbst regulierendes, offenes, mit seiner Umgebung durch permanenten Stoffaustausch in einem Fließgleichgewicht stehendes System mit eigenem Stoffwechsel, und Vermehrungsfähigkeit. Die Zelle kann separat kultiviert oder Teil eines Gewebes, insbesondere aus einem Organ, sein, und dort vereinzelt oder noch im Zellverband vorliegen.
• - Präparation aus einer Zelle: Darunter versteht man Präparate, die mittels chemischer, biologischer, mechanischer oder physikalischer Methoden unter Änderung der Zellstruktur hergestellt werden, beispielsweise Membranfragmente, isolierte Zellkompartimente, isoliertes Cytosol, oder aus Gewebe gewonnenes Homogenat.
• - Peptid: Verbindung aus über peptidische Bindungen zu Ketten verknüpften Aminosäuren. Ein Oligopeptid besteht aus zwischen 2 und 9 Aminosäuren, ein Polypeptid aus zwischen 10 und 100 Aminosäuren.
• - Protein: Verbindung aus über peptidische Bindungen zu Ketten verknüpften mehr als 100 Aminosäuren u. U. mit einer definierten Raumstruktur.
• - Teilprotein: Verbindung aus über peptidische Bindungen zu Ketten verknüpften mehr als 10 Aminosäuren u. U. mit einer definierten Raumstruktur aber ausgeschnitten bzw. ausgewählt aus einem definierten Priotein. Ein Teilprotein kann ein Peptid sein.
• - PIM1-Kinase: PIM3-Kinase: Ein Proto-Oncogen und eine Serin- Threonin-Kinase.
• - Polynukleotid: Das zugrundeliegende Nukleotid ist ein grundsätzlich aus Nucleinbase, Pentose und Phosphorsäure bestehender Grundbaustein der Nucleinsäuren. Diese entspricht einem hochmolekularen Polynucleotid aus mehreren Nukleotiden, die über Phosphorsäure- Pentose-Veresterung miteinander verknüpft sind. Unter dierr Erfindung fallen aber auch modifizierte Polynukleotide, die zwar die Basenabfolge beibehalten, aber über ein modifiziertes Rückrat statt der Phosphorsäure-Pentose verfügen.
• - zu mindestens 90 (95, 97)% ähnlich: Darunter ist zu verstehen, daß die mit erfaßten Polynucleotide in ihrem kodierenden Bereich beuzüglich der Basenabfolge zu mindestens 90% (95%, 97%) identisch mit der Referenz (Abbildung etc.) sind und die mit erfaßten Peptide und Proteine in ihrer Primärstruktur, der Abfolge der Aminosäuren zu mindestens 90% (95%, 97%) mit der Referenz identisch sind.
• - Gen: Mit dem Begriff Gen wird ein Genomabschnitt mit einer definierten Nukleotidsequenz bezeichnet, der die Information zur Synthese einer m- oder prä-mRNA oder einer sonstigen RNA (z. B. tRNA, rRNA, snRNA etc.) enthält. Es besteht aus kodierenden und nicht kodierenden Abschnitten.
• - Genfragment: Nukleinsäureabschnitt, der in seiner Basenabfolge einen Teilbereich eines Gens beinhaltet
• - Biomolekül: Allgemeiner Begriff für Nukleinsäuren oder Polyaminosäuren, insbesondere auch DNA, RNA, Peptide (Teilproteine) und Proteine, wobei diese Moleküle auch künstlich verändert sein dürfen. Im Sinne dieser Erfindung vorzugsweise Peptide (Teilproteine) und Proteine.
• - Bindung an das Peptid, Teilprotein oder Protein: Wechselwirkung zwischen Substanz und Peptid, Teilprotein oder Protein, die zu Fixierung führt.
• - funktionelle Parameter: darunter versteht man Meßgrößen eines Experimentes, die mit der Funktion eines Proteins (Ionenkanal, Rezeptor, Enzym) korrelieren
• - gentechnisch manipuliert: Manipulation von Zellen, Geweben oder Organismen derart, daß hier genetisches Material eingebracht wird
• - endogen exprimiert: Expression eines Proteins, die eine Zelllinie unter geeigneten Kulturbedingungen aufweist, ohne das dieses entsprechende Protein durch gentechnische Manipulation zur Expression veranlasst wurde
• - G-Protein: International übliche Abkürzung für ein Gunaosintriphosphat (GTP)-bindendes Protein, das als Signalprotein durch G-Protein gekoppelte Rezeptoren aktiviert wird
• - Reportergen: Generelle Bezeichnung für Gene, deren Genprodukte sich mit Hilfe einfacher biochemischer Methoden oder histochemischer Methoden einfach nachweisen lassen, wie z. B. Luziferase, alkalische Phosphatase oder Green Fluorescent Protein (GFP).
• - (rekombinantes) DNA-Konstrukt: Generelle Bezeichnung für jede Art von DNA-Molekülen, die durch die in vitro-Verknüpfung von DNA- Molekülen entstanden sind.
• - Klonierungsvektor: Generelle Bezeichnung für Nukleinsäure-Moleküle, die beim Klonieren als Träger von Fremdgenen oder Teilen dieser Gene dienen.
• - Expressionsvektor: Bezeichnung für speziell konstruierte Klonierungsvektoren, die nach Einbringen in eine geeignete Wirtszelle die Transcription und Translation des in den Vektor einklonierten Fremdgens erlauben.
• - LTR-Sequenz: Abkürzung für Long terminal repeat. Generelle Bezeichnung für längere Sequenzbereiche, die an beiden Enden eines linearen Genoms zu finden sind. Derartige Sequenzbereiche kommen z. B. in den Genomen von Retroviren und an den Enden eukaryontischer Transposons vor.
• - Poly-.A-Schwanz: die am 3'-Ende von messenger-RNAs durch Polyadenylierung angeheftenen Adenyl-Reste (ca. 20-250).
• - Promotor-Sequenz: Bezeichnung für einen DNA-Sequenzbereich, von dem aus die Transkription eines Gens, d. h. die Synthese der mRNA, gesteuert wird.
• - ORI-Sequenz: Abkürzung für Origin of replication. Die ORI-Sequenz erlaubt einem DNA-Molekül, sich als autonome Einheit in der Zelle zu vermehren.
• - Enhancer-Sequenz: Bezeichung für relativ kurze, zum Teil als Repetitionen auftretende, genetische Elemente, die in der Regel die Expression mancher Gene in unterschiedlichem Maße verstärken.
• - Transkriptionsfaktor: Bezeichnung für ein Protein, das über eine Bindung an spezifische DNA-Sequenzen, die Transkription eines Gens beeinflußt.
• - kultivieren: Zellen oder Gewebe unter geeigneten Kulturbedingungen halten
• - Bedingungen, die eine Expression erlauben, darunter versteht man die Auswahl und Anwendung von Kulturbedingungen die eine Expression des interessierenden Proteins erlauben, darunter gehören Temperaturänderung, Mediumwechsel, Zusatz von induzierenden Substanzen, Weglassen hemmender Substanzen.
• - Inkubationszeit: Zeitdauer für die Zellen oder Gewebe inkubiert, d. h. einer definierten Temperatur ausgesetzt werden.
• - Selektionsdruck: Anwendungen von Kulturbedingungen die Zellen mit einem bestimmtem Genprodukt, dem sog. Selektionsmarker, einen Wachstumsvorteil verschaffen.
• - Amphibienzelle, Zelle aus einem Tier der Klasse der Amphibia
• - Bakterienzelle, Zelle die dem Überreich der Eubacteria oder Archaebacteria zuzuordnen ist, oder von ihr abstammt.
• - Hefezelle, Zelle die der Ordnung der Endomycetalse zuzuordnen ist, oder von ihr abstammt.
• - Insektenzelle, Zelle die der Ordnung der Hexapoda zuzuordnen ist, oder von ihr abstammt.
• - native Säugetierzelle, aus einem Säugetier stammende Zelle, die in ihren relevanten Merkmalen der im Organismus befindlichen Zelle entspricht.
• - immortalisierte Säugetierzelle: Zelle die durch die angewendeten Kulturbedingungen oder gentechnische Manipulation die Eigenschaft erlangt hat, sich über die normalerweise übliche Teilungshäufigkeit hinaus (ca. 100) in der Kultur zu teilen.
• - markiert: durch entsprechende Modifizierung oder Derivatisierung für eine Nachweisreaktion zugänglich gemacht. Beispielsweise radioaktiv, fluoreszierend oder lumineszierend.
• - Ligand: Substanz, die an ein im Körper oder einer Zelle befindliches Molekül, im speziellen einen Rezeptor, bindet
• - Verdrängung: vollständiges oder partielles Entfernen eines Liganden von seiner Bindungsstelle
• - gebundene Aktivität: Biochemisch oder physikalisch erfaßter Meßwert, der mit der an einem Rezptor gebundenen Ligandenmenge korreliert
• - Regulation: die als Teil eines Regelprozese erfolgte Hemmung oder Aktivierung eines Vorgangs
• - Hemmung: als Sonderfall der Regulation die Verhinderung/Minderung eines Vorgangs
• - Aktivierung: als Sonderfall der Regulation die Verstärkung eines Vorgangs
• - Rezeptoren, Im weitesten Sinne alle im pro- oder eukaryoten Organismus vorhandenen Moleküle, an die ein Wirkstoff binden kann. Im engeren Sinne membrangebundene Proteine oder Komplexen mehrerer Proteine, die durch Bindung eines Wirkstoffes eine Änderung in der Zelle hervorrufen.
• - Ionenkanäle: Membrangebundene Proteine oder Komplexe mehrerer Proteine, durch die Kationen oder Anionen durch die Membran hindurchgelangen können.
• - Enzyme: Bezeichnung für Proteine oder Komplexe aus einer aktivierenden Nichteiweißkomponente mit einem Protein, die katalytische Eigenschaften besitzen.
• - Genexpression (exprimieren/exprimierbar): das Übersetzen der genetischen Information eines Genes in RNA (RNA-Expression) oder in Protein (Proteinexpression).
• - Ionenmilieu: Ionenkonzentration eines oder mehrerer Ionen in einem bestimmten Kompartiment.
• - Membranpotential: Spannungsdifferenz über eine Membran aufgrund eines Überschusses an Kationen auf der einen Seite und Anionen auf der anderen Seite der Membran.
• - Veränderung der Enzymaktivität: Hemmung oder Induktion der katalytischen Aktivität eines Enzyms.
• - 2^nd messenger: kleines Molekül, das als Antwort auf ein extrazelluläres Signal entweder im Cytosol gebildet wird oder in das Cytosol hineinwandert und dabei hilft die Information an das Zelliniere weiterzugeben, wie zum Beispiel cAMP, IP₃.
• - (Gen-)Sonde: Bezeichnung für jede Art von Nukleinsäuren, mit deren Hilfe man ein gesuchtes Gen oder eine bestimmte DNA-Sequenz nachweisen kann. Durch Derivatisierung der Gensonde (z. B. Biotin, magnetische Beads, Digoxinin) können zudem DNA-Moleküle aus einem Gemisch herausgezogen werden. Als Sonden werden klonierte Gene, Genfragmente, chemisch synthetisierte Oligonukleotide und auch RNA verwendet, die meist radioaktiv markiert ist.
• - DNA: Internationale Bezeichnung für Desoxyribonukleinsäure
• - genomische DNA: Generelle Bezeichnung für die bei eukaryontischen Organismen aus dem Zellkern einer Zelle stammenden DNA.
• - cDNA: Abkürzung für complementary DNA. Bezeichnung für die einzel- bzw. doppelsträngige DNA-Kopie eines RNA-Moleküls.
• - cDNA-Bank/Bibliothek: Bezeichung für eine Sammlung von willkürlich klonierten cDNA-Fragmenten, die zusammengenommen die Gesamtheit aller von einer Zelle oder einem Gewebe synthetisierten RNA repäsentieren.
• - cDNA-Klon: Bezeichnung für eine Population genetisch einheitlicher Zellen, die sich von einer einzigen Zelle ableiten, derart, daß diese Zelle eine künstlich eingebrachtes cDNA-Fragment enthält.
• - Hybridisierung: Durch Basenpaarung bewirkte Ausbildung eines doppelsträngigen Nukleinsäuremoleküls aus zwei getrennten Einzelsträngen.
• - stringente Bedingungen: Bedingungen, unter denen nur perfekt basengepaarte Nukleinsäure-Stränge gebildet werden und stabil bleiben.
• - isolieren: ein gesuchtes Molekül aus einem Gemisch herausfinden und abtrennen.
• - DNA-Sequenzierung: Bestimmung der Abfolge der von Basen in einem DNA-Molekül.
• - Nukleinsäuresequenz: Bezeichnung für die Primärstruktur eines DNA- Moleküls, d. h. die Abfolge der einzelnen Basen, aus denen sich eine DNA zusammensetzt.
• - Genspezifische Oligonukleotid Primer: Oligonukleinsäuren, also 10-40 Basen lange Nukleinsäurefragmente, die in ihrer Basenzusammensetzung eine stringente Hybridisierung an das gesuchte Gen oder die gesuchte cDNA erlauben.
• - Ermitteln von Oligonukleotid Primern: Die manuelle oder Computerunterstützte Suche von Oligonukleotiden zu einer vorgegebenen DNA-Sequenz, die für eine Hybridisierung und/oder eine Polymerase-Ketten Reaktion optimal geeignet sind.
• - PCR: Abkürzung für Polymerase-Kettenreaktion. In vitro-Verfahren zur selektiven Anreicherung von Nucleinsäure-Bereichen definierter Länge und definierter Sequenz aus einem Gemisch von Nukleinsäure- Molekülen.
• - DNA-Template: Nukleinsäuremolekül oder ein Gemisch von Nukleinsäuremolekülen, aus denen ein DNA-Abschnitt mit Hilfe der PCR (s. o.) vervielfältigt wird.
• - RNA: International gebräuchliche Abkürzung für Ribonukleinsäuren
• - mRNA: International gebräuchliche Abkürzung für messenger- Ribonukleinsäuren, die am Transfer der genetischen Information aus dem Kern in die Zelle beteiligt sind und die Information für die Synthese eines Polypetids oder eines Proteins beinhalten.
• - Antisense Polynukleotid: Eine aus mehreren natürlichen oder modifizierten Nukleinsäuren bestehendes Molekül, deren Basenabfolge komplementär zur Basenabfolge eines Teilbereiches einer in der Natur vorkommenden RNA ist.
• - PNA: International gebräuchliche Abkürzung für peptidic Nucleic Acids. Hierbei bilden peptidisch verknüpfte Aminosäuren eine Kette, wobei die Aminosäuren als Seitenkette eine für die Hybridisierung mit DNA oder RNA fähigen Base trägt.
• - Sequenz: Abfolge von Nukleotiden oder Aminosäuren. Im spezifischen Sinne dieser Erfindung ist damit die Nukleinsäuresequenz gemeint.
• - Ribozym: Bezeichnung für eine katalytisch aktive Ribonukleinsäure (z. B. Ligase, Endonuklease, Polymerase, Exonuklease)
• - DNA-Enzym: Bezeichnung für ein DNA-Molekül, das katalytische Aktivität beinhaltet (z. B. Ligase, Endonuklease, Polymerase, Exonuklease)
• - katalytische RNA/DNA: generelle Bezeichnung für Ribozyme bzw. DNA- Enzyme (s. o.).
• - Adenovirus: bei Vertebraten vorkommender cytopathogener Virus
• - Adenoassoziiertes Virus (AAV): Gehört zur Familie der Parvoviren. Für eine effektive Vermehrung des AAV ist eine Coinfektion der Wirtszellen mit Helferviren (z. B. Herpes-, Vaccina- oder Adenoviren) erforderlich. Die Eigenschaft von AAV, stabil in das Wirtsgenom zu integrieren, macht es als Transduktionsvektor für Säugetierzellen besonders interessant.
• - Herpesvirus: Viraler Erreger der Herpes-Infektion
• - posttranslationale Modifikation: Veränderung an Proteinen oder Polypetiden, die nach der Translation durchgeführt wird, hierzu zählen z. B. Phosphorylierung, Glykosylierung, Amidierung, Acetylierung oder Proteolyse.
• - glykosilieren: Bezeichnung für das Anhängen von einzelnen Zuckermolekülen oder ganzen Zuckerketten an Proteine.
• - phosphorylieren: Bezeichnung für das Anhängen von einem oder mehreren Phosphatresten an ein Protein, bevorzugt an die OH- Gruppen der Aminosäuren Serin, Threonin oder Tyrosin.
• - amidieren. Die Bezeichnung für das Umwandeln einer Carboxylfunktion in eine Amidfunktion, z. B. an den carboxyterminalen Aminosäurerest eines Peptides oder Proteins.
• - mit Membrananker versehen: Posttranslationelle Modifikation eines Proteins, oder eines anderen organischen Moleküls, derart daß es durch Anhängen eines hydrophoben Moleküls, geeigneterweise eine Fettsäure oder ein Derivat derselben, an die Lipiddoppelschicht- Membran von Zellen verankert wird.
• - spalten: in diesem spezifischen Fall die Spaltung eines Peptids oder Proteins in mehrere Untersequenzen.
• - verkürzen: Ein aus mehreren Einzelteilen bestehendes Molekül um eine oder mehrere Teile zu verkürzen.
• - Antikörper: Lösliche, oder an Zellmembranen gebundene, als Immunglobuline bezeichnete Proteine mit einer spezifischen Bindungsstelle für Antigene.
• - monoklonaler Antikörper: sind gegen eine einzige antigene Determinante eines Antigens gerichtete Antikörper mit extrem hoher Selektivität
• - polyklonaler Antikörper: Gemisch aus Antikörpern, die gegen mehrere Determinanten eines Antigens gerichtet sind.
• - transgen: genetisch verändert
• - nichthumanes Säugetier: Die Gesamtheit der Säugetiere (Klasse der Mammalia) mit Ausnahme der Spezies Mensch.
• - Keim-Zelle: Zelle mit haploidem Genom, die durch Verschmelzung mit einer zweiten Keimzelle die Bildung eines neuen Organismus ermöglicht.
• - somatische Zelle: diploide Zelle als Bestandteil eines Organismus
• - chromosomale Einbringung: Eingriff in die Nukleotidsequenz auf chromosomaler Ebene
• - Genom: Allgemeine Beschreibung für die Gesamtheit aller Gene in einem Organismus
• - Vorfahr des Tieres: Ein Tier (der Vorfahr), das auf natürliche oder künstliche Weise durch Weitergabe an seinem genetischen Material in direkter Linie mit einem anderen Tier (dem Nachfahren) verwandt ist.
• - exprimierbar: Ein Nukleinsäuremolekül ist dann exprimierbar, wenn es die Information zur Synthese eine Proteins oder Polypetids beinhaltet und mit entsprechenden regulatorischen Sequenzen versehen ist, die eine Synthese dieses Proteins oder Polypeptids in vitro oder in vivo erlauben. Wenn diese Voraussetzungen nicht mehr gegeben sind, beispielsweise durch Eingriff in der kodierenden Sequenz, ist das Nukleinsäuremolekül nicht mehr exprimierbar.
• - Nagetier: Tier aus der Ordnung der Rodentia, z. B. Ratte oder Maus
• - als schmerzregulierende Substanz identifizierbar: Substanz die bei Einbringung in einen lebenden Organismus eine Verhaltensänderung bewirkt, die der Fachmann als schmerzhemmend bezeichnet (antinozizeptiv, antihyperalgetisch oder antiallodynisch). Im Falle des Screeningverfahrens bezieht sich das darauf, daß die Substanz beim Screening durch stärkere Bindung oder Auslösung einer Änderung eines funktionellen Parameters deutlich, beispielsweise 100%, die Bindung oder Wechselwirkung des Durchschnitts der getesteten Substanzen übertrifft.
• - Verbindung: ein anderer Name für Molekül, als aus mehreren Atomen bestehend, hier ein durch das erfindungsgemäße Verfahren identifiziertes Molekül.
• - Wirkstoff: Eine Verbindung, die bei Anwendung an einem Organismus eine Veränderung in diesem Organismus hervorruft. Im Besonderen werden darunter organisch-chemisch synthetisierte Moleküle verstanden, die auf den Organismus eine heilende Wirkung ausüben. Hier insbesondere Moleküle, die an die erfindungsgemäßen Proteine und Peptide binden.
• - niedermolekular: Molekül mit einem Molekulargewicht < 2 kDa
• - Arzneimittel: ein Stoff entsprechend der Definition im Artikel 1 §2 des Gesetzes über den Verkehr mit Arzneimitteln
• - Diagnostikum: Verbindung oder Verfahren, das verwendet werden kann, um eine Krankheit zu diagnostizieren
• - Behandlung von Schmerz: Verfahren, mit dem Ziel Schmerzen zu lindern oder aufzuheben, oder das zu erwartende Auftreten von Schmerzen zu hemmen (preemptive Analgesie).
• - chronischer Schmerz: eine Schmerzempfindung von länger anhaltender Dauer, oft dadurch gekennzeichnet, daß sie über Zeitpunkt und Ort des initialen Stimulus hinausreicht, die Schmerzempfindlichkeit des Körpers steigert.
• - Gentherapie: Unter Gentherapie versteht man alle Verfahren, die das Ziel haben, genetische Erkrankungen durch geeignete Veränderungen des Genoms kausal zu behandeln.
• - In-vivo-Gentherapie: Einbringen von genetischem Material in den lebenden Organismus mit dem Ziel der Gentherapie. Man kann zwischen somatischem und Keimbahn-Eingriff unterscheiden, der einmal an diploiden Zellen und einmal an haploiden Zellen stattfindet.
• - In-vitro-Gentherapie: Einbringen von genetischem Material in Zellen außerhalb des menschlichen Körpers mit dem Ziel diese nachher wieder durch Einbringen in den menschlichen Körper zur Gentherapie zur verwenden.
• - Diagnostik: Verfahren, um eine Krankheit zu identifizieren.
• - Wirksamkeitsuntersuchung: Untersuchung mit dem Ziel die Wirksamkeit einer Verbindung nach Einwirkung auf einen lebenden Organismus zu untersuchen.

To explain the invention, further definitions are given below in addition to the explanations given in terms of terms in the general text, in order to clarify how certain terms, in particular those used in the claims, are to be understood and interpreted within the meaning of this invention.

• - Substance: This means a chemical compound. In the narrower sense, these are compounds that can potentially have an effect in the body, low molecular weight active substances, nucleic acids, fats, sugars, peptides or proteins, in particular here low molecular weight active substances.
• - Pharmaceutically relevant substance: For the purposes of the invention, a pharmaceutically relevant substance is a substance which, by binding to the biomolecules of groups I to III, could be effective in at least one of the indications mentioned and theoretically has the potential to physiologically display the symptoms directly or indirectly to influence, in particular appears as if it could be used therapeutically, for example in a drug.
• - Pain-regulating: In the sense of the invention, pain-regulating means that the substance influences the perception of pain directly or indirectly, in particular has a natural analgesic effect.
• Pain: In the sense of the invention, pain means in particular a sensation of pain, precise acute, chronic, neuropathic and inflammatory pain including migraine, in particular the pain is of the following types:
  chronic pain, especially musculoskeletal pain; neuropathic pain, especially allodyne pain, mechanical hyperalgesia or diabetic neuropathy; visceral pain, cerebral pain, peripheral pain or inflammation-related pain, especially peripheral inflammation pain; as well as migraines, cluster headache or the pain associated with trigeminal neuralgia.
• - Incubation: Incubation is the introduction and leaving of a biological test object, for example a cell or a protein, in a tempered medium such as in an incubator or on a water bath. Incubation under suitable conditions means hot under physiological conditions (e.g. 37 ° C pH 7.2) or under conditions in which an optimal measurement in the process is possible.
• - Cell: The cell is a self-regulating, open system, which is in a steady state with its environment through permanent mass exchange with its own metabolism and ability to reproduce. The cell can be cultured separately or be part of a tissue, in particular from an organ, and be isolated there or still in the cell structure.
• - Preparation from a cell: This is understood to mean preparations which are produced by means of chemical, biological, mechanical or physical methods while changing the cell structure, for example membrane fragments, isolated cell compartments, isolated cytosol, or homogenate obtained from tissue.
• - Peptide: combination of amino acids linked via chains to form peptide bonds. An oligopeptide consists of between 2 and 9 amino acids, a polypeptide of between 10 and 100 amino acids.
• - Protein: combination of more than 100 amino acids linked via peptide bonds to form chains and the like. U. with a defined spatial structure.
• - Partial protein: combination of more than 10 amino acids linked via peptide bonds to form chains and. U. with a defined spatial structure but cut out or selected from a defined priotein. A partial protein can be a peptide.
• - PIM1 kinase: PIM3 kinase: a proto-oncogene and a serine-threonine kinase.
• - Polynucleotide: The underlying nucleotide is a basic building block of nucleic acids consisting of nuclein base, pentose and phosphoric acid. This corresponds to a high-molecular polynucleotide consisting of several nucleotides which are linked to one another via phosphoric acid pentose esterification. However, the invention also includes modified polynucleotides which maintain the base sequence but have a modified backbone instead of the phosphoric acid pentose.
• - Similar to at least 90 (95, 97)%: This is to be understood to mean that the polynucleotides detected with their coding region are at least 90% (95%, 97%) identical to the reference (Figure etc.) with regard to the base sequence and those with detected peptides and proteins in their primary structure, the sequence of the amino acids are at least 90% (95%, 97%) identical to the reference.
• - Gen: The term gene is used to denote a genome section with a defined nucleotide sequence which contains the information for the synthesis of an m- or pre-mRNA or another RNA (e.g. tRNA, rRNA, snRNA etc.). It consists of coding and non-coding sections.
• - Gene fragment: nucleic acid section which contains a partial region of a gene in its base sequence
• - Biomolecule: General term for nucleic acids or polyamino acids, especially also DNA, RNA, peptides (partial proteins) and proteins, whereby these molecules may also be artificially changed. For the purposes of this invention, preferably peptides (partial proteins) and proteins.
• - Binding to the peptide, partial protein or protein: interaction between substance and peptide, partial protein or protein, which leads to fixation.
• - functional parameters: these are measured variables of an experiment that correlate with the function of a protein (ion channel, receptor, enzyme)
• - Genetically manipulated: manipulation of cells, tissues or organisms in such a way that genetic material is introduced here
• - Endogenously expressed: Expression of a protein which has a cell line under suitable culture conditions, without this corresponding protein having been induced to express it by genetic engineering
• - G-protein: Internationally abbreviation for a gunaosin triphosphate (GTP) -binding protein that is activated as a signal protein by receptors coupled to G-protein
• - Reporter gene: General term for genes whose gene products can be easily detected using simple biochemical methods or histochemical methods, such as. B. luciferase, alkaline phosphatase or green fluorescent protein (GFP).
• - (Recombinant) DNA construct: General term for any type of DNA molecule that has arisen from the in vitro linking of DNA molecules.
• - Cloning vector: General term for nucleic acid molecules that serve as carriers of foreign genes or parts of these genes during cloning.
• Expression vector: Name for specially constructed cloning vectors which, after introduction into a suitable host cell, allow the transcription and translation of the foreign gene cloned into the vector.
• - LTR sequence: Abbreviation for long terminal repeat. General term for longer sequences that can be found at both ends of a linear genome. Such sequence areas come e.g. B. in the genomes of retroviruses and at the ends of eukaryotic transposons.
• - Poly-A tail: the adenyl residues (approx. 20-250) attached to the 3 'end of messenger RNAs by polyadenylation.
• - Promoter sequence: Name for a DNA sequence region from which the transcription of a gene, ie the synthesis of the mRNA, is controlled.
• - ORI sequence: Abbreviation for Origin of Replication. The ORI sequence allows a DNA molecule to multiply as an autonomous unit in the cell.
• - Enhancer sequence: designation for relatively short genetic elements, some of which appear as repeats, which generally increase the expression of some genes to different degrees.
• - Transcription factor: Name for a protein that influences the transcription of a gene by binding to specific DNA sequences.
• - Cultivate: keep cells or tissues under suitable culture conditions
• - Conditions that allow expression, this means the selection and application of culture conditions that allow expression of the protein of interest, including temperature change, medium change, addition of inducing substances, omission of inhibitory substances.
• - Incubation time: time for the cells or tissues to be incubated, ie exposed to a defined temperature.
• - Selection pressure: applications of culture conditions that give cells a growth advantage with a specific gene product, the so-called selection marker.
• - Amphibian cell, cell from an animal of the amphibia class
• - bacterial cell, cell which is assigned to the domain of the Eubacteria or Archaebacteria, or originates from it.
• - Yeast cell, cell that can be assigned to or is derived from the order of the endomycetalse.
• - Insect cell, cell that can be assigned to or comes from the order of the Hexapoda.
• - Native mammalian cell, cell derived from a mammal, which has the relevant characteristics of the cell in the organism.
• - Immortalized mammalian cell: cell that has acquired the property of dividing in the culture beyond the normal division frequency (approx. 100) due to the culture conditions or genetic engineering manipulation used.
• - marked: made accessible for a detection reaction by appropriate modification or derivatization. For example radioactive, fluorescent or luminescent.
• - Ligand: substance that binds to a molecule in the body or a cell, in particular a receptor
• - Displacement: complete or partial removal of a ligand from its binding site
• - bound activity: biochemically or physically recorded measured value, which correlates with the amount of ligand bound to a receptor
• - Regulation: the inhibition or activation of a process that takes place as part of a control process
• - Inhibition: as a special case of regulation, the prevention / reduction of a process
• - Activation: as a special case of regulation, the reinforcement of a process
• - Receptors, in the broadest sense all molecules present in the pro- or eukaryotic organism to which an active substance can bind. In the narrower sense, membrane-bound proteins or complexes of several proteins that cause a change in the cell by binding an active ingredient.
• - Ion channels: membrane-bound proteins or complexes of several proteins through which cations or anions can pass through the membrane.
• - Enzymes: term for proteins or complexes of an activating non-protein component with a protein that have catalytic properties.
• - Gene expression (express / expressible): the translation of the genetic information of a gene into RNA (RNA expression) or into protein (protein expression).
• - Ion milieu: ion concentration of one or more ions in a specific compartment.
• - Membrane potential: voltage difference across a membrane due to an excess of cations on one side and anions on the other side of the membrane.
• - Change in enzyme activity: inhibition or induction of the catalytic activity of an enzyme.
• - 2 ^nd messenger: small molecule that is formed in response to an extracellular signal, either in the cytosol or migrates into the cytosol and thereby helps the information to the Zelliniere to pass, such as cAMP, IP _3rd
• - (Gene) probe: Name for each type of nucleic acid, with the help of which a gene or a specific DNA sequence can be detected. By derivatizing the gene probe (e.g. biotin, magnetic beads, digoxinin), DNA molecules can also be extracted from a mixture. Cloned genes, gene fragments, chemically synthesized oligonucleotides and also RNA, which is mostly radioactively labeled, are used as probes.
• - DNA: International term for deoxyribonucleic acid
• - Genomic DNA: General term for the DNA originating from the cell nucleus of a cell in eukaryotic organisms.
• - cDNA: Abbreviation for complementary DNA. Term for the single or double-stranded DNA copy of an RNA molecule.
• cDNA bank / library: designation for a collection of arbitrarily cloned cDNA fragments which, taken together, represent the entirety of all RNA synthesized by a cell or a tissue.
• - cDNA clone: name for a population of genetically uniform cells which are derived from a single cell, such that this cell contains an artificially introduced cDNA fragment.
• - Hybridization: Base pairing results in the formation of a double-stranded nucleic acid molecule from two separate single strands.
• - stringent conditions: conditions under which only perfectly base-paired nucleic acid strands are formed and remain stable.
• - isolate: find a desired molecule from a mixture and separate it.
• - DNA sequencing: determining the sequence of bases in a DNA molecule.
• - Nucleic acid sequence: Name for the primary structure of a DNA molecule, ie the sequence of the individual bases from which a DNA is composed.
• - Gene-specific oligonucleotide primers: oligonucleic acids, ie 10-40 base long nucleic acid fragments, which allow a stringent hybridization to the gene or cDNA searched for in their base composition.
• - Determination of oligonucleotide primers: The manual or computer-assisted search of oligonucleotides for a given DNA sequence that are optimally suited for hybridization and / or a polymerase chain reaction.
• - PCR: Abbreviation for polymerase chain reaction. In vitro method for the selective enrichment of nucleic acid areas of defined length and defined sequence from a mixture of nucleic acid molecules.
• - DNA template: nucleic acid molecule or a mixture of nucleic acid molecules from which a DNA section is reproduced with the help of PCR (see above).
• - RNA: Internationally used abbreviation for ribonucleic acids
• - mRNA: Internationally used abbreviation for messenger ribonucleic acids, which are involved in the transfer of the genetic information from the nucleus into the cell and which contain information for the synthesis of a polypeptide or a protein.
• - Antisense polynucleotide: A molecule consisting of several natural or modified nucleic acids, the base sequence of which is complementary to the base sequence of a portion of an RNA which occurs naturally.
• - PNA: Internationally used abbreviation for peptidic nucleic acids. Here, peptide-linked amino acids form a chain, the amino acids carrying as a side chain a base capable of hybridization with DNA or RNA.
• - Sequence: sequence of nucleotides or amino acids. In the specific sense of this invention, this means the nucleic acid sequence.
• - Ribozyme: Name for a catalytically active ribonucleic acid (e.g. ligase, endonuclease, polymerase, exonuclease)
• - DNA enzyme: name for a DNA molecule that contains catalytic activity (e.g. ligase, endonuclease, polymerase, exonuclease)
• - Catalytic RNA / DNA: general term for ribozymes or DNA enzymes (see above).
• - Adenovirus: cytopathogenic virus that occurs in vertebrates
• - Adeno-associated virus (AAV): belongs to the parvovirus family. For an effective multiplication of the AAV, a co-infection of the host cells with helper viruses (e.g. herpes, vaccina or adenovirus) is necessary. The ability of AAV to integrate stably into the host genome makes it particularly interesting as a transduction vector for mammalian cells.
• - Herpes virus: viral pathogen of the herpes infection
• - Post-translational modification: change in proteins or polypeptides, which is carried out after translation. B. phosphorylation, glycosylation, amidation, acetylation or proteolysis.
• - glycosylation: term for the attachment of individual sugar molecules or entire sugar chains to proteins.
• - phosphorylate: term for attaching one or more phosphate residues to a protein, preferably to the OH groups of the amino acids serine, threonine or tyrosine.
• - amidate. The term for converting a carboxyl function to an amide function, e.g. B. the carboxy-terminal amino acid residue of a peptide or protein.
• provided with membrane anchor: post-translational modification of a protein or other organic molecule such that it is anchored to the lipid bilayer membrane of cells by attaching a hydrophobic molecule, suitably a fatty acid or a derivative thereof.
• - cleave: in this specific case the cleavage of a peptide or protein into several sub-sequences.
• - Shorten: A molecule consisting of several individual parts by shortening one or more parts.
• - Antibodies: Soluble proteins or proteins bound to cell membranes called immunoglobulins with a specific binding site for antigens.
• - monoclonal antibodies: are antibodies directed against a single antigenic determinant of an antigen with extremely high selectivity
• polyclonal antibody: mixture of antibodies which are directed against several determinants of an antigen.
• - transgenic: genetically modified
• - non-human mammal: the totality of mammals (class of mammals) with the exception of the species human.
• - Germ cell: cell with a haploid genome, which by fusing with a second germ cell enables the formation of a new organism.
• - somatic cell: diploid cell as part of an organism
• - Chromosomal insertion: intervention in the nucleotide sequence at the chromosomal level
• - Genome: General description for the entirety of all genes in an organism
• - Ancestor of the animal: An animal (the ancestor) that is naturally or artificially related to another animal (the descendant) by passing on its genetic material in a direct line.
• - Expressible: A nucleic acid molecule is expressible if it contains the information for the synthesis of a protein or polypeptide and is provided with corresponding regulatory sequences which allow the synthesis of this protein or polypeptide in vitro or in vivo. If these requirements are no longer met, for example by intervention in the coding sequence, the nucleic acid molecule can no longer be expressed.
• - Rodent: animal from the order of the Rodentia, z. B. rat or mouse
• - Identifiable as a pain-regulating substance: Substance that brings about a change in behavior when introduced into a living organism, which the specialist calls pain-relieving (antinociceptive, antihyperalgesic or antiallodynic). In the case of the screening method, this refers to the fact that the substance, when it is screened by stronger binding or triggering a change in a functional parameter, clearly exceeds, for example 100%, the binding or interaction of the average of the substances tested.
• - Connection: a different name for a molecule than consisting of several atoms, here a molecule identified by the method according to the invention.
• - Active ingredient: A compound that when used on an organism causes a change in that organism. In particular, this means organic-chemically synthesized molecules that have a healing effect on the organism. Here in particular molecules that bind to the proteins and peptides according to the invention.
• - low molecular weight: molecule with a molecular weight <2 kDa
• - Medicinal product: a substance as defined in Article 1 §2 of the Medicines Act
• Diagnostic: compound or method that can be used to diagnose a disease
• - Treatment of pain: Procedure to relieve or relieve pain, or to inhibit the expected occurrence of pain (preemptive analgesia).
• - Chronic pain: a sensation of pain that lasts longer, often characterized by the fact that it extends beyond the time and place of the initial stimulus and increases the body's sensitivity to pain.
• - Gene therapy: Gene therapy is understood to mean all methods that have the goal of treating genetic diseases causally through suitable changes in the genome.
• - In vivo gene therapy: introduction of genetic material into the living organism with the aim of gene therapy. A distinction can be made between somatic and germline surgery, which takes place once on diploid cells and once on haploid cells.
• - In vitro gene therapy: introduction of genetic material into cells outside the human body with the aim of subsequently using them again for introduction into the human body for gene therapy.
• - Diagnostics: procedure to identify a disease.
• - Efficacy test: test with the aim of examining the effectiveness of a compound after exposure to a living organism.

In a preferred embodiment of the method the cell is pre step (a) genetically engineered. This is genetic material introduced into the cell, in particular one or more Polynucleotide sequences. In a further preferred variant of this In one embodiment, the genetic engineering manipulation allows the measurement at least one of the functional ones changed by the test substance Parameter. In this embodiment, genetic engineering Manipulation created conditions under which the change of a functional parameter measured at all or improved can be. It is particularly preferred that genetic engineering a form that is not endogenously expressed in the cell of a G protein is expressed or a reporter gene is introduced. among them is especially the genetic engineering introduction of an endogenous existing or physiologically unexpressed G protein (GTP- binding protein) into the cell, for example the Introduction of a chimeric G protein that changes the Signaling pathway or a promiscuous G protein that very is loyal. In turn, the introduction of a reporter gene is permitted the measurement of an (extracellularly triggered) induced expression of the Gene product.

In a further preferred embodiment, the cell is genetically manipulated in such a way that the cell has at least one polynucleotide according to one of Figs. 1a), 1c), 1e), 2a) or 2c) or at least 90%, preferably at least 95 %, in particular at least 97% similar polynucleotide. In this way it can be achieved, for example, that a partial protein or protein which is not endogenously expressed in the cell or preparation used in the method is synthesized by the cell. It is particularly preferred if the polynucleotide is contained in a recombinant DNA construct. A (recombinant) DNA construct is understood to mean a DNA molecule produced in vitro.

If the cell is genetically manipulated in the process before step a) it is preferred that the cell after the genetic engineering manipulation and before step (a) under conditions that allow expression, is cultivated, possibly under selection pressure. Cultivate under one understands cells or tissues in conditions that survive the Secure cells or their successor generation. Doing so the conditions here are chosen so that an expression of the by genetic manipulation of inserted material is made possible. For this, pH, oxygen content and temperature should be kept physiological be and added sufficient nutrients and necessary cofactors his. The selection pressure allows only the cells to be cultivated further for whom the genetic engineering manipulation was at least partially successful. This includes, for example, the introduction of antibiotic resistance via the DNA construct.

It is particularly preferred in the method according to the invention if the cell used is an amphibian cell, bacterial cell, yeast cell, Insect cell or an immortalized or native mammalian cell. Examples of amphibian cells are Xenopus oocytes, for bacterial cells E-coli cells, for yeast cells also Saccharomyces cerevisiae, for Insect cells Sf9 cells, for immortalized mammalian cell HeLa cells and for native mammalian cells, the CHO (Chinese Hamster Ovary) cell.

In a preferred measuring method for determining the binding of the Substance on partial protein or protein in the method according to the invention the binding is measured by the displacement of a known one labeled ligands from the partial protein or protein and / or via them bound activity of a labeled test substance. There is a ligand a molecule that binds to the protein or partial protein with high specificity, that by a likewise binding substance to be tested from the Binding site is displaced. One of the marks is the proof to understand facilitating artificial modification to the molecule. Examples are radioactive, fluorescent or luminescent labels.

In another preferred measurement method for determining the change in the functional parameters triggered by the binding of the substance to partial protein or protein in the method according to the invention, the measurement of at least one of the functional parameters changed by the test substance is carried out by measuring the regulation, inhibition and / or activation of receptors , ion channels and / or enzymes, especially via measuring the alteration of gene expression, the ion milieu, the pH or the membrane potential, the 2 ^nd messenger via alteration of the enzyme activity or concentration. Thus, on the one hand, the measurement of the effect of the substance via the influence of receptors, ion channels and / or enzymes is directly recorded, on the other hand, examples of changing parameters such as gene expression, ion milieu, pH, membrane potential, enzyme activity or concentration that are to be measured as preferred the 2 ^nd messenger. Here we mean by ionic environment in particular, the concentration of one or more ions in a cell compartment, in particular the cytosol, membrane potential under the Ladungsdiffferenz between two sides of a biomembrane and 2 ^nd messenger mediators of the intracellular signaling pathway such. B. cyclic AMP (cAMP), inosotole triphosphate (IP3) or diacylglycerol (DAG).

A particularly preferred object of the invention is a method according to the invention, in which a first method according to the invention is coupled with a second method according to the invention in such a way that the measured values and results of the first method with regard to the substance to be measured with the measured values and results of the second method with regard to measuring substance are compared, characterized in that in one of the two methods, hereinafter referred to as the main method, in step (a) the substance to be tested
either
with a biomolecule from group II: the protein BNPI and / or a protein according to one of Figs. 1b), 1d) or 1f) and / or a protein and / or a protein at least 90% similar to one of the aforementioned proteins and for which encodes a polynucleotide according to one of Figs. 1a), 1c) or 1e) or a polynucleotide at least 90% similar to it, and / or a protein which is encoded by a nucleic acid which is linked to a polynucleotide according to one of the Fig. 1a), 1c) or 1e) or their antisense binds polynucleotides, or an at least 10, preferably at least 15, in particular at least 20 amino acids long partial protein of one of the aforementioned proteins and / or a cell and / or a preparation from such a cell, which has synthesized at least one of the aforementioned proteins and / or partial proteins,
or
with a biomolecule from group III: the protein DNPI and / or a protein according to one of Fig. 2b) or 2d) and / or a protein at least 90% similar to one of these proteins and / or a protein for which a polynucleotide encoded according to one of Fig. 2a) or 2c) or a polynucleotide at least 90% similar to it, and / or a protein which is encoded by a nucleic acid which, under stringent conditions, is linked to a polynucleotide according to one of Fig. 2a) or 2c ) or their antisense binds polynucleotides, or a partial protein of at least 10, preferably at least 15, in particular at least 20 amino acids long, of one of the aforementioned proteins and / or a cell and / or a preparation from such a cell which contains at least one of the aforementioned proteins and / or Has synthesized partial proteins, is incubated,
and
that in the other of the two methods, hereinafter referred to as secondary method, in step (a) the substance to be tested is incubated with a biomolecule from group I or with a biomolecule from the group selected from group II and group III from which the biomolecule, with which the substance is incubated in the main procedure is not selected.

In this particularly preferred embodiment, in particular Combination of measurement of binding to or derived from BNPI Biomolecules or the measurement of the resulting modification cellular parameter on the one and the binding to DNPI and respectively derived biomolecules or the measurement of them resulting modification of cellular parameters on the other hand understand, because just a comparison given the completely separate but closely spaced distribution of the two channels in the tissue can provide important information about physiological functions. However, the differential comparison of the data allows identification optimizes pharmaceutically or medically effective substances.

A method according to the invention is further preferred in which the substances to be found are selected from:
Substances with efficacy in the indications or for the treatment of visual disorders, retinitis pigmentosa, optic degeneration, hearing disorders, tinitus, Menière's disease, sudden hearing loss, amyotrophic lateral sclerosis, neuralgia, weight regulation, obesity, Parkinson's disease, cataract, virus infections or bacterial infections, diabetic neuropathy , autoimmune diabetes, alcoholic neuropathy, HIV neuro-AIDS; Retinal degeneration, glaucoma, nystagmus, retinal detachment, diseases of the auditory and / or balance organ, diseases of the auditory or vesibular tract, sleep disorders, drug addiction, addiction and withdrawal, in particular with alcohol, nicotine, opiates, ecstasy or cocaine; Neuroinflammation, Insomnia, for adjuvant therapy by electrostimulation of the subthalamic nucleus in Parkinson's
preferably
Substances with efficacy in the indications or for the treatment of vision disorders, retinitis pigmentosa, optic degeneration, hearing disorders, tinitus, Menière's disease, sudden hearing loss, amyotrophic lateral sclerosis, weight regulation, obesity, cataracts, virus infections or bacterial infections, retinal degeneration, glaucoma, nystagmus, retinal detachment , Diseases of the auditory and / or balance organ, diseases of the auditory or vesibular tract, drug addiction, addiction and withdrawal, particularly in the case of alcohol, nicotine, opiates, ecstasy or cocaine; neuroinflammation
in particular
Substances with efficacy in the indications or for the treatment of visual disturbances, retinitis pigmentosa, optic degeneration, cataract, retinal detachment, retinal degeneration, glaucoma or nystagmus
and or
Hearing disorders, tinitus, Meniere's disease, sudden hearing loss, diseases of the hearing and / or balance organ or diseases of the auditory or vesibular tract.

Another object of the invention is a connection identifiable as a pharmaceutically relevant substance with efficacy in at least one of the aforementioned indications by an inventive Method. Here connection refers in particular to low molecular weight active ingredients, but also on peptides, proteins and Nucleic acids. Identifiable means that the connection is the Feature that it is in the screening method according to the invention in terms of binding significantly stronger, preferably twice as strong binds like the average of the substances to be tested or regarding the change in functional parameters significantly from the average of the testing substances deviates. It is particularly preferred if the compound of the invention is a low molecular weight compound.

• a) eines Polynukleotids, vorzugsweise einer DNA oder RNA, kodierend für BNPI oder DNPI oder eines Polynukleotids, vorzugsweise einer DNA oder RNA, welches einer der in einer der Abb. 1a), 1c), 1e), 2a), 2c) oder 2e) dargestellten Nukleotidsequenzen zu wenigstens 90%, vorzugsweise zu wenigstens 95%, insbesondere zu wenigstens 97% oder genau entspricht,
• b) eines Polynukleotids, insbesondere eines Antisense Polynukleotids oder einer PNA, vorzugsweise eines DNA- Enzyms oder Ribozyms, eines Ribozyms oder sonstigen DNA-Enzyms oder einer katalytischen RNA oder DNA, das eine Nukleotid-Sequenz aufweist, die in der Lage ist, spezifisch an eines der unter Punkt a) aufgeführten Polynukleotide zu binden,
• c) eines Vektors enthaltend ein Polynukleotid gemäß einem der Punkte a) oder b), insbesondere eines Expressionsvektors und/oder insbesondere abgeleitet von einem Virus, beispielsweise dem Adenovirus, Adenoassoziiertem Virus oder Herpesvirus und/oder insbesondere enthaltend mindestens eine LTR-, Poly A-, Promotor- und/oder ORI- Sequenz,
• d) von BNPI und/oder DNPI und/oder eines Proteins gemäß einer der Abb. 1b), 1d), 1f), 2b) oder 2d) und/oder eines zu einem dieser vorgenannten Proteine zu mindestens 90%, vorzugsweise mindestens 95%, insbesondere mindestens 97% ähnlichen Proteins und/oder eines Proteins, für das ein Polynukleotid gemäß einer der Abb. 1a), 1c), 1e), 2a) oder 2c) oder ein dazu zu mindestens 90%, vorzugsweise mindestens 95%, insbesondere mindestens 97% ähnliches Polynukleotid kodiert, und/oder eines Proteins, das durch eine Nukleinsäure kodiert wird, die unter stringenten Bedingungen an ein Polynukleotid gemäß einer der Abb. 1a), 1c), 1e), 2a) oder 2c) oder dessen Antisense Polynukleotide bindet oder eines mindestens 10, vorzugsweise mindestens 15, insbesondere mindestens 20 Aminosäuren langen Teilproteins eines der vorgenannten Proteine, wobei das Protein oder Teilprotein gegebenenfalls posttranslational modifiziert, insbesondere glykosiliert, phosphoryliert, amidiert, methyliert, acetyliert, ADP-ribosyliert, hydroxyliert, mit einem Membrananker versehen, gespalten oder verkürzt wurde,
• e) eines Antikörpers, vorzugsweise eines monoklonalen oder polyklonalen Antikörpers, gegen eines der Proteine oder Teilproteine gemäß Punkt d),
• f) einer Zelle, vorzugsweise einer Amphibienzelle, Bakterienzelle, Hefezelle, Insektenzelle oder einer immortalisierten oder nativen Säugetierzelle, enthaltend ein Polynukleotid gemäß einem der Punkte a) oder b), einen Vektor gemäß Punkt c), ein Protein oder Teilprotein gemäß Punkt d) oder einen Antikörper gemäß Punkt e)
• g) einer erfindungsgemäßen Verbindung identifizierbar als pharmazeutisch relevante Substanz mit Wirksamkeit in mindestens einer der vorgenannten Indikationen wie oben beschrieben und/oder
• h) eines Wirkstoffs, vorzugsweise eines niedermolekularen Wirkstoffs, der an ein Protein oder Teilprotein gemäß Punkt d) bindet,
  zur Herstellung eines Arzneimittels zur Behandlung von
  Sehstörungen, Retinitis pigmentosa, Opticus Degeneration, Hörstörungen, Tinitus, M. Menière, Hörsturz, Schizophrenie, Manien, Depression, Schlaganfall, Hirntrauma, Querschnittslähmung, amyotrophe Lateralsklerose, Neuralgie, Gewichtsregulation, Obesitas, Anorexia nervosa, Epilepsie, Hemibalismus, Chorea Huntington, Stress, Morbus Parkinson, TIA (Transiente Ischämische Attacken), Emesis, insbesondere Hyperemesis beispielsweise bei Chemotherapie, Schwindel, in jeglicher Form, Katarakt, Arthritis, Hyperaktivität, Entwicklungsstörungen, Tollwut, Virus-Infektionen oder bakterielle Infektionen, Grippe, Malaria, Creutzfeld-Jacob, Inflammatory Bowel disease, Morbus Crohn, cardiovaskuläre und cardiorespiratorische Funktionsstörungen, Hypertonie, Störungen der Baroafferenz oder Chemoafferenz, Toxoplasmose, Asthma, Autoimmunität im zentralen und peripheren Nervensystem, diabetische Neuropathie, autoimmuner Diabetes, alkoholische Neuropathie, HIV-Neuro-Aids; Störungen des autonomen Nervensystems, Störungen des Nervensystems des Verdauungstraktes, Übererregbarkeit, insbesondere glutamatvermittelte Übererregbarkeit, Neurodegeneration insbesondere bei Morbus Alzheimer, Morbus Alzheimer, Ischämie; Encephalitis insbesondere virale oder bakterielle; Prionerkrankung, Rasmussen-Encephalitis, HIV-Encephalitis, Demyelinisierung insbesondere bei multipler Sklerose, Retinadegeneration, Glaukom, Nystagmus, Netzhautablösung, Erkrankungen des Cerebellums, cerebelläre Ataxie, Erkrankungen der Basalganglien, Erkrankungen des Pallidums, Erkrankungen des Hör- und/oder Gleichgewichtsorgans, Erkrankungen der Hörbahn oder Vesibularbahn, Störungen des Gedächtnisses, Störungen des Lernens, Störungen der Kognition, Stiff-Man-Syndrom, Restless Leg- Syndrom, Angstzustände, Phobien, Schlafstörungen; Drogenabhängigkeit, -sucht und -entzug insbesondere bei Alkohol, Nikotin, Opiaten, Ecstasy oder Kokain; Hepatoencephalopathie mit Alkoholintoxikation, Hepatoencephalopathie ohne Alkoholintoxikation, neurotoxikologisch bedingte Erkrankungen, Erkrankungen des spinalen Motoneurons, Muskelatrophien, Muskeldystrophien, Erkrankungen der Hinterstrangbahnen, alkoholische Neuropathien, Neuroinflammation, Befindlichkeitsstörungen bei Infektionen oder Fieber, Stress, Geschmacksstörungen, Nahrungsmittelallergien, Chinese-Restaurant-Syndrom, Agression, Paranoia, Hirnerschütterung, neuroendokrine Störungen, Tourrette-Syndrom, cerebrovaskuläre Spasmen, neuronale Apoptose, Neurodegeneration, neuronale Nekrose, Astrocytose, Burn-out- Syndrom, Sudden-Infant-Death (plötzlicher Kindstod), Herzinfarkt, Insomnia, retrograde Amnesie, multiple Sklerose, Jet-lag, Störungen der Sexualfunktion, wie Impotenz oder Priapismus oder mit Wirksamkeit zur Förderung der Mikrogliaaktivierung, des Lernens, der Kognition oder des Gedächtnisses, zur Neuroprotektion, zur Liquordiagnostik neurostatischer Erkrankungen oder zur adjuvanten Therapie per Elektrostimulation des Nucleus subthalamicus bei Parkinson.

Another object of the invention is the use

• a) a polynucleotide, preferably a DNA or RNA, coding for BNPI or DNPI or a polynucleotide, preferably a DNA or RNA, which is one of the in Fig. 1a), 1c), 1e), 2a), 2c) or 2e ) the nucleotide sequences shown correspond to at least 90%, preferably to at least 95%, in particular to at least 97% or exactly,
• b) a polynucleotide, in particular an antisense polynucleotide or a PNA, preferably a DNA enzyme or ribozyme, a ribozyme or other DNA enzyme or a catalytic RNA or DNA, which has a nucleotide sequence which is capable of specifically bind one of the polynucleotides listed under point a),
• c) a vector containing a polynucleotide according to one of the items a) or b), in particular an expression vector and / or in particular derived from a virus, for example the adenovirus, adeno-associated virus or herpes virus and / or in particular containing at least one LTR, poly A , Promoter and / or ORI sequence,
• d) BNPI and / or DNPI and / or a protein according to one of Figs. 1b), 1d), 1f), 2b) or 2d) and / or one of these proteins to at least 90%, preferably at least 95% , in particular at least 97% similar protein and / or a protein for which a polynucleotide according to one of Figs. 1a), 1c), 1e), 2a) or 2c) or at least 90%, preferably at least 95%, in particular encodes at least 97% similar polynucleotide, and / or a protein which is encoded by a nucleic acid which, under stringent conditions, is attached to a polynucleotide according to one of FIGS. 1a), 1c), 1e), 2a) or 2c) or its antisense polynucleotide binds or one of at least 10, preferably at least 15, in particular at least 20 amino acids long partial protein of one of the aforementioned proteins, the protein or partial protein optionally being post-translationally modified, in particular glycosylated, phosphorylated, amidated, methylated, acetylated, ADP-ribosylated, hydroxylated, provided with a membrane anchor, split or shortened,
• e) an antibody, preferably a monoclonal or polyclonal antibody, against one of the proteins or partial proteins according to point d),
• f) a cell, preferably an amphibian cell, bacterial cell, yeast cell, insect cell or an immortalized or native mammalian cell, containing a polynucleotide according to one of points a) or b), a vector according to point c), a protein or partial protein according to point d) or an antibody according to point e)
• g) a compound of the invention identifiable as a pharmaceutically relevant substance with activity in at least one of the aforementioned indications as described above and / or
• h) an active ingredient, preferably a low molecular weight active ingredient, which binds to a protein or partial protein according to point d),
  for the manufacture of a medicament for the treatment of
  Visual disturbances, retinitis pigmentosa, optic degeneration, hearing disorders, tinitus, M. Meniere, sudden hearing loss, schizophrenia, mania, depression, stroke, brain trauma, paraplegia, amyotrophic lateral sclerosis, neuralgia, weight regulation, obesity, anorexia nervosa, epilepsy, choroidal stress, hemibalism , Parkinson's disease, TIA (transient ischemic attacks), emesis, especially hyperemesis, for example with chemotherapy, dizziness, in any form, cataract, arthritis, hyperactivity, developmental disorders, rabies, virus infections or bacterial infections, flu, malaria, Creutzfeld-Jacob, Inflammatory bowel disease, Crohn's disease, cardiovascular and cardiorespiratory dysfunction, hypertension, disorders of baroafference or chemoafference, toxoplasmosis, asthma, autoimmunity in the central and peripheral nervous system, diabetic neuropathy, autoimmune diabetes, alcoholic neuropathy, HIV-neuroids; Autonomic nervous system disorders, digestive tract nervous system disorders, hyperexcitability, especially glutamate-mediated hyperexcitability, neurodegeneration, especially in Alzheimer's disease, Alzheimer's disease, ischemia; Encephalitis especially viral or bacterial; Prion disease, Rasmussen encephalitis, HIV encephalitis, demyelination, particularly in the case of multiple sclerosis, retinal degeneration, glaucoma, nystagmus, retinal detachment, cerebellar diseases, cerebellar ataxia, diseases of the basal ganglia, diseases of the pallidum, diseases of the hearing organ and / or balance Auditory or vesibular tract, memory disorders, learning disorders, cognitive disorders, Stiff-Man syndrome, restless leg syndrome, anxiety, phobias, sleep disorders; Drug addiction, addiction and withdrawal, especially with alcohol, nicotine, opiates, ecstasy or cocaine; Hepatoencephalopathy with alcohol intoxication, hepatoencephalopathy without alcohol intoxication, neurotoxicological diseases, diseases of the spinal motor neurons, muscle atrophies, muscular dystrophies, diseases of the posterior tract, alcoholic neuropathies, neuroinflammation, disorders of the well-being with infections or fever, stress, taste disorders, Chinese food, food syndrome, food allergy Paranoia, concussion, neuroendocrine disorders, Tourrette syndrome, cerebrovascular spasms, neuronal apoptosis, neurodegeneration, neuronal necrosis, astrocytosis, burn-out syndrome, sudden infant death (sudden childhood death), heart attack, insomnia, retrograde amnesia, multiple Jet-lag, disorders of sexual function such as impotence or priapism or with effectiveness for promoting microglia activation, learning, cognition or memory, for neuroprotection, for CSF diagnosis of neurostatic diseases or he for adjuvant therapy by electrostimulation of the subthalamic nucleus in Parkinson's.

• a) eines Polynukleotids, vorzugsweise einer DNA oder RNA, kodierend für BNPI oder DNPI oder eines Polynukleotids, vorzugsweise einer DNA oder RNA, welches einer der in einer der Abb. 1a), 1c), 1e), 2a), 2c) oder 2e) dargestellten Nukleotidsequenzen zu wenigstens 90%, vorzugsweise zu wenigstens 95%, insbesondere zu wenigstens 97% entspricht,
• b) eines Polynukleotids, insbesondere eines Antisense Polynukleotids oder einer PNA, vorzugsweise eines DNA- Enzyms oder Ribozyms, eines Ribozyms oder sonstigen DNA-Enzyms oder einer katalytischen RNA oder DNA, das eine Nukleotid-Sequenz aufweist, die in der Lage ist, spezifisch an eines der unter Punkt a) aufgeführten Polynukleotide zu binden,
• c) eines Vektors enthaltend ein Polynukleotid gemäß einem der Punkte a) oder b), insbesondere eines Expressionsvektors und/oder insbesondere abgeleitet von einem Virus, beispielsweise dem Adenovirus, Adenoassoziiertem Virus oder Herpesvirus und/oder insbesondere enthaltend mindestens eine LTR-, Poly A-, Promotor- und/oder ORI- Sequenz,
• d) einer Zelle, vorzugsweise einer Amphibienzelle, Bakterienzelle, Hefezelle, Insektenzelle oder einer immortalisierten oder nativen Säugetierzelle, enthaltend ein Polynukleotid gemäß einem der Punkte a) oder b) oder einen Vektor gemäß Punkt c)

zur Herstellung eines Arzneimittels zum Einsatz in der Gentherapie. Dabei ist es besonders bevorzugt, wenn es sich um In-vivo oder In-vitro Gentherapie handelt. Unter Gentherapie versteht man eine Therapieform, bei der durch die Einführung von Nukleinsäuren in Zellen ein Effektorgen, meist ein Protein, exprimiert wird. Man unterscheidet prinzipiell In-vivo- und In-vitro-Verfahren. In In-vitro-Verfahren werden Zellen aus dem Organismus entfernt und ex-vivo mit Vektoren transfiziert, um anschließend wieder in denselben oder in einen anderen Organismus eingebracht zu werden. Bei der In-vivo-Gentherapie werden Vektoren, beispielsweise zur Bekämpfung von Tumoren, systemisch (z. B. über die Blutbahn) oder direkt in das Zielgewebe (z. B. in einen Tumor) appliziert. Another object of the invention is the use

• a) a polynucleotide, preferably a DNA or RNA, coding for BNPI or DNPI or a polynucleotide, preferably a DNA or RNA, which is one of the in Fig. 1a), 1c), 1e), 2a), 2c) or 2e ) corresponds to at least 90%, preferably at least 95%, in particular at least 97% of the nucleotide sequences shown,
• b) a polynucleotide, in particular an antisense polynucleotide or a PNA, preferably a DNA enzyme or ribozyme, a ribozyme or other DNA enzyme or a catalytic RNA or DNA, which has a nucleotide sequence which is capable of specifically bind one of the polynucleotides listed under point a),
• c) a vector containing a polynucleotide according to one of the items a) or b), in particular an expression vector and / or in particular derived from a virus, for example the adenovirus, adeno-associated virus or herpes virus and / or in particular containing at least one LTR, poly A , Promoter and / or ORI sequence,
• d) a cell, preferably an amphibian cell, bacterial cell, yeast cell, insect cell or an immortalized or native mammalian cell, containing a polynucleotide according to one of items a) or b) or a vector according to item c)

for the manufacture of a medicament for use in gene therapy. It is particularly preferred if it is in vivo or in vitro gene therapy. Gene therapy is a form of therapy in which an effector gene, usually a protein, is expressed by the introduction of nucleic acids into cells. A basic distinction is made between in-vivo and in-vitro processes. In in vitro methods, cells are removed from the organism and transfected with vectors ex vivo, in order to be subsequently reintroduced into the same or into another organism. In in vivo gene therapy, vectors, for example for combating tumors, are applied systemically (for example via the bloodstream) or directly into the target tissue (for example in a tumor).

When used in gene therapy, it is also preferred if it is a medicament with efficacy in the indication or for the treatment of
Visual disturbances, retinitis pigmentosa, optic degeneration, hearing disorders, tinitus, M. Meniere, sudden hearing loss, schizophrenia, mania, depression, stroke, brain trauma, paraplegia, amyotrophic lateral sclerosis, neuralgia, weight regulation, obesity, anorexia nervosa, epilepsy, choroidal stress, hemibalism , Parkinson's disease, TIA (transient ischemic attacks), emesis, especially hyperemesis, for example with chemotherapy, dizziness, in any form, cataract, arthritis, hyperactivity, developmental disorders, rabies, virus infections or bacterial infections, flu, malaria, Creutzfeld-Jacob, Inflammatory bowel disease, Crohn's disease, cardiovascular and cardiorespiratory dysfunction, hypertension, disorders of baroafference or chemoafference, toxoplasmosis, asthma, autoimmunity in the central and peripheral nervous system, diabetic neuropathy, autoimmune diabetes, alcoholic neuropathy, HIV-neuroids; Autonomic nervous system disorders, digestive tract nervous system disorders, hyperexcitability, especially glutamate-mediated hyperexcitability, neurodegeneration, especially in Alzheimer's disease, Alzheimer's disease, ischemia; Encephalitis especially viral or bacterial; Prion disease, Rasmussen encephalitis, HIV encephalitis, demyelination, particularly in the case of multiple sclerosis, retinal degeneration, glaucoma, nystagmus, retinal detachment, cerebellar disorders, cerebellar ataxia, disorders of the basal ganglia, diseases of the pallidum, disorders of the hearing organ and / or balance Auditory or vesibular tract, memory disorders, learning disorders, cognitive disorders, Stiff-Man syndrome, restless leg syndrome, anxiety, phobias, sleep disorders; Drug addiction, addiction and withdrawal, especially with alcohol, nicotine, opiates, ecstasy or cocaine; Hepatoencephalopathy with alcohol intoxication, hepatoencephalopathy without alcohol intoxication, neurotoxicological diseases, diseases of the spinal motor neurons, muscle atrophies, muscular dystrophies, diseases of the posterior tract, alcoholic neuropathies, neuroinflammation, sensory disorders with infections or fever, stress, taste disorders, Chinese food, food syndrome, food allergy Paranoia, concussion, neuroendocrine disorders, Tourrette syndrome, cerebrovascular spasms, neuronal apoptosis, neurodegeneration, neuronal necrosis, astrocytosis, burn-out syndrome, sudden infant death (sudden childhood death), heart attack, insomnia, retrograde amnesia, multiple Jet-lag, disorders of sexual function such as impotence or priapism or with effectiveness for promoting microglia activation, learning, cognition or memory, for neuroprotection, for CSF diagnosis of neurostatic diseases or he for adjuvant therapy by electrostimulation of the subthalamic nucleus in Parkinson's
is.

When used in gene therapy, the use of a is also preferred Polynucleotide, which is an antisense polynucleotide or PNA is, or part of a ribozyme or other DNA enzyme or a catalytic RNA or DNA.

• a) eines Polynukleotids, vorzugsweise einer DNA oder RNA, kodierend für BNPI oder DNPI oder eines Polynukleotids, vorzugsweise einer DNA oder RNA, welches einer der in einer der Abb. 1a), 1c), 1e), 2a), 2c) oder 2e) dargestellten Nukleotidsequenzen zu wenigstens 90%, vorzugsweise 95%, insbesondere zu wenigstens 97% entspricht,
• b) eines Polynukleotids, insbesondere eines Antisense Polynukleotids oder einer PNA, vorzugsweise eines DNA- Enzyms oder Ribozyms, eines Ribozyms oder sonstigen DNA-Enzyms oder einer katalytischen RNA oder DNA, das eine Nukleotid-Sequenz aufweist, die in der Lage ist, spezifisch an eines der unter Punkt a) aufgeführten Polynukleotide zu binden,
• c) eines Vektors enthaltend ein Polynukleotid gemäß einem der Punkte a) oder b), insbesondere eines Expressionsvektors und/oder insbesondere abgeleitet von einem Virus, beispielsweise dem Adenovirus, Adenoassoziiertem Virus oder Herpesvirus und/oder insbesondere enthaltend mindestens eine LTR-, Poly A-, Promotor- und/oder ORI- Sequenz,
• d) von BNPI und/oder DNPI und/oder eines Proteins gemäß einer der Abb. 1b), 1d), 1f), 2b) oder 2d) und/oder eines zu einem dieser vorgenannten Proteine zu mindestens 90%, vorzugsweise mindestens 95%, insbesondere mindestens 97% ähnlichen Proteins und/oder eines Proteins, für das ein Polynukleotid gemäß einer der Abb. 1a), 1c), 1e), 2a) oder 2c) oder ein dazu zu mindestens 90%, vorzugsweise mindestens 95%, insbesondere mindestens 97% ähnliches Polynukleotid kodiert, und/oder eines Proteins, das durch eine Nukleinsäure kodiert wird, die unter stringenten Bedingungen an ein Polynukleotid gemäß einer der Abb. 1a), 1c), 1e), 2a) oder 2c) oder dessen Antisense Polynukleotide bindet oder eines mindestens 10, vorzugsweise mindestens 15, insbesondere mindestens 20 Aminosäuren langen Teilproteins eines der vorgenannten Proteine, wobei das Protein oder Teilprotein gegebenenfalls posttranslational modifiziert, insbesondere glykosiliert, phosphoryliert, amidiert, methyliert, acetyliert, ADP-ribosyliert, hydroxyliert, mit einem Membrananker versehen, gespalten oder verkürzt wurde,
• e) eines Antikörpers, vorzugsweise eines monoklonalen oder polyklonalen Antikörpers, gegen eines der Proteine oder Teilproteine gemäß Punkt d),
• f) einer Zelle, vorzugsweise einer Amphibienzelle, Bakterienzelle, Hefezelle, Insektenzelle oder einer immortalisierten oder nativen Säugetierzelle, enthaltend ein Polynukleotid gemäß einem der Punkte a) oder b), einen Vektor gemäß Punkt c), ein Protein oder Teilprotein gemäß Punkt d) oder einen Antikörper gemäß Punkt e),
• g) einer erfindungsgemäßen Verbindung identifizierbar als pharmazeutisch relevante Substanz mit Wirksamkeit in mindestens einer der vorgenannten Indikationen wie oben beschrieben und/oder
• h) eines Wirkstoffs, vorzugsweise eines niedermolekularen Wirkstoffs, der an ein Protein oder Teilprotein gemäß Punkt d) bindet,

zur Herstellung eines Diagnostikums zur Diagnose eines Zustands ausgewählt aus
Sehstörungen, Retinitis pigmentosa, Opticus Degeneration, Hörstörungen, Tinitus, M. Menière, Hörsturz, Schizophrenie, Manien, Depression, Schlaganfall, Hirntrauma, Querschnittslähmung, amyotrophe Lateralsklerose, Neuralgie, Gewichtsregulation, Obesitas, Anorexia nervosa, Epilepsie, Hemibalismus, Chorea Huntington, Stress, Morbus Parkinson, TIA (Transiente Ischämische Attacken), Emesis, insbesondere Hyperemesis beispielsweise bei Chemotherapie, Schwindel, in jeglicher Form, Katarakt, Arthritis, Hyperaktivität, Entwicklungsstörungen, Tollwut, Virus-Infektionen oder bakterielle Infektionen, Grippe, Malaria, Creutzfeld-Jacob, Inflammatory Bowel disease, Morbus Crohn, cardiovaskuläre und cardiorespiratorische Funktionsstörungen, Hypertonie, Störungen der Baroafferenz oder Chemoafferenz, Toxoplasmose, Asthma, Autoimmunität im zentralen und peripheren Nervensystem, diabetische Neuropathie, autoimmuner Diabetes, alkoholische Neuropathie, HIV-Neuro-Aids; Störungen des autonomen Nervensystems, Störungen des Nervensystems des Verdauungstraktes, Übererregbarkeit, insbesondere glutamatvermittelte Übererregbarkeit, Neurodegeneration insbesondere bei Morbus Alzheimer, Morbus Alzheimer, Ischämie; Encephalitis insbesondere virale oder bakterielle; Prionerkrankung, Rasmussen-Encephalitis, HIV-Encephalitis, Demyelinisierung insbesondere bei multipler Sklerose, Retinadegeneration, Glaukom, Nystagmus, Netzhautablösung, Erkrankungen des Cerebellums, cerebelläre Ataxie, Erkrankungen der Basalganglien, Erkrankungen des Pallidums, Erkrankungen des Hör- und/oder Gleichgewichtsorgans, Erkrankungen der Hörbahn oder Vesibularbahn, Störungen des Gedächtnisses, Störungen des Lernens, Störungen der Kognition, Stiff-Man-Syndrom, Restless Leg- Syndrom, Angstzustände, Phobien, Schlafstörungen; Drogenabhängigkeit, -sucht und -entzug insbesondere bei Alkohol, Nikotin, Opiaten, Ecstasy oder Kokain; Hepatoencephalopathie mit Alkoholintoxikation, Hepatoencephalopathie ohne Alkoholintoxikation, neurotoxikologisch bedingte Erkrankungen, Erkrankungen des spinalen Motoneurons, Muskelatrophien, Muskeldystrophien, Erkrankungen der Hinterstrangbahnen, alkoholische Neuropathien, Neuroinflammation, Befindlichkeitsstörungen bei Infektionen oder Fieber, Stress, Geschmacksstörungen, Nahrungsmittelallergien, Chinese-Restaurant-Syndrom, Agression, Paranoia, Hirnerschütterung, neuroendokrine Störungen, Tourrette-Syndrom, cerebrovaskuläre Spasmen, neuronale Apoptose, Neurodegeneration, neuronale Nekrose, Astrocytose, Burn-out- Syndrom, Sudden-Infant-Death (plötzlicher Kindstod), Herzinfarkt, Insomnia, retrograde Amnesie, multiple Sklerose, Jet-lag, Störungen der Sexualfunktion, wie Impotenz oder Priapismus. Another object of the invention is the use

• a) a polynucleotide, preferably a DNA or RNA, coding for BNPI or DNPI or a polynucleotide, preferably a DNA or RNA, which is one of the in Fig. 1a), 1c), 1e), 2a), 2c) or 2e ) corresponds to at least 90%, preferably 95%, in particular at least 97% of the nucleotide sequences shown,
• b) a polynucleotide, in particular an antisense polynucleotide or a PNA, preferably a DNA enzyme or ribozyme, a ribozyme or other DNA enzyme or a catalytic RNA or DNA, which has a nucleotide sequence which is capable of specifically bind one of the polynucleotides listed under point a),
• c) a vector containing a polynucleotide according to one of the items a) or b), in particular an expression vector and / or in particular derived from a virus, for example the adenovirus, adeno-associated virus or herpes virus and / or in particular containing at least one LTR, poly A , Promoter and / or ORI sequence,
• d) BNPI and / or DNPI and / or a protein according to one of Figs. 1b), 1d), 1f), 2b) or 2d) and / or one of these proteins to at least 90%, preferably at least 95% , in particular at least 97% similar protein and / or a protein for which a polynucleotide according to one of Figs. 1a), 1c), 1e), 2a) or 2c) or at least 90%, preferably at least 95%, in particular encodes at least 97% similar polynucleotide, and / or a protein which is encoded by a nucleic acid which, under stringent conditions, is attached to a polynucleotide according to one of FIGS. 1a), 1c), 1e), 2a) or 2c) or its antisense polynucleotide binds or one of at least 10, preferably at least 15, in particular at least 20 amino acids long partial protein of one of the aforementioned proteins, the protein or partial protein optionally being post-translationally modified, in particular glycosylated, phosphorylated, amidated, methylated, acetylated, ADP-ribosylated, hydroxylated, provided with a membrane anchor, split or shortened,
• e) an antibody, preferably a monoclonal or polyclonal antibody, against one of the proteins or partial proteins according to point d),
• f) a cell, preferably an amphibian cell, bacterial cell, yeast cell, insect cell or an immortalized or native mammalian cell, containing a polynucleotide according to one of points a) or b), a vector according to point c), a protein or partial protein according to point d) or an antibody according to point e),
• g) a compound of the invention identifiable as a pharmaceutically relevant substance with activity in at least one of the aforementioned indications as described above and / or
• h) an active ingredient, preferably a low molecular weight active ingredient, which binds to a protein or partial protein according to point d),

selected for the manufacture of a diagnostic agent for diagnosing a condition
Visual disturbances, retinitis pigmentosa, optic degeneration, hearing disorders, tinitus, M. Meniere, sudden hearing loss, schizophrenia, mania, depression, stroke, brain trauma, paraplegia, amyotrophic lateral sclerosis, neuralgia, weight regulation, obesity, anorexia nervosa, epilepsy, choroidal stress, hemibalism , Parkinson's disease, TIA (transient ischemic attacks), emesis, especially hyperemesis, for example with chemotherapy, dizziness, in any form, cataract, arthritis, hyperactivity, developmental disorders, rabies, virus infections or bacterial infections, flu, malaria, Creutzfeld-Jacob, Inflammatory bowel disease, Crohn's disease, cardiovascular and cardiorespiratory dysfunction, hypertension, disorders of baroafference or chemoafference, toxoplasmosis, asthma, autoimmunity in the central and peripheral nervous system, diabetic neuropathy, autoimmune diabetes, alcoholic neuropathy, HIV-neuroids; Autonomic nervous system disorders, digestive tract nervous system disorders, hyperexcitability, especially glutamate-mediated hyperexcitability, neurodegeneration, especially in Alzheimer's disease, Alzheimer's disease, ischemia; Encephalitis especially viral or bacterial; Prion disease, Rasmussen encephalitis, HIV encephalitis, demyelination, particularly in the case of multiple sclerosis, retinal degeneration, glaucoma, nystagmus, retinal detachment, cerebellar diseases, cerebellar ataxia, diseases of the basal ganglia, diseases of the pallidum, diseases of the hearing organ and / or balance Auditory or vesibular tract, memory disorders, learning disorders, cognitive disorders, Stiff-Man syndrome, restless leg syndrome, anxiety, phobias, sleep disorders; Drug addiction, addiction and withdrawal, especially with alcohol, nicotine, opiates, ecstasy or cocaine; Hepatoencephalopathy with alcohol intoxication, hepatoencephalopathy without alcohol intoxication, neurotoxicological diseases, diseases of the spinal motor neurons, muscle atrophies, muscular dystrophies, diseases of the posterior tract, alcoholic neuropathies, neuroinflammation, disorders of the well-being with infections or fever, stress, taste disorders, Chinese food, food syndrome, food allergy Paranoia, concussion, neuroendocrine disorders, Tourrette syndrome, cerebrovascular spasms, neuronal apoptosis, neurodegeneration, neuronal necrosis, astrocytosis, burn-out syndrome, sudden infant death (sudden childhood death), heart attack, insomnia, retrograde amnesia, multiple Jet lag, sexual dysfunction, such as impotence or priapism.

Diagnostics is the analysis of a clinical picture assigned symptoms and under efficacy studies Studies on the effectiveness of substances to be tested, especially their medical effectiveness.

Another object of the invention is a method for Production of a peptide or protein according to the invention, in which one cell of the invention which is a polynucleotide of the invention and / or contains, cultivated and optionally the peptide or protein is isolated.

• a) eines Polynukleotids, vorzugsweise einer DNA oder RNA, kodierend für BNPI oder DNPI oder eines Polynukleotids, vorzugsweise einer DNA oder RNA, welches einer der in einer der Abb. 1a), 1c), 1e), 2a), 2c) oder 2e) dargestellten Nukleotidsequenzen zu wenigstens 90%, vorzugsweise 95%, insbesondere zu wenigstens 97% entspricht,
• b) eines Polynukleotids, insbesondere eines Antisense Polynukleotids oder einer PNA, vorzugsweise eines DNA-Enzyms oder Ribozyms, eines Ribozyms oder sonstigen DNA-Enzyms oder einer katalytischen RNA oder DNA, das eine Nukleotid-Sequenz aufweist, die in der Lage ist, spezifisch an eines der unter Punkt a) aufgeführten Polynukleotide zu binden,
• c) eines Vektors enthaltend ein Polynukleotid gemäß einem der Punkte a) oder b), insbesondere eines Expressionsvektors und/oder insbesondere abgeleitet von einem Virus, beispielsweise dem Adenovirus, Adenoassoziiertem Virus oder Herpesvirus und/oder insbesondere enthaltend mindestens eine LTR-, Poly A-, Promotor- und/oder ORI-Sequenz,
• d) von BNPI und/oder DNPI und/oder eines Proteins gemäß einer der Abb. 1b), 1d), 1f), 2b) oder 2d) und/oder eines zu einem dieser vorgenannten Proteine zu mindestens 90%, vorzugsweise mindestens 95%, insbesondere mindestens 97% ähnlichen Proteins und/oder eines Proteins, für das ein Polynukleotid gemäß einer der Abb. 1a), 1c), 1e), 2a) oder 2c) oder ein dazu zu mindestens 90%, vorzugsweise mindestens 95%, insbesondere mindestens 97% ähnliches Polynukleotid kodiert, und/oder eines Proteins, das durch eine Nukleinsäure kodiert wird, die unter stringenten Bedingungen an ein Polynukleotid gemäß einer der Abb. 1a), 1c), 1e), 2a) oder 2c) oder dessen Antisense Polynukleotide bindet oder eines mindestens 10, vorzugsweise mindestens 15, insbesondere mindestens 20 Aminosäuren langen Teilproteins eines der vorgenannten Proteine, wobei das Protein oder Teilprotein gegebenenfalls posttranslational modifiziert, insbesondere glykosiliert, phosphoryliert, amidiert, methyliert, acetyliert, ADP- ribosyliert, hydroxyliert, mit einem Membrananker versehen, gespalten oder verkürzt wurde,
• e) eines Antikörpers, vorzugsweise eines monoklonalen oder polyklonalen Antikörpers, gegen eines der Proteine oder Teilproteine gemäß Punkt d),
• f) einer Zelle, vorzugsweise einer Amphibienzelle, Bakterienzelle, Hefezelle, Insektenzelle oder einer immortalisierten oder nativen Säugetierzelle, enthaltend ein Polynukleotid gemäß einem der Punkte a) oder b), einen Vektor gemäß Punkt c), ein Protein oder Teilprotein gemäß Punkt d) oder einen Antikörper gemäß Punkt e) in einem Verfahren zur Auffindung pharmazeutisch relevanter Substanzen mit Wirksamkeit in den Indikationen oder zur Behandlung von
  Sehstörungen, Retinitis pigmentosa, Opticus Degeneration, Hörstörungen, Tinitus, M. Menière, Hörsturz, Schizophrenie, Manien, Depression, Schlaganfall, Hirntrauma, Querschnittslähmung, amyotrophe Lateralsklerose, Neuralgie, Gewichtsregulation, Obesitas, Anorexia nervosa, Epilepsie, Hemibalismus, Chorea Huntington, Stress, Morbus Parkinson, TIA (Transiente Ischämische Attacken), Emesis, insbesondere Hyperemesis beispielsweise bei Chemotherapie, Schwindel, in jeglicher Form, Katarakt, Arthritis, Hyperaktivität, Entwicklungsstörungen, Tollwut, Virus-Infektionen oder bakterielle Infektionen, Grippe, Malaria, Creutzfeld-Jacob, Inflammatory Bowel disease, Morbus Crohn, cardiovaskuläre und cardiorespiratorische Funktionsstörungen, Hypertonie, Störungen der Baroafferenz oder Chemoafferenz, Toxoplasmose, Asthma, Autoimmunität im zentralen und peripheren Nervensystem, diabetische Neuropathie, autoimmuner Diabetes, alkoholische Neuropathie, HIV-Neuro-Aids; Störungen des autonomen Nervensystems, Störungen des Nervensystems des Verdauungstraktes, Übererregbarkeit, insbesondere glutamatvermittelte Übererregbarkeit, Neurodegeneration insbesondere bei Morbus Alzheimer, Morbus Alzheimer, Ischämie; Encephalitis insbesondere virale oder bakterielle; Prionerkrankung, Rasmussen-Encephalitis, HIV-Encephalitis, Demyelinisierung insbesondere bei multipler Sklerose, Retinadegeneration, Glaukom, Nystagmus, Netzhautablösung, Erkrankungen des Cerebellums, cerebelläre Ataxie, Erkrankungen der Basalganglien, Erkrankungen des Pallidums, Erkrankungen des Hör- und/oder Gleichgewichtsorgans, Erkrankungen der Hörbahn oder Vesibularbahn, Störungen des Gedächtnisses, Störungen des Lernens, Störungen der Kognition, Stiff-Man-Syndrom, Restless Leg-Syndrom, Angstzustände, Phobien, Schlafstörungen; Drogenabhängigkeit, -sucht und -entzug insbesondere bei Alkohol, Nikotin, Opiaten, Ecstasy oder Kokain; Hepatoencephalopathie mit Alkoholintoxikation, Hepatoencephalopathie ohne Alkoholintoxikation, neurotoxikologisch bedingte Erkrankungen, Erkrankungen des spinalen Motoneurons, Muskelatrophien, Muskeldystrophien, Erkrankungen der Hinterstrangbahnen, alkoholische Neuropathien, Neuroinflammation, Befindlichkeitsstörungen bei Infektionen oder Fieber, Stress, Geschmacksstörungen, Nahrungsmittelallergien, Chinese- Restaurant-Syndrom, Agression, Paranoia, Hirnerschütterung, neuroendokrine Störungen, Tourrette-Syndrom, cerebrovaskuläre Spasmen, neuronale Apoptose, Neurodegeneration, neuronale Nekrose, Astrocytose, Burn-out-Syndrom, Sudden-Infant-Death (plötzlicher Kindstod), Herzinfarkt, Insomnia, retrograde Amnesie, multiple Sklerose, Jet-lag, Störungen der Sexualfunktion, wie Impotenz oder Priapismus oder mit Wirksamkeit zur Förderung der Mikrogliaaktivierung, des Lernens, der Kognition oder des Gedächtnisses, zur Neuroprotektion, zur Liquordiagnostik neurostatischer Erkrankungen oder zur adjuvanten Therapie per Elektrostimulation des Nucleus subthalamicus bei Parkinson.

Another object of the invention is the use

• a) a polynucleotide, preferably a DNA or RNA, coding for BNPI or DNPI or a polynucleotide, preferably a DNA or RNA, which is one of the in Fig. 1a), 1c), 1e), 2a), 2c) or 2e ) corresponds to at least 90%, preferably 95%, in particular at least 97% of the nucleotide sequences shown,
• b) a polynucleotide, in particular an antisense polynucleotide or a PNA, preferably a DNA enzyme or ribozyme, a ribozyme or other DNA enzyme or a catalytic RNA or DNA, which has a nucleotide sequence which is capable of specifically bind one of the polynucleotides listed under point a),
• c) a vector containing a polynucleotide according to one of the items a) or b), in particular an expression vector and / or in particular derived from a virus, for example the adenovirus, adeno-associated virus or herpes virus and / or in particular containing at least one LTR, poly A , Promoter and / or ORI sequence,
• d) BNPI and / or DNPI and / or a protein according to one of Figs. 1b), 1d), 1f), 2b) or 2d) and / or one of these proteins to at least 90%, preferably at least 95% , in particular at least 97% similar protein and / or a protein for which a polynucleotide according to one of Figs. 1a), 1c), 1e), 2a) or 2c) or at least 90%, preferably at least 95%, in particular encodes at least 97% similar polynucleotide, and / or a protein which is encoded by a nucleic acid which, under stringent conditions, is attached to a polynucleotide according to one of FIGS. 1a), 1c), 1e), 2a) or 2c) or its antisense polynucleotide binds or one of at least 10, preferably at least 15, in particular at least 20 amino acids long partial protein of one of the aforementioned proteins, the protein or partial protein optionally being post-translationally modified, in particular glycosylated, phosphorylated, amidated, methylated, acetylated, ADP- ribosylated, hydroxylated, provided with a membrane anchor, split or shortened,
• e) an antibody, preferably a monoclonal or polyclonal antibody, against one of the proteins or partial proteins according to point d),
• f) a cell, preferably an amphibian cell, bacterial cell, yeast cell, insect cell or an immortalized or native mammalian cell, containing a polynucleotide according to one of points a) or b), a vector according to point c), a protein or partial protein according to point d) or an antibody according to point e) in a process for the detection of pharmaceutically relevant substances with efficacy in the indications or for the treatment of
  Visual disturbances, retinitis pigmentosa, optic degeneration, hearing disorders, tinitus, M. Meniere, sudden hearing loss, schizophrenia, mania, depression, stroke, brain trauma, paraplegia, amyotrophic lateral sclerosis, neuralgia, weight regulation, obesity, anorexia nervosa, epilepsy, choroidal stress, hemibalism , Parkinson's disease, TIA (transient ischemic attacks), emesis, especially hyperemesis, for example with chemotherapy, dizziness, in any form, cataract, arthritis, hyperactivity, developmental disorders, rabies, virus infections or bacterial infections, flu, malaria, Creutzfeld-Jacob, Inflammatory bowel disease, Crohn's disease, cardiovascular and cardiorespiratory dysfunction, hypertension, disorders of baroafference or chemoafference, toxoplasmosis, asthma, autoimmunity in the central and peripheral nervous system, diabetic neuropathy, autoimmune diabetes, alcoholic neuropathy, HIV-neuroids; Autonomic nervous system disorders, digestive tract nervous system disorders, hyperexcitability, especially glutamate-mediated hyperexcitability, neurodegeneration, especially in Alzheimer's disease, Alzheimer's disease, ischemia; Encephalitis especially viral or bacterial; Prion disease, Rasmussen encephalitis, HIV encephalitis, demyelination, particularly in the case of multiple sclerosis, retinal degeneration, glaucoma, nystagmus, retinal detachment, cerebellar disorders, cerebellar ataxia, disorders of the basal ganglia, diseases of the pallidum, disorders of the hearing organ and / or balance Auditory or vesibular tract, memory disorders, learning disorders, cognitive disorders, Stiff-Man syndrome, restless leg syndrome, anxiety, phobias, sleep disorders; Drug addiction, addiction and withdrawal, especially with alcohol, nicotine, opiates, ecstasy or cocaine; Hepatoencephalopathy with alcohol intoxication, hepatoencephalopathy without alcohol intoxication, neurotoxicological diseases, diseases of the spinal motor neurons, muscle atrophies, muscular dystrophies, diseases of the posterior tract, alcoholic neuropathies, neuroinflammation, sensory disorders with infections or fever, stress, taste disorders, Chinese food, food syndrome, food allergy Paranoia, concussion, neuroendocrine disorders, Tourrette syndrome, cerebrovascular spasms, neuronal apoptosis, neurodegeneration, neuronal necrosis, astrocytosis, burn-out syndrome, sudden infant death (sudden childhood death), heart attack, insomnia, retrograde amnesia, multiple Jet-lag, disorders of sexual function such as impotence or priapism or with effectiveness for promoting microglia activation, learning, cognition or memory, for neuroprotection, for CSF diagnosis of neurostatic diseases or he for adjuvant therapy by electrostimulation of the subthalamic nucleus in Parkinson's.

In general, it is preferred for all of the aforementioned uses according to the invention if the indication or the disease to be treated or diagnosed is selected from
Visual disturbances, retinitis pigmentosa, optic degeneration, hearing disorders, tinitus, M. Meniere, sudden hearing loss, amyotrophic lateral sclerosis, neuralgia, weight regulation, obesity, Parkinson's disease, cataracts, virus infections or bacterial infections, diabetic neuropathy, autoimmune diabetes, alcoholic neuropathy, HIV -AIDS; Retinal degeneration, glaucoma, nystagmus, retinal detachment, diseases of the auditory and / or balance organ, diseases of the auditory or vesibular tract, sleep disorders, drug addiction, addiction and withdrawal, in particular with alcohol, nicotine, opiates, ecstasy or cocaine; Neuroinflammation, Insomnia, for adjuvant therapy by electrostimulation of the subthalamic nucleus in Parkinson's
preferably
Visual disturbances, retinitis pigmentosa, optic degeneration, hearing disorders, tinitus, M. Meniere, sudden hearing loss, amyotrophic lateral sclerosis, weight regulation, obesity, cataract, viral infections or bacterial infections, retinal degeneration, glaucoma, nystagmus, retinal detachment, diseases of the hearing and / or balance organ Diseases of the auditory or vesibular tract, drug addiction, addiction and withdrawal, particularly in the case of alcohol, nicotine, opiates, ecstasy or cocaine; neuroinflammation
in particular
Visual disturbances, retinitis pigmentosa, optic degeneration, cataract, retinal detachment, retinal degeneration, glaucoma or nystagmus
or
Hearing disorders, tinitus, Meniere's disease, sudden hearing loss, diseases of the hearing and / or balance organ or diseases of the auditory or vesibular tract.

With the polynucleotide used according to the invention, the shown gene fragments themselves, as well as a polynucleotide that either completely or at least part of the coding sequence of the corresponds to the fragment of the corresponding gene. With that too Polynucleotides are meant, the at least 90%, preferably 95%, in particular at least 97% agreement in the base sequence with the coding sequence of the polynucleotides shown or the have coding sequence of the gene. It is more preferred that it the polynucleotide is RNA or single- or double-stranded DNA, especially mRNA or cDNA. It is also preferred that it the polynucleotide is an antisense polynucleotide or PNA acts that has a sequence that is capable of specific to a to bind the polynucleotide of the invention. Here one understands PNA "peptidic nucleic acid" (peptidic nucleic acid), although the Base pairs, but the backbone is peptide-bound. On Antisense polynucleotide shows the complementary base sequence at least part of a base nucleic acid. Is also preferred it that the polynucleotide is part of a ribozyme or other DNA enzyme or a catalytic RNA or DNA. Among ribozyme is one To understand catalytically active ribonucleic acid, under DNA enzyme corresponding deoxyribonucleic acid, ie catalytic RNA or DNA.

A very particularly preferred object of the invention is a polynucleotide or oligonucleotide, in particular used according to the invention, in which at least one of the nucleotides, in particular several of the nucleotides, are "Locked Nucleic Acids"("LNA's") or at least one of the nucleotides, in particular all nucleotides Are phosphorothioates, preferably one in which several of the nucleotides are "Locked Nucleic Acids"("LNA's")."Locked nucleic acids"("LNA's") are ribonucleotides that contain a methylene bridge that connects the 2'-oxygen of the ribose with the 4'-carbon (see Fig. 27). An overview of the LNA's is given by Braasch DA and Corey, DR (2001), Locked nucleic acids (LNA); fine-tuning the recognition of DNA and RNA. Chem. Biol. 8, 1-7. This article is an integral part of the present description and disclosure. LNA's are offered, for example, by Proligo, Boulder, CO, USA. Phosphorothiates are also known to the person skilled in the art and can be ordered, for example, from MWG-Biotech AG, Ebersberg, Germany.

The vector used according to the invention means one Nucleic acid molecule that is used in genetic engineering to Contain or transfer foreign genes. Is particularly preferred that it is an expression vector. He thus serves the Expression of the contained foreign gene, the polynucleotide. Further such a vector is preferred, which is derived from a virus, for example the adenovirus, adeno-associated virus or herpes virus and / or he has at least one LTR, poly A, promoter and / or ORI Contains sequence. An LTR is a "long terminal repeat", one at the end section for viruses. Poly-A sequence is a more than 20 adenosine residues long tail. A promoter sequence is the Control area for transcription.

It is preferred for a protein used or a partial protein derived therefrom if it has been post-translationally modified, in particular glycosylated, phosphorylated, amidated, methylated, acetylated, ADP-ribosylated, hydroxylated, provided with a membrane anchor, cleaved or shortened. Post-translational modifications can be found, for example, in Voet / Voet, Biochemistry, 1 ^st Edition, 1990, pp. 935-938.

It is particularly preferred for use according to the invention if the polynucleotide (possibly according to point a) and / or point b)) an RNA or a single- or double-stranded DNA, in particular mRNA or is cDNA.

It is particularly preferred for use according to the invention if the polynucleotide (possibly according to point b)) is part of a Ribozyme or other DNA enzyme or a catalytic RNA or DNA is.

It is particularly preferred for use according to the invention if the vector (optionally according to point c)) is an expression vector.

It is also special for use according to the invention preferred if the vector (if necessary according to point c)) is derived from a virus, for example the adenovirus, adeno-associated virus or herpes virus and / or he has at least one LTR, poly A, promoter and / or ORI sequence contains.

It is for an inventive use (not gene therapy) particularly preferred if the protein or partial protein (optionally post-translationally modified in accordance with point d)), in particular glycosylated, phosphorylated, amidated, methylated, acetylated, ADP-ribosylated, hydroxylated, provided with a membrane anchor, split or shortened has been.

It is for an inventive use (not gene therapy) particularly preferred if the antibody (possibly according to point e)) is a monoclonal or polyclonal antibody.

It is particularly preferred for use according to the invention if the cell (possibly according to point f)) is a Amphibian cell, bacterial cell, yeast cell, insect cell or one immortalized or native mammalian cell.

It is particularly preferred for use according to the invention if the connection (if necessary according to point g)) is a low molecular compound.

It is particularly preferred for use according to the invention if the active ingredient mentioned is a low molecular weight according to point h) Active ingredient is.

Another object of the invention is a method for treatment, of a non-human mammal or human, the one Treatment of visual disturbances, retinitis pigmentosa, opticus Degeneration, hearing disorders, tinitus, M. Meniere, sudden hearing loss, schizophrenia, Mania, depression, stroke, brain trauma, paraplegia, amyotrophic lateral sclerosis, neuralgia, weight regulation, obesity, Anorexia nervosa, epilepsy, hemibalism, Huntington's disease, stress, Parkinson's disease, Alzheimer's, TIA (transient ischemic attacks), Emesis, especially hyperemesis, for example in chemotherapy, Dizziness, any form, cataract, arthritis, hyperactivity, Developmental disorders, rabies, viral infections or bacterial Infections, flu, malaria, Creutzfeld-Jacob, inflammatory bowel disease, Crohn's disease, cardiovascular and cardiorespiratory Dysfunction, hypertension, disorders of baroafference or Chemoafference, toxoplasmosis, asthma, central and autoimmunity peripheral nervous system, diabetic neuropathy, autoimmune Diabetes, alcoholic neuropathy, HIV neuro-AIDS; Disorders of the autonomic nervous system, disorders of the nervous system of the Digestive tract, hyperexcitability, especially glutamate-mediated Hyperexcitability, neurodegeneration especially in Alzheimer's disease, Alzheimer's disease, ischemia; Encephalitis especially viral or bacterial; Prion disease, Rasmussen encephalitis, HIV encephalitis, amyotrophic lateral sclerosis, demyelination especially in multiple Sclerosis, retinal degeneration, glaucoma, nystagmus, retinal detachment, Cerebellar diseases, cerebellar ataxia, diseases of the Basal ganglia, diseases of the pallidum, diseases of the hearing and / or balance organ, diseases of the auditory pathway or Vesibular tract, memory disorders, learning disorders, Cognitive disorders, Stiff-Man syndrome, restless leg syndrome, Anxiety, phobias, sleep disorders, anorexia nervosa; Drug addiction, addiction and withdrawal, especially with alcohol, Nicotine, opiates, ecstasy or cocaine; With hepatoencephalopathy Alcohol intoxication, hepatoencephalopathy without alcohol intoxication, neurotoxicological diseases, diseases of the spinal Motor neurons, muscle atrophies, muscular dystrophies, diseases of the Posterior tracts, alcoholic neuropathies, neuroinflammation, Disorders of well-being with infections or fever, stress, Taste disorders, food allergies, Chinese restaurant Syndrome, aggression, paranoia, concussion, neuroendocrine Disorders, Tourrette syndrome, cerebrovascular spasms, neuronal Apoptosis, neurodegeneration, neuronal necrosis, astrocytosis, burn-out Syndrome, sudden infant death (sudden child death), heart attack, Insomnia, retrograde amnesia, multiple sclerosis, jet lag, disorders of the Sexual function, such as impotence or priapism, or a promotion of Microglia activation, learning, cognition or memory, Neuroprotection, CSF diagnosis of neurostatic diseases or adjuvant therapy by electrostimulation of the subthalamic nucleus Parkinson needed by administering an invention Medicament, especially those containing an inventive Substance and / or an active ingredient that binds to BNPI and / or DNPI.

For example, administration may take the form of a drug such as described above.

The following examples and figures are intended to illustrate the invention, without limiting it to that.

Illustrations and examples pictures

Fig. 1a cDNA sequence of BNPI, human; TO: NM_020309

FIG. 1b amino acid sequence of BNPI, human; TO: NM_020309

FIG. 1c cDNA sequence of BNPI, human; No .: AAT42064 from WO 96/34288

FIG. 1d amino acid sequence of BNPI, human; No .: AAT42064 from WO 96/34288

Fig. 1e cDNA sequence from BNPI, rat; AN: U07609

Fig. 1f amino acid sequence of BNPI, rat; AN: U07609

Fig. 2a cDNA sequence of DNPI, human; TO: AB032435

FIG. 2b shows the amino acid sequence of DNPI, human; TO: AB032435

Figure 2c cDNA sequence from DNPI, rat; AN: AF271235

Figure 2d amino acid sequence of DNPI, rat; AN: AF271235

Fig. 3 Differential expression of DNPI and BNPI in synapses and motor areas of the lumbar spinal cord of the rat (s. Example 2a)

Fig. 4 Differential expression of DNPI and BNPI in synapses of the dorsal horn-areas of the lumbar spinal cord of the rat (s. Example 2b)

Fig. 5 Differential expression of DNPI and BNPI in synapses of the sacral spinal cord of the rat (s. Example 2c)

Fig. 6 Differential expression of DNPI and BNPI in synapses of the medullo-cervicospinalen line of Trigeminalnervs the rat (s. Example 2d)

Fig. 7 Differential expression of DNPI and BNPI in regions of the rat (see Example 2e)

Fig. 8 Differential expression of DNPI and BNPI Hinregionen in the rat (s. Example 2f)

Fig. 9 Differential expression of DNPI and BNPI in regions of the rat (see Example 2g)

Fig. 10 Differential expression of DNPI and BNPI Hinregionen in the rat (s. Example 2h)

Fig. 11 Differential expression of DNPI and BNPI Hinregionen in the rat (s. Example 2i)

Fig. 12 Differential expression of DNPI and BNPI in regions of the rat (see Example 2j)

Fig. 13 Differential expression of DNPI and BNPI Hinregionen in the rat (s. Example 2k)

Fig. 14 Differential expression of DNPI and BNPI Hinregionen in the rat (s. Example 2l)

Fig. 15 Differential expression of DNPI and BNPI Hinregionen in the rat (s. Example 2m)

(S. Example 2n) Fig. 16 Differential expression of DNPI and BNPI Hinregionen in the rat

Fig. 17 Differential expression of DNPI and BNPI Hinregionen in the rat (s. Example 2o)

Fig. 18 Differential expression of DNPI and BNPI in outward regions of the rat (see Example 2p)

Fig. 19 Differential expression of DNPI and BNPI in regions of the rat (see Example 2q)

Fig. 20 Differential expression of DNPI and BNPI in outward regions of the rat, where AS is called anti-sense and relates to the coloration.

Fig. 21 Differential expression of DNPI and BNPI in outward regions of the rat, where AS is called anti-sense and relates to the coloration.

Examples example 1 Differential consideration of expression between DNPI and BNPI about immuncytochemical staining

Polyclonal rabbit stains were used for immunohistochemical staining. Antisera against the recombinant DNPI or BNPI fusion protein used. Generally, sections of different regions of the CNS were created and the expression of DNPI compared with that of BNPI. The The procedure corresponded to the cuts and the coloring Persson S., Schäfer MK-H., Nohr D., Ekström G., Post C., Nyberg F. and Weihe E. (1994) Neuroscience 63; 313-326 or Nohr D., Schäfer MK-H., Romeo H., Persson S., Nyberg F. Post C. and Weihe E. (1999), Neuroscience 93; 759-773 described method, the Disclosure of this article is expressly part of the presented here Disclosure of the invention is made.

Example 2a to Fig. 3

The differential distribution of the immunoreactivity of BNPI and DNPI in the lumbar spinal cord of the rat can be seen. The adjacent deparafined sections A to D are colored as follows:
A = anti-DNPI;
B = anti-DNPI pre-adsorbed with DNPI fusion protein;
C = anti-BNPI;
D = anti-BNPI pre-adsorbed with BNPI fusion protein;

The DNPI (A) and BNPI (C) immune dyes were full of homologous recombinant BNPI- (D) and BNPI- (B) fusion protein pre-adsorbable, which proves the specificity of the immune response.

The mutually exclusive distribution pattern of DNPI and BNPI immunostaining in the outer and deep dorsal horn. (A; C). Dotted immunostaining from DNPI is in the synaptic Emmissions of the outer dorsal horn (Lamina 1 and substantia gelatinosaa) (arrow in A), while BNPI completely lacks immunoreactivity (Arrows in B). Accumulation of strong positive dotted BNPI Immunostaining is present in the deeper dorsal horn, while DNPI staining is relatively low. DNPI is present in the lateral spinal nucleus (LSN in A), while BNPI is completely absent (LSN in C). DNPI is in the Lamina X around the central channel abundant, while BNPI is rare. BNPI immunostaining is weak in the lateral ventral horn and low or absent in the medial Ventral horn. Through the whole ventral horn is point-like DNPI staining abundant, somewhat less in the lateral horn compared to the medial Ventral horn. There is weak BNPI and DNPI staining in some Cell bodies of the motor neurons located in the ventral horn, but not was pre-adsorbed by the homologous transporter fusion proteins and was therefore classified as non-specific.

Example 2b to Fig. 4

It is the differential distribution of the immunoreactivity of BNPI and DNPI in the left lateral superficial dorsal lumbar spinal cord (left lateral superficial dorsal lumbar spinal cord) of the rat. A and B colored for BNPI (A) and DNPI (B) show many punctiform Staining for DNPI in Lamina I and substantia gelatinosa where BNPI is almost completely absent. Next are dense Complex DNPI positive points in the lateral spinal nucleus too see where BNPI is almost completely missing. Fine DNPI are positive points also found in the deeper dorsal horn, albeit with less Density.

Example 2c to Fig. 5

It is the differential distribution of the immunoreactivity of BNPI and DNPI seen in the sacral spinal cord of the rat. The adjacent sections A and B colored for BNPI (A) and DNPI (B), respectively, show mutual Exclusion zones of punctured DNPI and BNPI immunostaining in the Dorsal horn. DNPI is present throughout the Gray Matter and is in the very outer layers of the dorsal horn where there is a concentrated forms a narrow band on the border to White Matter. DNPI is abundant in the lateral spinal nucleus and in the lamina X as well as in the lamina V / VI and throughout the ventral horn. BNPI is abundant in the deep dorsal horn and rarely in Ventralhorn.

Example 2d to Fig. 6

It is the differential distribution of the immunoreactivity of BNPI and DNPI in the lower medulla oblongate at the transition to the cervical Spinal cord to see. The adjacent sections A and B each for BNPI (A) and DNPI (B) colored show a preferred accumulation of the BNPI staining in the medial part of the spinal trigeminal nucleus and in the middle and lower part of the dorsal medulla. it's just a very weak staining seen with BNPI in the ventral medulla. Is DNPI abundant in the gray matter of the medulla. DNPI staining overlaps with the BNPI staining in the inner spinal nucleus V. It should be noted that BNPI also in the upper spinal trigeminal nucleus, which is equal to the spinal substantia gelatinosa. DNPI staining is in Areas weaker in which BNPI is present, weaker than in Areas where BNPI is low or absent. There are a few BNPI points seen in the ventral Gray Motor area.

Example 2e to Fig. 7

Complementary differential distribution of DNPI and BNPI immunoreactivity in 2 subsequent sections of the rat brain in pain-relevant brain regions such as sensory parietal cortex; cingular cortex, thalamus, corpus amygdaloideum as well as hypothalamus. DNPI is concentrated in the cortex in the granular sensory layers, especially in Lamina IV; BNPI is abundant in the cortex but weaker in the Lamina IV than in other Laminae. In the cingulate cortex (C vs D as a high magnification), the distribution of DNPI and BNPI is mutually complementary or reciprocal in the density of the respective synapses. DNPI clearly outweighs BNPI in the thalamus, BNPI is sparse in the hypothalamus, DNPI is abundant. Abundant BNPI overpowers in the hypocampus over sparse DNPI with mutually complementary distribution.
Thalamus = Th,
Amygdala = Amyg.
Hippocampus = hip,
Cingular Cortex = Cg,
Hypothalamus = hy,
parietal cortex = PC.

Example 2f of Fig. 8

Complementary differential distribution of DNPI and BNPI Immunoreactivity in pain-relevant brain regions such as the cingular cortex (Cg) and tectum as well as dorsal periaqueductal gray. DNPI dominance in tectum and dorsal gray. Follow-up sections of a rat brain through the upper mesencephalon.

Example 2g for Fig. 9

Complementary differential distribution of DNPI and BNPI Immunoreactivity in pain-relevant brain regions such as Tectum (T) as well periaqueductal gray (PAG). DNPI dominance in the tectum and dorsal Gray. Note the differential distribution of DNPI and BNPI in the body Medial geniculate (cgm) of the auditory canal. Follow-up sections of a rat brain through the upper mesencephalon; Level colliculus superior.

Example 2h for Fig. 10

Abundance of DNPI over BNPI in the habenulae (Hb). DNPI is present in the entire habenular complex (low magnification, upper picture; high magnification, middle figure). BNPI is only in the media Habular core (mHb lower figure, follow-up section to the middle figure).

In the following examples 21 to 2q and the associated Fig. 11-19 the term VGLUT1 for BNPI and VGLUT2 for DNPI is used. The terms are each completely synonymous, completely identical in content and relate to the same subject, i.e. VGLUT1 = BNPI and VGLUT2 = DNPI. "preabs" means pre-absorption with VGLUT1 or VGLUT2 fusion protein before immunostaining.

Example 2i for Fig. 11

This is a comparison between VGLUT1 and VGLUT2 regarding the Distribution and specificity in the lumbar spinal cord over the Immunoreactivity.

The adjacent sections A-D are alternating with anti-VGLUT2 (A), anti-VGLUT2, pre-absorbed with VGLUT2 fusion protein (B), anti-VGLUT1 (C) and anti-VGLUT1, pre-absorbed with VGLUT1 fusion protein (D) colored. The immunoreactions in (A) and (C) are complete with homologous recombinant fusion protein pre-absorbed (B) and (D) what shows the specificity of the immune response. Note the differential Distribution pattern in the superficial and deep dorsal horn (A; C). Punctiform immunostaining for VGLUT2 is in the superficial dorsal horn recognizable (arrows in A indicate lamina 1 and substantia gelatinosa) where the immunoreactivity with VGLUT1 is minimal (arrows in C). Note also the accumulation of more positive point-like VGLUT1 in the deep dorsal horn, where VGLUT2 is relatively weak. VGLUT2 is present in the lateral spinal nucleus (LSN; arrows in A), where VGLUT1 is only slightly represented (arrows in C) .VGLUT2 is strong in Lamina X around the central channel around where VGLUT1 is rare. The immunostaining of VGLUT1 is weak to moderate in the lateral ventral horn and very thin in the medial ventral horn. A fine punctiform VGLUT2 Staining is dense and abundant in the Ventralhorn (VH).

Example 2j to Fig. 12

This is a comparison between VGLUT1 and VGLUT2 regarding the Distribution in the forebrain (1).

Pairs of low-power and high-power micrographs of two Adjacent frontal sections are alternatively for VGLUT2 (A-D, I, K, M) and VGLUT1 (E-H, J, L, N) colored. This shows the clear difference and the partial mutual exclusivity in distribution, density and Intensity of VGLUT1 and VGLUT2 immunoreactivity (ir) in selected cortical, hippocampal, diencephalic and limbic areas.

Hypothalamus and Thalamus (A, E)

Pointed VGLUT2-ir is relative strongly across the hypothalamus and thalamus, where VGLUT-2 is a limited distribution to the hypothalamic, ventral premammillary nucleus (PMV) and on parts of the thalamic nucleus including the posterior thalamic nucleus (LP), the dorsal lateral geniculate nucleus (DLG) and the ventral posteromedial thalamic nucleus (VPM) shows. Olivar Prctal Nucleus (OPT); dorsal anterior pretectal nucleus (APTD); precommisural nucleus (PRC).

Cortex (A; E; I; J: K; L; M: N)

The VGLUT2 staining is in one band of the neocortex containing Lamina IV moderate. It is weak in one neocortical band contain Lamina VI and minimal in the others neocortical layers. Intense point VGLUT1-ir is very strong in the entire cortex, including the pririform cortex (pir) and something less pronounced in the neocortical band of Lamina VI, where moderate VCGLUT2 staining accumulated. Note the mutual Exclusion of VGLUT1 and VGLUT2 staining in the layers of the retrospenial granular cortex (RSG in A and E) that in strong Magnification can be shown in (I) and (J). The big enlargements M and N from the Lamina IV in K and L show different densities of the punctiform VGLUT1- and VGLUT2-ir in comparison between immunonegative neuronal cell bodies and processes.

Hippocampus (A, E; B-D, F-H)

Thin VGLUT2-ir points are mostly limited to the granular layers (g) of the dentate gyrus (DG) and the pyramidal layer (p) of the fields CA1, CA2 and CA3 of the Hippocampus. Dense V-GLUT1-ir points are very strong above that entire hippocampus with the exception of the granular (g) and pyramidal (p) cell layers. Marked with rectangles Sections in A and corresponding sections on adjacent ones Sections in E are magnified in B-D and F-H shown. the differential distribution and density of the VGLUT1-ir and VGLUT2-ir in the Oriens layer (o), pyramidal layer (p), in the stratum radiatum (r) and the stratum lacunosum molecular (I) of CA1 (B, F) and CA3 (C, G) and in the molecular (m), granular (g) and polymorphic (p) layer of the dentate gyrus (DG) (D, H).

Amygdala Complex

There is some overlap here, however the differential density and intensity of immunostaining of VGLUT1-ir and VGLUT2-ir points in the posterior basomedial amygdaloid nucleus (BMP), in the lateral amygdaloid nucleus (La) and in the cortical amygdaloids nucleus (Co.) as well as in the adjacent dorsal endopiriform nucleus (DEn) is clearly visible.

It is further noted that "white matter" and fiber tracts VGLUT1- and VGLUT2 are negative (posterior commisure (pc), fornix (f), fasciculus retroflexus (fr), mammillothalamic tract (mt).

Example 2k to Fig. 13)

This is a comparison between VGLUT1 and VGLUT2 regarding the Distribution in the forebrain (2).

Pairs of low-power and high-power micrographs from two adjacent front sections are alternatively colored for VGLUT2 (AB, E, G) and VGLUT1 (CD, F, H). This shows the clear difference and the partial mutual exclusivity in the distribution, density and intensity of VGLUT1 and VGLUT2 immunoreactivity (ir) in the neocortex (Lamina IV, VI) Caudate Putamen (CPu), Globulus pallidum (GP), piriform cortex ( Pir), nucleus accumbens core (AcC), nucleus accumbens rim (AcSh), ventral pallidum (VP), olfactory tubercle (Tu), islands of Calleja (ICj), the ventral diagonal band (VDB) and the lateral septum (LS) , In the CPu, VGLUT1 is slightly less represented than VGLUT2. VGLUT2 is present in the globus pallidum (GP) (B), where VGLUT1 is almost completely absent (D). In the piriform Cortex (Pir) and the islands of Calleja (ICj) the punctiform VGLUT1-ir is stronger and denser than for VGLUT2-ir. Note the accumulation of weak to moderate VGLUT1-ir in the pyramidal cell layers in (E), where VGLUT2-ir is almost completely absent (F). Also note a certain overlap and reciprocity in the coloring of VGLUT1 and VGLUT2 in the ICj (G, H) as well as the absence of VGLUT1-ir and VGLUT2-ir in the commissural fiber tract / corpus callosum (cc (, anterior commissure (ac).
Bars in A, C = 1 mm, in B, D = 500 µm; in EH = 200 µm.

Example 2l to Fig. 14)

This is a comparison between VGLUT1 and VGLUT2 regarding the Distribution in the thalamic and hypothalamic nucleus.

Adjacent frontal sections (A, B) of the diencephalon show the nucleus-specific differential strong occurrences of VGLUT2 (A) and VGLUT1 (B) in the thalamus and hypothalamus. This is very important to note strong occurrence of VGLUT2-ir (A) in the paraventricular thalamic Nucleus (PVA), reunited thalamic nucleus (Re), reticular thalamic nucleus (Rt), paracentral thalamic nucleus (PC) and anterodorsal thalamic nucleus (AD). VGLUT1-ir (B) is almost missing here completely or occurs only in low concentration. VGLUT1 (B) occurs moderately in the posterior thalamic nucleus (PT), where VGLUT2 (A) is rare. VGLUT1 is almost completely absent in the stria medullaris (sm) where VGLUT2-ir is rare.

Adjacent frontal sections C, D of the diencephalon show the Frequency of VGLUT2 (C) in the anterior hypothalamic nucleus (AH) but the rarity in the paraventricular nucleus (PVN) and extreme Rarity of VGLUT1-ir in the anterior hypothalamic nucleus (AH) and complete absence in the PVN. Also note the presence of VGLUT1 (D) in contrast to the absence of CGLUT2 (C) in the ventromedial thalamic nucleus (VM) and the reuniens thalamic nucleus (Re).

Adjacent frontal sections of the hypothalamus (E, F) show the Frequency of VGLUT2 in the LH, in the ventromedial thalamic nucleus (VHM) and the dorsomedial thalamic nucleus (DM) and the Rarity of VGLUT1 in the core of the VMH but moderate occurrence in its edge. Note the weak coloring of VGLUT2 in the median eminence (ME). VGLUT1 and VGLUT2 are missing in the Fiber tracts of the Formix (f) and mammillothalamic tract (mt). Third ventricle (3V); Bar = 500 µm (for A-F).

Example 2m to Fig. 15)

This is a comparison between VGLUT1 and VGLUT2 regarding the Distribution in the epithalamus.

High-power micrographs from adjacent sections, alternatively stained for VGLUT2 (A) and VGLUT1 (B), show the abundance of VGLUT2 in both the medial hastular nucleus (MHb) and the lateral hastular nucleus (LHb). It should be noted that VGLUT1-ir is less dense in MHb than VGLUT2-ir. CGLUT1 is almost completely absent in LHb.
Bar = 100 µm (for A, B).

Example 2n to Fig. 16)

This is a comparison between VGLUT1, and tyrosine hydroxylase VGLUT2 regarding the distribution in the mesencephalon and metathalamus.

Low-power (A, C, E) and high-power micrographs (B, D, F) of three adjacent sections are colored alternately for tyrosine hydroxylase (TH), VGLUT2 and VGLUT1 and show the differential distribution, density and Intensity of immunostaining for VGLUT1 and VGLUT2 compared to TH. VGLUT2-ir points are concentrated in the tectum, with the highest amounts found in the superficial "gray" layer of the upper colliculus (SuG) and lower amounts in the intermediate "gray" layer of the upper colliculus (InG), while these in the optical nucleus layer of the upper colliculus (Op) are rare. VGLUT2-ir points are present in the entire tegmentum including the nucleus ruber (R) and the TH-positive pars compacta of substantia nigra (SNC) and are particularly enriched in dorsal periaqueductal gray (PAG) and especially in the medial terminal nucleus of the "accessory optic" tract "(MT), the optical access tract, as well as in the mediocaudal part of the lateral posterior nucleus (LPMC), in the posterior intralaminar thalamic nucleus (PIL) in the peripeduncular nucleus (PP) and in the suprageniculate thalamic nucleus (SG). VGKUT1-ir is minimal here. VGLUT 1 staining is seen in moderate amounts in the ventral medial geniculate nucleus (MGV), where VGLUT2 amounts are minimal. VGLUT1 is only minimally present in the entire tectum, the periaquaeductal gray and the tegmetum and is almost completely absent in the substantia nigra pars compacta (SNC) and the pars reticulais (SNR) weak VGLUT2 staining is present in the neuronal perikarya and puncta in the SNR (D, high-powered micrograph from the one marked by a rectangle in (C), where VGLUT1 is almost completely missing (corresponding in F)). Mesencephalic aqueduct (Aq.)
Bars in A, C, E = 1 mm; in B, D, F = 200 µm.

Example 2o to Fig. 17)

This is a comparison between VGLUT1 and VGLUT2 regarding the Distribution in the pontomedullary brain stem.

Low-power and high-power micrographs of two adjacent front sections are colored alternately for VGLUT2 (AD) and VGLUT1 (EH). This shows a large amount of punctiform VGLUT2 immunoreactivity (ir) (B, D) in the medial upper olive (MSO) where VGLUT1-ir is low (F, H). VGLUT2-ir is relatively weak in the nucleus of the trapezoid body (TZ) (BC), where VGLUT1-ir is present in large quantities (FG). It should be noted that clearly VGLUT1-positive confluent large dots enclose immunonegative neuronal cell bodies in the TC (G). Strong VGLUT1-ir points are in the central sensory nucleus of the trigeminal nerve (Pr5), where VGLUT2-ir is very low. Moderately positive VGLUT1 points are present in the motor trigeminal nucleus (Mo5) where VGLUT2-ir is low. VGLUT1-ir and VGLUT2-ir are represented in small amounts in the lateral medial parabrachial nucleus (LPB, MPB). Moderate VGLUT2-ir accumulates in the locus coerulus (LC), where VGLUT1-ir is very low. VGLUT1-ir and VGLUT2-ir are absent in the pyramidal tract (pyr). Adjacent sectors (I, J) alternately colored for VGLUT2 (I) and VGLUT1 (J) show a large amount of punctiform VGLUT1 immunoreactivity (ir) in the anterior ventral cochlear nucleus (VCA), where VGLUT2 is in principle completely absent. A high-power micrograph (K) from J shows strongly positive VGLUT-ir points that include immunonegative neuronal cell bodies and processes. VGLUT1-ir points are more numerous in the dorsal cochlear nucleus (DC) than VGLUT2-ir positive points.
Bars in A, E = 500 µm; in B, F, I, J = 200 µm; in C, D, G, H, K = 25 µm.

Example 2p to Fig. 18)

This is a comparison between VGLUT1 and VGLUT2 regarding the Distribution in the lower brain stem.

Low-power and high-power micrographs from two adjacent front sections are colored alternately for VGLUT2 (A, C, E, G) and VGLUT1 (B, D, F, H), show a moderate amount of small punctiform VGLUT2 immunoreactivity ( ir) in the superficial spinal trigeminal nucleus (Sp5), which is marked by arrows (A, G), where VGLUT1-ir is in principle completely absent (arrows in B, H). VGLUT2 is moderately present in the door motor motor nucleus of the vagus (10), hypoglossal nucleus (12), the reticular formation (Rt) and in the ventral part of the solitary tract (SoIV) (A, C, E,), where VGLUT1 in principle completely missing (B, D, F). VGLUT2-ir is very low in the dorsal solitary tract (SoID). Note the overweight VGLUT1 in deep Sp5 (B, F, H), in the cuneate (Cu) and in the delicate nucleus (GR), where VGLUT2-ir is low. Stars mark the central channel.
Bars in A, B = 500 µm; C, D = 200 µm, E, F = 100 µm; G, H = 100 µm.

Example 2q to Fig. 19)

This is a comparison between VGLUT1 and VGLUT2 regarding the Distribution in the cerebellum.

Low-power and high-power micrographs of two adjacent front sections, alternately colored for VGLUT2 (A, B) and VGLUT1 (C, D), show an extreme density of intensely colored VGLUT1-positive points in the molecular layer (m), very few VGLUT1 points around Somata of the Purkinje cell in the Purkinje cell layer (p) and dense glomeruli-like accumulation of strongly colored confluent VGLUT1 points in the granular layer (g). VGLUT2-ir points are much less dense in the molecular layer where they are arranged in a ribbon-like manner. VGLUT2-ir dots that form glomerular-like structures in the glomerular layer (g) are less dense than those that stain for VGLUT1.
Bars in A, C = 500 µm; in B, D = 100 µm.

Discussion and analysis of example 2 in general

The differential distribution of BNPI and DNPI in synapses of the primary afferent, spinal trigeminal and supraspinal system is one strong evidence for a selective influence of sensory functions by selective modulation of the DNPI or BNPI-mediated glutamate Transport.

The presence of BNPI and DNP in the DRG indicates the possibility peripheral neurogenic inflammation selectively through selective intervention on the DNPI or BNPI target. The presence in the DRG is indexed also an immunomodulatory role and corresponding targeting. A presence of BNPI and DNPI in the sensory vagus or Glossopharyngeus ganglion indicates the target for baroafference, Chemoafference, cardiovascular or cardiorespiratory function, including asthma, hypertension etc., as well as for emesis. It is interesting Distribution also for the gut-brain axis, i.e. regulation of saturation, "Inflammatory bowel disease" or Crohn 's disease as well as for Autoimmunity in the central or peripheral nervous system, autoimmune Diabetes, alcoholic neuropathy, alcohol-induced chronic Pancreatitis with neuroproliferation (Fink et al. With Weihe; Neuroscience). The distribution in the CNS and PNS alone makes these targets too interesting objects in the rest of the above Indications.

A crucial point was also that BNPI and DNPI in the afferent areas to the sensory areas of the eye and the What could be demonstrated in combination with the ear Other findings play an important role in vision disorders, retinitis pigmentosa, optic degeneration, cataract, retinal detachment, Retinal degeneration, glaucoma or nystagmus or hearing disorders, tinitus, M. Menière, sudden hearing loss, diseases of the hearing and / or Balance organ or diseases of the auditory or vesibular tract suggests.

It is also crucial that the distribution of VGLUT2 in most Regions of the brain and spinal cord complementary and mutually exclusive to the expression of VGLUT1. Together the two glutamate transporters could be used to ingest glutamate through synaptic vesicles of all central glutamatergic neurons to be responsible.

It was found here that the thalamic and brain stem relay Centers of the visual and statoacoustic path through differential VGLUT1 and VGLUT2 controlled signals are driven. Thalamic and Mesenephalic relay centers of the visual system like the superior colliculus and the dorsolateral geniculate nucleus and the medial terminal nucleus of the "accessory optic tract" optical systems are specifically VGLUT2 controlled, which suggests that the retinal ganglionic cells that make up the third neuron of the optical Represent sense, are at least partially coated with VGLUT2. In contrast, the brainstem get cochlear, and olivary trapezoidal the metathalamic medial geniculate relay center of the auditory path strong input from VGLUT1-coated glutamatergic synapses.

Different nuclei of the brainstem visual system receive one strong input from VGLUT2 synaptic points. Hence the Brainstem of the optical system exclusively through VGLUT2 glutamatergic synapses.

The following results and conclusions result from the Investigations: DNPI is a new marker for glutamatergic synaptic Vesicles, where there are 2 different types of neurons, or synapses gives. VGLUT1 and VGLUT2 show a differential distribution pattern.

Overall, the distribution of BNPI and DNPI in the CNS and PNS show that this has a role in the various already above indicated indications play for with the invention Medicinally effective methods applying to these targets Connections are searched.

Example 3 Carrying out the screening process with measurement of the binding on the displacement of a radiolabeled ligand

A nucleic acid segment that codes for BNPI is in a Expression vector cloned, which is a constitutive expression (e.g. CMV- Promoter) or an inducible expression in eukaryotic cells allowed. The DNA is extracted using a suitable transfection method, e.g. B. with Lipofectamine (Roche Diagnostics) in eukaryotic cells (e.g. CHO- Cells, HEK293 cells or NIH-3T3 cells). The cells are in the presence of a selection reagent (e.g. Zeocin, Hygromycin or Neomycin) cultivated so that only the cells that survive have taken up the DNA construct, and in the long-term Selection, also incorporated into the genome.

From these cells, membrane fractions are obtained that BNPI contained in large quantities and used for a binding assay can be. This consists of 1.) containing the BNPI Membranes 2.) a radiolabelled ligand 3.) a Binding buffer (e.g. 50 mM HEPES pH 7.4, 1 mM EDTA) and that Binding to be examined ligands. After incubating the above mentioned reaction mixtures (for z. B. 30-60 min) at a suitable The temperature (mostly room temperature) becomes the unbound filtered off radioactive ligand molecules. The remaining amount of bound Ligand is added after adding a scintillation cocktail in a β- Counter (e.g. Trilux, Wallac) measured. Shows the test substance one Binding to BMPI, this is called reduced radioactive incorporation detected. This method is suitably miniaturized in such a way that it can be carried out in (96-, 384- or 1536-well) microtiter plates can to this method using a robot in the so-called Perform high-throughput screening (HTS) procedures.

Example 4 Carrying out the screening method according to the invention with BNPI and measurement of those changed by the binding of the substance functional parameters

A nucleic acid segment which codes for BNPI is cloned in an expression vector which has an inducible expression in prokaryotes such as e.g. BE coli allowed. Here, the nucleic acid section is modified so that it is expressed as a fusion protein with an additional N- or C-terminal amino acid sequence. This sequence should allow purification via a specific procedure, with unchanged function of the BNPI, e.g. B. Glutathione S-transferase fragment, which allows isolation from the protein mixture by binding to glutathione. After transfection of the bacteria, induction of the gene (e.g. with IPTG in the Iac promoter) and disruption of the bacteria, the fusion proteins are purified and used in an in vitro kinase experiment. Here 5 µg protein at 30 ° C for 30 minutes in 50 µl kinase buffer (20 mM PIPES, pH 7.0, 5 mM MnCl ₂ , 7 mM β-mercaptoethanol, 0.4 mM spermine, 10 mM rATP) supplemented with 10 µCi [γ ³² P] ATP. Purified histone H1 protein (Sigma) or bacterially expressed GST-NFATc1 fusion protein are added as substrates. After the incubation period, the unincorporated [γ- ³² P] ATP is filtered off and the amount of ³² phosphate incorporated is determined by β-scintillation (Trilux, Wallac). In an experiment to detect new BNPI inhibitors, the test substances are also incubated in this approach and a decrease in the ³² P incorporation is used as an indicator for an inhibitor. This method is suitably miniaturized so that it can be carried out in (96-, 384- or 1536-well) microtiter plates in order to carry out this method by means of a robot in the so-called high-throughput screening (HTS) method.

Example 5 Carrying out the screening method according to the invention with DNPI and measurement of those changed by the binding of the substance functional parameters

The process is carried out as described in Example 4 with the Exception that instead of a nucleic acid section which codes for BNPI, a Nucleic acid section was used, which codes for DNPI.

Example 6 Example of a medicine for tinitus treatment containing one Compound tablet formulation according to the invention

Tablets can be produced by directly compressing mixtures of the compound according to the invention with corresponding auxiliaries or by compressing compound-containing granules (with optionally other auxiliaries). The granules can either by wet granulation with z. B. aqueous granulating liquids and subsequent drying of these granules or by dry granulation z. B. be produced by compacting. direct compression z. B. per tablet: 25 mg compound of the invention 271 mg LudipressTM (granules for direct tableting from lactose monohydrate, povidone K30 and crospovidone) 4 mg magnesium stearate 300 mg total

Prepare a homogeneous mixture of the active ingredient with the excipients and compress them on a tablet press to tablets with a ∅ of 10 mm. dry granulation z. B. per tablet: 25 mg compound of the invention 166 mg Microcrystalline cellulose 80 mg Low substituted hydroxypropyl cellulose (I-HPC LH 11 ™) 5 mg Highly disperse silicon dioxide 4 mg magnesium stearate 280 mg total

Prepare a homogeneous mixture of the compound with the microcrystalline cellulose and the I-HPC and compact them. After sieving the compressed material, the resulting granulate is mixed with magnesium stearate and silicon dioxide and compressed to tablets with a Tabletten of 9 mm on a tablet press. wet granulation z. B. per tablet 25 mg compound of the invention 205 mg Microcrystalline cellulose 6 mg Povidon K30 10 mg crospovidone 4 mg magnesium stearate 250 mg total

Homogeneous mixture of the compound with the microcrystalline Produce cellulose and the crospovidone and these in one Granulate the granulator with an aqueous solution of the povidone. The moist granules are then re-granulated and re- drying in a drying cabinet (50 ° C.) for 10 h. The dry granules are combined with the magnesium stearate sieved, final mixed and made into tablets on a tablet press a ∅ of 8 mm.

Example 7 Example of a medicine for tinitus treatment containing one compound of the invention - parenteral solution

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Claims (21)

1. Process for the detection of pharmaceutically relevant substances with efficacy in the indications or for the treatment of
Visual disturbances, retinitis pigmentosa, optic degeneration, hearing disorders, tinitus, M. Meniere, sudden hearing loss, schizophrenia, mania, depression, stroke, brain trauma, paraplegia, amyotrophic lateral sclerosis, neuralgia, weight regulation, obesity, anorexia nervosa, epilepsy, choroidal stress, hemibalism , Parkinson's disease, TIA (transient ischemic attacks), emesis, especially hyperemesis, for example with chemotherapy, dizziness, in any form, cataract, arthritis, hyperactivity, developmental disorders, rabies, virus infections or bacterial infections, flu, malaria, Creutzfeld-Jacob, Inflammatory bowel disease, Crohn's disease, cardiovascular and cardiorespiratory dysfunction, hypertension, disorders of baroafference or chemoafference, toxoplasmosis, asthma, autoimmunity in the central and peripheral nervous system, diabetic neuropathy, autoimmune diabetes, alcoholic neuropathy, HIV-neuroids; Autonomic nervous system disorders, digestive tract nervous system disorders, hyperexcitability, especially glutamate-mediated hyperexcitability, neurodegeneration, especially in Alzheimer's disease, Alzheimer's disease, ischemia; Encephalitis especially viral or bacterial; Prion disease, Rasmussen encephalitis, HIV encephalitis, demyelination, particularly in the case of multiple sclerosis, retinal degeneration, glaucoma, nystagmus, retinal detachment, cerebellar disorders, cerebellar ataxia, disorders of the basal ganglia, diseases of the pallidum, disorders of the hearing organ and / or balance Auditory or vesibular tract, memory disorders, learning disorders, cognitive disorders, Stiff-Man syndrome, restless leg syndrome, anxiety, phobias, sleep disorders; Drug addiction, addiction and withdrawal, especially with alcohol, nicotine, opiates, ecstasy or cocaine; Hepatoencephalopathy with alcohol intoxication, hepatoencephalopathy without alcohol intoxication, neurotoxicological diseases, diseases of the spinal motor neurons, muscle atrophies, muscular dystrophies, diseases of the posterior tract, alcoholic neuropathies, neuroinflammation, sensory disorders with infections or fever, stress, taste disorders, Chinese food, food syndrome, food allergy Paranoia, concussion, neuroendocrine disorders, Tourrette syndrome, cerebrovascular spasms, neuronal apoptosis, neurodegeneration, neuronal necrosis, astrocytosis, burn-out syndrome, sudden infant death (sudden childhood death), heart attack, insomnia, retrograde amnesia, multiple Jet-lag, disorders of sexual function such as impotence or priapism or with effectiveness for promoting microglia activation, learning, cognition or memory, for neuroprotection, for CSF diagnosis of neurostatic diseases or he for adjuvant therapy by electrostimulation of the subthalamic nucleus in Parkinson's
with the following process steps: a) Incubation of a substance to be tested under suitable conditions with at least one biomolecule from Group I: the protein BNPI and / or DNPI and / or a protein according to one of Figs. 1b), 1d), 1f), 2b) or 2d) and / or a protein which is at least 90% similar to one of the abovementioned proteins and / or a protein for which a polynucleotide according to one of Figs. 1a), 1c), 1e), 2a) or 2c) or at least 90% of this encoded a similar polynucleotide, and / or a protein which is encoded by a nucleic acid which, under stringent conditions, binds to a polynucleotide according to one of Figs. 1a), 1c), 1e), 2a) or 2c) or its antisense polynucleotides, or an at least 10, preferably at least 15, in particular at least 20 amino acids long partial protein of one of the aforementioned proteins and / or a cell and / or a preparation from such a cell, the at least one of the aforementioned proteins and partial proteins, or biomolecules, synthesized b) measurement of the binding of the test substance to the protein (s) and / or partial protein (s) synthesized by the cell or measurement of at least one of the by the binding of the test substance to the protein (s) and / or partial protein / s, or Biomolecule (s) changed functional parameters. 2. The method according to claim 1, characterized in that the Cell is genetically manipulated before step (a). 3. The method according to claim 2, characterized in that the genetic engineering manipulation measuring at least one of the the test substance allows changed functional parameters. 4. The method according to claim 3, characterized in that by the genetic engineering manipulation is not endogenous in the cell expressed form of a G protein or a reporter gene is introduced. 5. The method according to any one of claims 2-4, characterized in that the cell is genetically manipulated so that the cell at least one polynucleotide according to one of Fig. 1a), 1c), 1e), 2a) or 2c) or one contains at least 90%, preferably at least 95%, in particular at least 97% similar polynucleotide. 6. The method according to claim 5, characterized in that the Polynucleotide is contained in a recombinant DNA construct. 7. The method according to any one of claims 2 to 6, characterized characterized in that the cell after genetic engineering according to claim 2 and before step (a) according to claim 1 below Conditions that allow expression is cultivated, possibly under selection pressure. 8. The method according to any one of claims 1 to 7, characterized characterized in that the cell is an amphibian cell, bacterial cell, Yeast cell, insect cell or an immortalized or native Is mammalian cell. 9. The method according to any one of claims 1 to 8, characterized characterized that the measurement of the binding via displacement a known labeled ligand of the partial protein and / or Protein and / or the activity bound to it marked test substance. 10. The method according to any one of claims 1 to 8, characterized in that the measurement of at least one of the functional parameters changed by the test substance takes place by measuring the regulation, inhibition and / or activation of receptors, ion channels and / or enzymes, in particular by measuring the alteration of gene expression, the ion milieu, the pH or the membrane potential, the 2 ^nd messenger via alteration of the enzyme activity or concentration. 11. The method according to any one of claims 1 to 10, in which a first method according to one of claims 1 to 10 is coupled with a second method according to one of claims 1 to 10 such that the measured values and results of the first method with respect to those to be measured Substance are compared with the measured values and results of the second method with respect to the substance to be measured, characterized in that in one of the two methods, hereinafter referred to as the main method, in step (a) the substance to be tested
either
with a biomolecule from group II: the protein BNPI and / or a protein according to one of Figs. 1b), 1d) or 1f) and / or a protein and / or a protein at least 90% similar to one of the aforementioned proteins and for which encodes a polynucleotide according to one of Figs. 1a), 1c) or 1e) or a polynucleotide at least 90% similar to it, and / or a protein which is encoded by a nucleic acid which is linked to a polynucleotide according to one of the Fig. 1a), 1c) or 1e) or their antisense binds polynucleotides, or an at least 10, preferably at least 15, in particular at least 20 amino acids long partial protein of one of the aforementioned proteins and / or a cell and / or a preparation from such a cell, which has synthesized at least one of the aforementioned proteins and / or partial proteins,
or
with a biomolecule from group III: the protein DNPI and / or a protein according to one of Fig. 2b) or 2d) and / or a protein at least 90% similar to one of these proteins and / or a protein for which a polynucleotide encoded according to one of Fig. 2a) or 2c) or a polynucleotide at least 90% similar to it, and / or a protein which is encoded by a nucleic acid which, under stringent conditions, is linked to a polynucleotide according to one of Fig. 2a) or 2c ) or their antisense binds polynucleotides, or a partial protein of at least 10, preferably at least 15, in particular at least 20 amino acids long, of one of the aforementioned proteins and / or a cell and / or a preparation from such a cell which contains at least one of the aforementioned proteins and / or Has synthesized partial proteins, is incubated,
and
that in the other of the two methods, hereinafter referred to as secondary method, in step (a) the substance to be tested is incubated with a biomolecule from group I or with a biomolecule from the group selected from group II and group III from which the biomolecule, with which the substance is incubated in the main procedure is not selected. 12. The method according to any one of claims 1 to 11, characterized in that the substances to be found are selected from:
Substances with efficacy in the indications or for the treatment of visual disorders, retinitis pigmentosa, optic degeneration, hearing disorders, tinitus, Menière's disease, sudden hearing loss, amyotrophic lateral sclerosis, neuralgia, weight regulation, obesity, Parkinson's disease, cataract, virus infections or bacterial infections, diabetic neuropathy , autoimmune diabetes, alcoholic neuropathy, HIV neuro-AIDS; Retinal degeneration, glaucoma, nystagmus, retinal detachment, diseases of the auditory and / or balance organ, diseases of the auditory or vesibular tract, sleep disorders, drug addiction, addiction and withdrawal, in particular with alcohol, nicotine, opiates, ecstasy or cocaine; Neuroinflammation, Insomnia, for adjuvant therapy by electrostimulation of the subthalamic nucleus in Parkinson's
preferably
Substances with efficacy in the indications or for the treatment of vision disorders, retinitis pigmentosa, optic degeneration, hearing disorders, tinitus, Menière's disease, sudden hearing loss, amyotrophic lateral sclerosis, weight regulation, obesity, cataracts, virus infections or bacterial infections, retinal degeneration, glaucoma, nystagmus, retinal detachment , Diseases of the auditory and / or balance organ, diseases of the auditory or vesibular tract, drug addiction, addiction and withdrawal, particularly in the case of alcohol, nicotine, opiates, ecstasy or cocaine; neuroinflammation
in particular
Substances with efficacy in the indications or for the treatment of visual disturbances, retinitis pigmentosa, optic degeneration, cataract, retinal detachment, retinal degeneration, glaucoma or nystagmus
and or
Hearing disorders, tinitus, Meniere's disease, sudden hearing loss, diseases of the hearing and / or balance organ or diseases of the auditory or vesibular tract. 13. Connection identifiable by a method according to one of the Claims 1 to 12 as a pharmaceutically relevant substance Efficacy in at least one of the indications according to claim 1 or 12. 14. A compound according to claim 13, characterized in that it is a low molecular weight compound. 15. Use a) a polynucleotide, preferably a DNA or RNA, coding for BNPI or DNPI or a polynucleotide, preferably a DNA or RNA, which is one of the in Fig. 1a), 1c), 1e), 2a), 2c) or 2e ) the nucleotide sequences shown correspond to at least 90%, preferably to at least 95%, in particular to at least 97% or exactly, b) a polynucleotide, in particular an antisense polynucleotide or a PNA, preferably a DNA enzyme or ribozyme, a ribozyme or other DNA enzyme or a catalytic RNA or DNA, which has a nucleotide sequence which is capable of specifically bind one of the polynucleotides listed under point a), c) a vector containing a polynucleotide according to one of the items a) or b), in particular an expression vector and / or in particular derived from a virus, for example the adenovirus, adeno-associated virus or herpes virus and / or in particular containing at least one LTR, poly A , Promoter and / or ORI sequence, d) BNPI and / or DNPI and / or a protein according to one of Figs. 1b), 1d), 1f), 2b) or 2d) and / or one of these proteins to at least 90%, preferably at least 95% , in particular at least 97% similar protein and / or a protein for which a polynucleotide according to one of Figs. 1a), 1c), 1e), 2a) or 2c) or at least 90%, preferably at least 95%, in particular encodes at least 97% similar polynucleotide, and / or a protein which is encoded by a nucleic acid which, under stringent conditions, is attached to a polynucleotide according to one of FIGS. 1a), 1c), 1e), 2a) or 2c) or its antisense polynucleotide binds or one of at least 10, preferably at least 15, in particular at least 20 amino acids long partial protein of one of the aforementioned proteins, the protein or partial protein optionally being post-translationally modified, in particular glycosylated, phosphorylated, amidated, methylated, acetylated, ADP-ribosylated, hydroxylated, provided with a membrane anchor, split or shortened, e) an antibody, preferably a monoclonal or polyclonal antibody, against one of the proteins or partial proteins according to point d), f) a cell, preferably an amphibian cell, bacterial cell, yeast cell, insect cell or an immortalized or native mammalian cell, containing a polynucleotide according to one of points a) or b), a vector according to point c), a protein or partial protein according to point d) or an antibody according to point e) g) a compound according to any one of claims 13 or 14 and / or h) an active ingredient, preferably a low molecular weight active ingredient, which binds to a protein or partial protein according to point d), for the manufacture of a medicament for the treatment of
Visual disturbances, retinitis pigmentosa, optic degeneration, hearing disorders, tinitus, M. Meniere, sudden hearing loss, schizophrenia, mania, depression, stroke, brain trauma, paraplegia, amyotrophic lateral sclerosis, neuralgia, weight regulation, obesity, anorexia nervosa, epilepsy, choroidal stress, hemibalism , Parkinson's disease, TIA (transient ischemic attacks), emesis, especially hyperemesis, for example with chemotherapy, dizziness, in any form, cataract, arthritis, hyperactivity, developmental disorders, rabies, virus infections or bacterial infections, flu, malaria, Creutzfeld-Jacob, Inflammatory bowel disease, Crohn's disease, cardiovascular and cardiorespiratory dysfunction, hypertension, disorders of baroafference or chemoafference, toxoplasmosis, asthma, autoimmunity in the central and peripheral nervous system, diabetic neuropathy, autoimmune diabetes, alcoholic neuropathy, HIV-neuroids; Autonomic nervous system disorders, digestive tract nervous system disorders, hyperexcitability, especially glutamate-mediated hyperexcitability, neurodegeneration, especially in Alzheimer's disease, Alzheimer's disease, ischemia; Encephalitis especially viral or bacterial; Prion disease, Rasmussen encephalitis, HIV encephalitis, demyelination, particularly in the case of multiple sclerosis, retinal degeneration, glaucoma, nystagmus, retinal detachment, cerebellar diseases, cerebellar ataxia, diseases of the basal ganglia, diseases of the pallidum, diseases of the hearing organ and / or balance Auditory or vesibular tract, memory disorders, learning disorders, cognitive disorders, Stiff-Man syndrome, restless leg syndrome, anxiety, phobias, sleep disorders; Drug addiction, addiction and withdrawal, especially with alcohol, nicotine, opiates, ecstasy or cocaine; Hepatoencephalopathy with alcohol intoxication, hepatoencephalopathy without alcohol intoxication, neurotoxicological diseases, diseases of the spinal motor neurons, muscle atrophies, muscular dystrophies, diseases of the posterior tract, alcoholic neuropathies, neuroinflammation, disorders of the well-being with infections or fever, stress, taste disorders, Chinese food, food syndrome, food allergy Paranoia, concussion, neuroendocrine disorders, Tourrette syndrome, cerebrovascular spasms, neuronal apoptosis, neurodegeneration, neuronal necrosis, astrocytosis, burn-out syndrome, sudden infant death (sudden childhood death), heart attack, insomnia, retrograde amnesia, multiple Jet-lag, disorders of sexual function such as impotence or priapism or with effectiveness for promoting microglia activation, learning, cognition or memory, for neuroprotection, for CSF diagnosis of neurostatic diseases or he for adjuvant therapy by electrostimulation of the subthalamic nucleus in Parkinson's. 16. Use a) a polynucleotide, preferably a DNA or RNA, coding for BNPI or DNPI or a polynucleotide, preferably a DNA or RNA, which is one of the in Fig. 1a), 1c), 1e), 2a), 2c) or 2e ) corresponds to at least 90%, preferably at least 95%, in particular at least 97% of the nucleotide sequences shown, b) a polynucleotide, in particular an antisense polynucleotide or a PNA, preferably a DNA enzyme or ribozyme, a ribozyme or other DNA enzyme or a catalytic RNA or DNA, which has a nucleotide sequence which is capable of specifically bind one of the polynucleotides listed under point a), c) a vector containing a polynucleotide according to one of the items a) or b), in particular an expression vector and / or in particular derived from a virus, for example the adenovirus, adeno-associated virus or herpes virus and / or in particular containing at least one LTR, poly A , Promoter and / or ORI sequence, d) a cell, preferably an amphibian cell, bacterial cell, yeast cell, insect cell or an immortalized or native mammalian cell, containing a polynucleotide according to one of items a) or b) or a vector according to item c) for the manufacture of a medicament for use in gene therapy. 17. Use according to claim 16, characterized in that it is in vivo or in vitro gene therapy. 18. Use according to any one of claims 16 or 17, characterized in that it is a drug with effectiveness in the indication or for the treatment of
Visual disturbances, retinitis pigmentosa, optic degeneration, hearing disorders, tinitus, M. Meniere, sudden hearing loss, schizophrenia, mania, depression, stroke, brain trauma, paraplegia, amyotrophic lateral sclerosis, neuralgia, weight regulation, obesity, anorexia nervosa, epilepsy, choroidal stress, hemibalism , Parkinson's disease, TIA (transient ischemic attacks), emesis, especially hyperemesis, for example with chemotherapy, dizziness, in any form, cataract, arthritis, hyperactivity, developmental disorders, rabies, virus infections or bacterial infections, flu, malaria, Creutzfeld-Jacob, Inflammatory bowel disease, Crohn's disease, cardiovascular and cardiorespiratory dysfunction, hypertension, disorders of baroafference or chemoafference, toxoplasmosis, asthma, autoimmunity in the central and peripheral nervous system, diabetic neuropathy, autoimmune diabetes, alcoholic neuropathy, HIV-neuroids; Autonomic nervous system disorders, digestive tract nervous system disorders, hyperexcitability, especially glutamate-mediated hyperexcitability, neurodegeneration, especially in Alzheimer's disease, Alzheimer's disease, ischemia; Encephalitis especially viral or bacterial; Prion disease, Rasmussen encephalitis, HIV encephalitis, demyelination, particularly in the case of multiple sclerosis, retinal degeneration, glaucoma, nystagmus, retinal detachment, cerebellar disorders, cerebellar ataxia, disorders of the basal ganglia, diseases of the pallidum, disorders of the hearing organ and / or balance Auditory or vesibular tract, memory disorders, learning disorders, cognitive disorders, Stiff-Man syndrome, restless leg syndrome, anxiety, phobias, sleep disorders; Drug addiction, addiction and withdrawal, especially with alcohol, nicotine, opiates, ecstasy or cocaine; Hepatoencephalopathy with alcohol intoxication, hepatoencephalopathy without alcohol intoxication, neurotoxicological diseases, diseases of the spinal motor neurons, muscle atrophies, muscular dystrophies, diseases of the posterior tract, alcoholic neuropathies, neuroinflammation, sensory disorders with infections or fever, stress, taste disorders, Chinese food, food syndrome, food allergy Paranoia, concussion, neuroendocrine disorders, Tourrette syndrome, cerebrovascular spasms, neuronal apoptosis, neurodegeneration, neuronal necrosis, astrocytosis, burn-out syndrome, sudden infant death (sudden childhood death), heart attack, insomnia, retrograde amnesia, multiple Jet-lag, disorders of sexual function such as impotence or priapism or with effectiveness for promoting microglia activation, learning, cognition or memory, for neuroprotection, for CSF diagnosis of neurostatic diseases or he for adjuvant therapy by electrostimulation of the subthalamic nucleus in Parkinson's
is. 19. Use a) a polynucleotide, preferably a DNA or RNA, coding for BNPI or DNPI or a polynucleotide, preferably a DNA or RNA, which is one of the in Fig. 1a), 1c), 1e), 2a), 2c) or 2e ) corresponds to at least 90%, preferably 95%, in particular at least 97% of the nucleotide sequences shown, b) a polynucleotide, in particular an antisense polynucleotide or a PNA, preferably a DNA enzyme or ribozyme, a ribozyme or other DNA enzyme or a catalytic RNA or DNA, which has a nucleotide sequence which is capable of specifically bind one of the polynucleotides listed under point a), c) a vector containing a polynucleotide according to one of the items a) or b), in particular an expression vector and / or in particular derived from a virus, for example the adenovirus, adeno-associated virus or herpes virus and / or in particular containing at least one LTR, poly A , Promoter and / or ORI sequence, d) BNPI and / or DNPI and / or a protein according to one of Figs. 1b), 1d), 1f), 2b) or 2d) and / or one of these proteins to at least 90%, preferably at least 95% , in particular at least 97% similar protein and / or a protein for which a polynucleotide according to one of Figs. 1a), 1c), 1e), 2a) or 2c) or at least 90%, preferably at least 95%, in particular encodes at least 97% similar polynucleotide, and / or a protein which is encoded by a nucleic acid which, under stringent conditions, is attached to a polynucleotide according to one of FIGS. 1a), 1c), 1e), 2a) or 2c) or its antisense polynucleotide binds or one of at least 10, preferably at least 15, in particular at least 20 amino acids long partial protein of one of the aforementioned proteins, the protein or partial protein optionally being post-translationally modified, in particular glycosylated, phosphorylated, amidated, methylated, acetylated, ADP-ribosylated, hydroxylated, provided with a membrane anchor, split or shortened, e) an antibody, preferably a monoclonal or polyclonal antibody, against one of the proteins or partial proteins according to point d), f) a cell, preferably an amphibian cell, bacterial cell, yeast cell, insect cell or an immortalized or native mammalian cell, containing a polynucleotide according to one of points a) or b), a vector according to point c), a protein or partial protein according to point d) or an antibody according to point e), g) a compound according to any one of claims 13 or 14 and / or h) an active ingredient, preferably a low molecular weight active ingredient, which binds to a protein or partial protein according to point d), selected for the manufacture of a diagnostic agent for diagnosing a condition
Visual disturbances, retinitis pigmentosa, optic degeneration, hearing disorders, tinitus, M. Meniere, sudden hearing loss, schizophrenia, mania, depression, stroke, brain trauma, paraplegia, amyotrophic lateral sclerosis, neuralgia, weight regulation, obesity, anorexia nervosa, epilepsy, choroidal stress, hemibalism , Parkinson's disease, TIA (transient ischemic attacks), emesis, especially hyperemesis, for example with chemotherapy, dizziness, in any form, cataract, arthritis, hyperactivity, developmental disorders, rabies, virus infections or bacterial infections, flu, malaria, Creutzfeld-Jacob, Inflammatory bowel disease, Crohn's disease, cardiovascular and cardiorespiratory dysfunction, hypertension, disorders of baroafference or chemoafference, toxoplasmosis, asthma, autoimmunity in the central and peripheral nervous system, diabetic neuropathy, autoimmune diabetes, alcoholic neuropathy, HIV-neuroids; Autonomic nervous system disorders, digestive tract nervous system disorders, hyperexcitability, especially glutamate-mediated hyperexcitability, neurodegeneration, especially in Alzheimer's disease, Alzheimer's disease, ischemia; Encephalitis especially viral or bacterial; Prion disease, Rasmussen encephalitis, HIV encephalitis, demyelination, particularly in the case of multiple sclerosis, retinal degeneration, glaucoma, nystagmus, retinal detachment, cerebellar diseases, cerebellar ataxia, diseases of the basal ganglia, diseases of the pallidum, diseases of the hearing organ and / or balance Auditory or vesibular tract, memory disorders, learning disorders, cognitive disorders, Stiff-Man syndrome, restless leg syndrome, anxiety, phobias, sleep disorders; Drug addiction, addiction and withdrawal, especially with alcohol, nicotine, opiates, ecstasy or cocaine; Hepatoencephalopathy with alcohol intoxication, hepatoencephalopathy without alcohol intoxication, neurotoxicological diseases, diseases of the spinal motor neurons, muscle atrophies, muscular dystrophies, diseases of the posterior tract, alcoholic neuropathies, neuroinflammation, disorders of the well-being with infections or fever, stress, taste disorders, Chinese food, food syndrome, food allergy Paranoia, concussion, neuroendocrine disorders, Tourrette syndrome, cerebrovascular spasms, neuronal apoptosis, neurodegeneration, neuronal necrosis, astrocytosis, burn-out syndrome, sudden infant death (sudden childhood death), heart attack, insomnia, retrograde amnesia, multiple Jet lag, sexual dysfunction, such as impotence or priapism. 20. Use a) a polynucleotide, preferably a DNA or RNA, coding for BNPI or DNPI or a polynucleotide, preferably a DNA or RNA, which is one of the in Fig. 1a), 1c), 1e), 2a), 2c) or 2e ) corresponds to at least 90%, preferably 95%, in particular at least 97% of the nucleotide sequences shown, b) a polynucleotide, in particular an antisense polynucleotide or a PNA, preferably a DNA enzyme or ribozyme, a ribozyme or other DNA enzyme or a catalytic RNA or DNA, which has a nucleotide sequence which is capable of specifically bind one of the polynucleotides listed under point a), c) a vector containing a polynucleotide according to one of the items a) or b), in particular an expression vector and / or in particular derived from a virus, for example the adenovirus, adeno-associated virus or herpes virus and / or in particular containing at least one LTR, poly A , Promoter and / or ORI sequence, d) BNPI and / or DNPI and / or a protein according to one of Figs. 1b), 1d), 1f), 2b) or 2d) and / or one of these proteins to at least 90%, preferably at least 95% , in particular at least 97% similar protein and / or a protein for which a polynucleotide according to one of Figs. 1a), 1c), 1e), 2a) or 2c) or at least 90%, preferably at least 95%, in particular encodes at least 97% similar polynucleotide, and / or a protein which is encoded by a nucleic acid which, under stringent conditions, is attached to a polynucleotide according to one of FIGS. 1a), 1c), 1e), 2a) or 2c) or its antisense polynucleotide binds or one of at least 10, preferably at least 15, in particular at least 20 amino acids long partial protein of one of the aforementioned proteins, the protein or partial protein optionally being post-translationally modified, in particular glycosylated, phosphorylated, amidated, methylated, acetylated, ADP- ribosylated, hydroxylated, provided with a membrane anchor, split or shortened, e) an antibody, preferably a monoclonal or polyclonal antibody, against one of the proteins or partial proteins according to point d), f) a cell, preferably an amphibian cell, bacterial cell, yeast cell, insect cell or an immortalized or native mammalian cell, containing a polynucleotide according to one of points a) or b), a vector according to point c), a protein or partial protein according to point d) or an antibody according to point e) in a process for the detection of pharmaceutically relevant substances with efficacy in the indications or for the treatment of
Visual disturbances, retinitis pigmentosa, optic degeneration, hearing disorders, tinitus, M. Meniere, sudden hearing loss, schizophrenia, mania, depression, stroke, brain trauma, paraplegia, amyotrophic lateral sclerosis, neuralgia, weight regulation, obesity, anorexia nervosa, epilepsy, choroidal stress, hemibalism , Parkinson's disease, TIA (transient ischemic attacks), emesis, especially hyperemesis, for example with chemotherapy, dizziness, in any form, cataract, arthritis, hyperactivity, developmental disorders, rabies, virus infections or bacterial infections, flu, malaria, Creutzfeld-Jacob, Inflammatory bowel disease, Crohn's disease, cardiovascular and cardiorespiratory dysfunction, hypertension, disorders of baroafference or chemoafference, toxoplasmosis, asthma, autoimmunity in the central and peripheral nervous system, diabetic neuropathy, autoimmune diabetes, alcoholic neuropathy, HIV-neuroids; Autonomic nervous system disorders, digestive tract nervous system disorders, hyperexcitability, especially glutamate-mediated hyperexcitability, neurodegeneration, especially in Alzheimer's disease, Alzheimer's disease, ischemia; Encephalitis especially viral or bacterial; Prion disease, Rasmussen encephalitis, HIV encephalitis, demyelination, particularly in the case of multiple sclerosis, retinal degeneration, glaucoma, nystagmus, retinal detachment, cerebellar disorders, cerebellar ataxia, disorders of the basal ganglia, diseases of the pallidum, disorders of the hearing organ and / or balance Auditory or vesibular tract, memory disorders, learning disorders, cognitive disorders, Stiff-Man syndrome, restless leg syndrome, anxiety, phobias, sleep disorders; Drug addiction, addiction and withdrawal, especially with alcohol, nicotine, opiates, ecstasy or cocaine; Hepatoencephalopathy with alcohol intoxication, hepatoencephalopathy without alcohol intoxication, neurotoxicological diseases, diseases of the spinal motor neurons, muscle atrophies, muscular dystrophies, diseases of the posterior tract, alcoholic neuropathies, neuroinflammation, sensory disorders with infections or fever, stress, taste disorders, Chinese food, food syndrome, food allergy Paranoia, concussion, neuroendocrine disorders, Tourrette syndrome, cerebrovascular spasms, neuronal apoptosis, neurodegeneration, neuronal necrosis, astrocytosis, burn-out syndrome, sudden infant death (sudden childhood death), heart attack, insomnia, retrograde amnesia, multiple Jet-lag, disorders of sexual function such as impotence or priapism or with effectiveness for promoting microglia activation, learning, cognition or memory, for neuroprotection, for CSF diagnosis of neurostatic diseases or he for adjuvant therapy by electrostimulation of the subthalamic nucleus in Parkinson's. 21. Use according to one of claims 15, 18, 19 or 20, characterized in that the indication or the disease to be treated or diagnosed is selected from
Visual disturbances, retinitis pigmentosa, optic degeneration, hearing disorders, tinitus, M. Meniere, sudden hearing loss, amyotrophic lateral sclerosis, neuralgia, weight regulation, obesity, Parkinson's disease, cataracts, virus infections or bacterial infections, diabetic neuropathy, autoimmune diabetes, alcoholic neuropathy, HIV -AIDS; Retinal degeneration, glaucoma, nystagmus, retinal detachment, diseases of the auditory and / or balance organ, diseases of the auditory or vesibular tract, sleep disorders, drug addiction, addiction and withdrawal, in particular with alcohol, nicotine, opiates, ecstasy or cocaine; Neuroinflammation, Insomnia, for adjuvant therapy by electrostimulation of the subthalamic nucleus in Parkinson's
preferably
Visual disturbances, retinitis pigmentosa, optic degeneration, hearing disorders, tinitus, M. Meniere, sudden hearing loss, amyotrophic lateral sclerosis, weight regulation, obesity, cataract, viral infections or bacterial infections, retinal degeneration, glaucoma, nystagmus, retinal detachment, diseases of the hearing and / or balance organ Auditory or vesibular tract, drug addiction, addiction and withdrawal, particularly in the case of alcohol, nicotine, opiates, ecstasy or cocaine; neuroinflammation
in particular
Visual disturbances, retinitis pigmentosa, optic degeneration, cataract, retinal detachment, retinal degeneration, glaucoma or nystagmus
or
Hearing disorders, tinitus, Meniere's disease, sudden hearing loss, diseases of the hearing and / or balance organ or diseases of the auditory or vesibular tract.