WO2007048846A1 - Use of iron-chelating compounds, cyclic adenosine monophosphate-increasing compounds or combinations thereof for treating axonal lesions in the cns - Google Patents

Use of iron-chelating compounds, cyclic adenosine monophosphate-increasing compounds or combinations thereof for treating axonal lesions in the cns Download PDF

Info

Publication number
WO2007048846A1
WO2007048846A1 PCT/EP2006/067878 EP2006067878W WO2007048846A1 WO 2007048846 A1 WO2007048846 A1 WO 2007048846A1 EP 2006067878 W EP2006067878 W EP 2006067878W WO 2007048846 A1 WO2007048846 A1 WO 2007048846A1
Authority
WO
WIPO (PCT)
Prior art keywords
use according
compounds
iron
casev
lesion
Prior art date
Application number
PCT/EP2006/067878
Other languages
German (de)
French (fr)
Inventor
Hans Werner Müller
Original Assignee
Neuraxo Biopharmaceuticals Gmbh
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Neuraxo Biopharmaceuticals Gmbh filed Critical Neuraxo Biopharmaceuticals Gmbh
Publication of WO2007048846A1 publication Critical patent/WO2007048846A1/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/28—Bone marrow; Haematopoietic stem cells; Mesenchymal stem cells of any origin, e.g. adipose-derived stem cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/401—Proline; Derivatives thereof, e.g. captopril
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • the present invention relates to the use of cell implants and / or at least one pharmaceutically acceptable compound for
  • the technical problem underlying the invention was the increase in the likelihood of near complete axon regeneration following injury trauma.
  • the problem underlying the invention is solved by the
  • Iron chelators are typically compounds that can interact with iron in coordinative interactions. In particular, lone pairs of electrons in the compounds are used for this purpose.
  • the use according to the invention protects the otherwise declining by apoptotic processes neurons and thus increases the probability Near-complete axon regeneration because only living neurons can regenerate their axon.
  • axonal lesions can be treated which are caused by traumatic effects, in particular by pinching and / or severing of axons, and / or inflammatory processes, in particular those occurring in the course of neuro-degenerative processes.
  • iron chelating compound N-oxaloglycine; Zn salts; Pyridine derivatives, such as 5-Arylcarbonylamino- or 5-Arylcarbamoylderivate, 2-carboxylate, 2,5 dicarboxylates, their ethyl esters or
  • compounds which promote axon growth can be used those which are neuronal growth and / or the expression of growth-promoting proteins such as neurotrophic factors, fibroblast growth factors, chemokines such as SDF-I, neural cells
  • Adhesion molecules such as Ll (NILE) stimulate growth-associated proteins such as GAP43 and anti-apoptotic proteins such as bcl-2.
  • According to the invention can be used as inhibitors of the intracellular Rho signal pathway z.
  • Activated macrophages Activated macrophages, OEC (olfactory ensheathing cells), adult or embryonic stem cells.
  • the application of the substance (s) to be used according to the invention is typically carried out locally in the injury or damage region in the nervous system, in the case of the soluble substances, in particular also by delayed release.
  • the iron chelating compound and / or CASEV and / or axon growth promoting compounds and / or inhibitors of the intracellular Rho signaling pathway are administered in therapeutically effective amounts, such as 1 ng / kg to 1 mg / kg body weight.
  • therapeutically effective amounts such as 1 ng / kg to 1 mg / kg body weight.
  • FIG. 1 shows a retrograde fluoro-gold marker of pyramidal neurons in the sensorimotor cortex of the rat brain.
  • FIG. 2 shows the neuroprotective long-term effect on primary motor neurons in the rat brain by local application of the iron chelator BPY-DCA and / or cAMP (8Br-cAMP) in the injured spinal cord.
  • Cerebral sections Hydroxystilbamidine (FluoroGold) is a suitable axonal tracer for the retrograde labeling of primary motor neurons in the sensorimotor cortex of the rat.
  • Th7 Th7 injected into the spinal cord.
  • FIG. 1 shows the retrograde fluoro gold labeling of pyramidal neurons in a section preparation (20 ⁇ m) from the sensorimotor cortex (layer V) of the rat brain (sham control).
  • PFA Paraformaldehyde
  • Retrograde axonal tracing of cerebral projection neurons under different treatment conditions after spinal cord injury Retrograde axonal tracing of cerebral projection neurons under different treatment conditions after spinal cord injury.
  • Testparameter Presentation of surviving cortical neurons by retrograde
  • Lesion type wire-knife lesion of the spinal cord at the height of the thoracic segment Th8 Animal groups: sham, lesion without treatment (control with injection of a buffer solution), lesion with RPT treatment Time points: 1 week, 4 weeks Tracer: FluoroGold (retrograde) Standard ("Scouten" wire knife) lesion
  • Animal groups (a) sham, (b) buffer lesion control, (c) lesion with iron chelator (BPY-DCA), (d) lesion with cAMP (8Br-cAMP) and (e) lesion with iron chelator plus cAMP (RPT).
  • BPY-DCA lesion with iron chelator
  • cAMP lesion with cAMP
  • RPT lesion with iron chelator plus cAMP
  • Coronal sections were obtained over the coordinate range of Bregma +0.9 to -2.1. Each 10th scan was photographed by fluorescence microscopic observation and retrograde labeled cortical neurons were counted in both hemispheres. 16 Sections (32 hemispheres) of 3 animals per test condition were counted and statistically evaluated (see evaluation in the annex).
  • FIG. 2 shows, by way of example, the different densities of retrogradely marked pyramidal neurons in the sensorimotor cortex in the intact animal
  • FIG. 2A sham control
  • FIG. 2B lesion control
  • FIG. 2C Local application of BPY-DCA and / or 8Br-cAMP to the spinal cord has a neuroprotective effect on cortical pyramidal neurons of layer V in the sensorimotor cortex
  • the lesion control with Tris buffer shows a clearly recognizable decrease of labeled pyramidal neurons in layer V four weeks after spinal cord injury
  • the retrograde labeling of the cortical pyramidal neurones in cell layer V with fluoro gold gives a very reliable, defined, homogeneous and highly reproducible marking of the sensorimotor brain region in all the animals examined.
  • the brain area of the retrograde labeled neurons extends over approximately 4.4 mm in rostrocaudaler Alignment and is distributed symmetrically over both Hemispheren.
  • the marked cell layer appears as a strip with a height of approx. 0.5 mm and a medio-lateral width of 0.8 to 2 mm, depending on the rostrocaudal distance from the bregma.
  • the lesion-related cell losses are after 4 weeks in one

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Biomedical Technology (AREA)
  • Engineering & Computer Science (AREA)
  • Neurology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Neurosurgery (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Cell Biology (AREA)
  • Developmental Biology & Embryology (AREA)
  • Immunology (AREA)
  • Psychiatry (AREA)
  • Hospice & Palliative Care (AREA)
  • Hematology (AREA)
  • Biotechnology (AREA)
  • Virology (AREA)
  • Zoology (AREA)
  • Psychology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

The invention relates to cell implants and/or at least one pharmaceutically acceptable compound selected from the group consisting of iron chelating agents, cyclic adenosine monophosphate level-increasing compounds (CASEV), axon growth promoting compounds, inhibitors of the intracellular Rho signal path or combinations thereof for producing a drug for protecting neurons in the CNS that are damaged by axonal lesion from being destructed.

Description

VERWENDUNG VON EISEN CHELATISIERENDEN VERBINDUNGEN, ZYKLISCHES ADENOSINMONOPHOSPHAT ERHÖHENDE VERBINDUNGEN ODER KOMBINATIONEN DAVON ZUR BEHANDLUNG VON AXONALEN LÄSIONEN IM ZNS USE OF IRON CHELATIZING COMPOUNDS, CYCLIC ADENOSINE MONOPHOSPHATE INCREASING COMPOUNDS OR COMBINATIONS THEREOF FOR THE TREATMENT OF AXONAL LESIONS IN THE CNS
Die vorliegende Erfindung betrifft die Verwendung von Zellimplantaten und/oder mindestens einer pharmazeutisch akzeptablen Verbindung zurThe present invention relates to the use of cell implants and / or at least one pharmaceutically acceptable compound for
Herstellung eines Arzneimittels.Production of a drug.
Es ist bekannt, dass nach Durchtrennung von absteigenden motorischen Faserbahnen (z.B. kortikospinaler Trakt) im Rückenmark der Ratte ein erheblicher Anteil (30-40%) der betroffenen Hirnneurone in der motorischen Hirnrinde durch programmierten Zelltod (Apoptose) zugrunde gehen (Hains et al., 2003).It is known that after transection of descending motor fiber tracts (eg corticospinal tract) in the spinal cord of the rat, a considerable proportion (30-40%) of the affected brain neurons in the motor cortex are destroyed by programmed cell death (apoptosis) (Hains et al. 2003).
Das der Erfindung zu Grunde liegende technische Problem war die Erhöhung der Wahrscheinlichkeit einer nahezu vollständigen Axonregeneration nach einem verletzungsbedingten Trauma. Gelöst wird das der Erfindung zu Grunde liegende Problem durch dieThe technical problem underlying the invention was the increase in the likelihood of near complete axon regeneration following injury trauma. The problem underlying the invention is solved by the
Verwendung von Zellimplantaten oder mindestens einer pharmazeutisch akzeptablen Verbindung ausgewählt aus der Gruppe bestehend aus Eisenchelatoren, zyklischen Adenosinmonophosphat-Spiegel erhöhenden Verbindungen (CASEV), Axonwachstum fördernden Verbindungen, Inhibitoren des intrazellulären Rho-Signalweges oder Kombinationen davon zur Herstellung eines Arzneimittels zur Protektion von durch axonale Läsion verletzten Neuronen im ZNS vor ihrem damit verbundenem Untergang, insbesondere durch die Protektion der verletzten Neuronen vor apoptotischen Prozessen. Eisenchelatoren sind typischerweise Verbindungen, die mit Eisen in koordinative Wechselwirkungen treten können. Dazu dienen insbesondere freie Elektronenpaare in den Verbindungen.Use of cell implants or at least one pharmaceutically acceptable compound selected from the group consisting of iron chelators, cyclic adenosine monophosphate level increasing compounds (CASEV), axon growth promoting compounds, inhibitors of the intracellular Rho signaling pathway or combinations thereof for the manufacture of a medicament for protection by axonal lesion injured neurons in the CNS before their associated demise, in particular by the protection of injured neurons from apoptotic processes. Iron chelators are typically compounds that can interact with iron in coordinative interactions. In particular, lone pairs of electrons in the compounds are used for this purpose.
Die erfindungsgemäße Verwendung schützt die sonst durch apoptotische Prozesse untergehenden Neurone und erhöht somit die Wahrscheinlichkeit einer nahezu vollständigen Axonregeneration, da nur lebende Neurone ihr Axon regenerieren können .The use according to the invention protects the otherwise declining by apoptotic processes neurons and thus increases the probability Near-complete axon regeneration because only living neurons can regenerate their axon.
Erfindungsgemäß können axonale Läsionen behandelt werden, die durch traumatische Einwirkungen, insbesondere durch Quetschung und/oder Durchtrennung von Axonen, und/oder entzündliche Prozesse, insbesonderen solchen, die im Verlauf von neuro-degenerativen Prozessen auftreten, hervorgerufen werden.According to the invention, axonal lesions can be treated which are caused by traumatic effects, in particular by pinching and / or severing of axons, and / or inflammatory processes, in particular those occurring in the course of neuro-degenerative processes.
Erfindungsgemäß verwendet werden als Eisen chelatisierende Verbindung N-Oxaloglycin; Zn-Salze; Pyridinderivate, wie 5-Arylcarbonylamino- oder 5- Arylcarbamoylderivate, 2-Carboxylat, 2,5 Dicarboxylate, ihre Ethylester oderAccording to the invention used as iron chelating compound N-oxaloglycine; Zn salts; Pyridine derivatives, such as 5-Arylcarbonylamino- or 5-Arylcarbamoylderivate, 2-carboxylate, 2,5 dicarboxylates, their ethyl esters or
Ethylamide oder -5-Acyl Sulfonamide, 2,4 Dicarboxylate, ihre Ethylester oder Ethylamide oder Dimethoxyethylamide; 3,4'-Bipyridine, wie 5 Amino-6-(lH)- one, l,6-Dihydro-2-methyl-6-oxo-5-carbonitril; 2,2'-Bipyridine, wie 5,5'- Dicarbonsäure oder ihre pharmazeutisch annehmbaren Salze, 4,4'- Dicarbonsäureethylester oder -ethylamide; 3,4'-Dihydroxybenzoate, wie dieEthylamides or -5-acyl sulfonamides, 2,4 dicarboxylates, their ethyl esters or ethylamides or dimethoxyethyl amides; 3,4'-bipyridines, such as 5-amino-6- (1H) -one, 1, 6-dihydro-2-methyl-6-oxo-5-carbonitrile; 2,2'-bipyridines, such as 5,5'-dicarboxylic acid or its pharmaceutically acceptable salts, 4,4'-dicarboxylic acid ethyl ester or ethylamides; 3,4'-dihydroxybenzoates, such as
Diethylester; Prolin und strukturelle und funktionelle Analoga; ß- Aminopropionitril; Desferrioxamine; Deferasirox; Deferiprone; Anthra- cyclines; 2,7,8-Trihydroxy Anthrachinone, Fibrostatin-C; Coumalinsäure ihre pharmazeutisch annehmbaren Salze; 5-Oxaproline, ß-Lactam Antibiotika. Erfindungsgemäß verwendet werden als CASEV zyklische Nukleotidanaloga und Phosphodiesterase Inhibitoren sowie Kombinationen davon.diethyl ester; Proline and structural and functional analogs; β-aminopropionitrile; desferrioxamine; deferasirox; deferiprone; Anthracyclines; 2,7,8-trihydroxy anthraquinones, Fibrostatin-C; Coumalic acid their pharmaceutically acceptable salts; 5-oxaprolines, β-lactam antibiotics. CASEV cyclic nucleotide analogs and phosphodiesterase inhibitors and combinations thereof are used according to the invention.
Erfindungsgemäß können als Axonwachstum fördernde Verbindungen solche verwendet werden, die neuronales Wachstum und/oder die Expression von wachstumsfördernden Proteinen wie Neurotrophe Faktoren, Fibroblasten Wachstumsfaktoren, Chemokine wie SDF-I, NeuralzellenAccording to the invention, compounds which promote axon growth can be used those which are neuronal growth and / or the expression of growth-promoting proteins such as neurotrophic factors, fibroblast growth factors, chemokines such as SDF-I, neural cells
Adhäsions Moleküle wie Ll (NILE), mit Wachstum assoziierte Proteine wie GAP43 und anti-apoptotischen Proteinen wie bcl-2 stimulieren.Adhesion molecules such as Ll (NILE) stimulate growth-associated proteins such as GAP43 and anti-apoptotic proteins such as bcl-2.
Erfindungsgemäß können als Inhibitoren des intrazellulären Rho- Signalweges z. B. Derivate der Exoenzym C3-Transferase oder Antikörper gegen das Nogo-Protein bzw. Antikörper gegen seine Signal-vermittelnden Rezeptoren verwendet werden.According to the invention can be used as inhibitors of the intracellular Rho signal pathway z. As derivatives of exoenzyme C3 transferase or antibodies against the Nogo protein or antibodies against its signal-mediating receptors.
Erfindungsgemäß können als Implantatzellen z. B. aktivierte Makrophagen, OEC (olfactory ensheathing cells), adulte oder embryonale Stammzellen verwendet werden.According to the invention can be used as implant cells z. Activated macrophages, OEC (olfactory ensheathing cells), adult or embryonic stem cells.
Die Applikation der erfindungsgemäß zu verwendenden Substanz(en) erfolgt typischerweise lokal im Verletzungs- bzw. Schädigungsbereich im Nervensystem, bei den löslichen Substanzen insbesondere auch durch verzögerte Freisetzung. Beispielsweise wird die Eisen chelatisierende Verbindung alleine oder inThe application of the substance (s) to be used according to the invention is typically carried out locally in the injury or damage region in the nervous system, in the case of the soluble substances, in particular also by delayed release. For example, the iron chelating compound alone or in
Kombination mit CASEV und/oder mit Axonwachstum fördernden Verbindungen und/oder mit Inhibitoren des intrazellulären Rho- Signalweges und/oder Zellimplantaten intrathekal (intraparenchymal, intraventrikulär, intraläsional und/oder intramedullär) appliziert. Beispielsweise wird die Eisen chelatisierende Verbindung alleine oder inCombination with CASEV and / or with axon growth promoting compounds and / or with inhibitors of intracellular Rho signaling pathway and / or cell implants intrathecally (intraparenchymal, intraventricular, intralesional and / or intramedullary) applied. For example, the iron chelating compound alone or in
Kombination mit CASEV und/oder mit Axonwachstum fördernden Verbindungen und/oder mit Inhibitoren des intrazellulären Rho- Signalweges systemisch (oral, intravenös) appliziert.Combination with CASEV and / or with axon growth promoting compounds and / or with inhibitors of the intracellular Rho-signaling systemic (oral, intravenous) applied.
Typischerweise wird die Eisen chelatisierende Verbindung und/oder CASEV und/oder Axonwachstum fördernde Verbindungen und/oder Inhibitoren des intrazellulären Rho-Signalweges in therapeutisch wirksamen Mengen, wie 1 ng/kg bis 1 mg/kg Körpergewicht verabreicht. Dem Fachmann ist geläufig, wie Dosis-Wirkungsfindungen für die in Betracht kommenden Behandlungen durchzuführen sind. Erfindungsgemäß wird ein Verfahren zur Protektion von durch axonaleTypically, the iron chelating compound and / or CASEV and / or axon growth promoting compounds and / or inhibitors of the intracellular Rho signaling pathway are administered in therapeutically effective amounts, such as 1 ng / kg to 1 mg / kg body weight. The person skilled in the art knows how to perform dose-response determinations for the treatments in question. According to the invention, a method for the protection of by axonal
Läsion verletzten Neuronen im ZNS bereitgestellt, wobei eisenchelatisierende Substanzen oder deren Kombination mit CASEV und/oder Axonwachstum fördernden Verbindungen und/oder mit Inhibitoren des intrazellulären Rho-Signalweges und/oder Zellimplantaten am Ort der axonalen Läsion verabreicht werden. - A -Lesions of injured neurons are provided in the CNS, with iron chelating agents or their combination with CASEV and / or axon growth promoting compounds and / or inhibitors of the intracellular Rho signaling pathway and / or cell implants being administered at the site of the axonal lesion. - A -
Über noch unbekannte molekulare Mechanismen und vermutlich retrograde axonale Fernwirkungen wird der entfernt liegende Zellkörper der verletzten Nervenzelle im Gehirn vor dem apoptotischen Zelluntergang geschützt. Diese erfindungsgemäße protektive Fernwirkung vom Verletzungsort der Faserbahnen im Rückenmark bis zu den Zellkörpern der Neurone im Gehirn war überraschend. Auf der Grundlage dieser neuen Erkenntnis basiert die innovative Behandlungsmethode.Unknown molecular mechanisms and probably retrograde axonal distant effects protect the distant cell body of the injured nerve cell in the brain from apoptotic cell death. This protective long-range action according to the invention from the point of injury of the fiber tracts in the spinal cord to the cell bodies of the neurons in the brain was surprising. Based on this new insight, the innovative treatment method is based.
Die vorliegende Erfindung wird anhand der folgenden Beispiele näher erläutert.The present invention will be further illustrated by the following examples.
Figur 1 zeigt eine retrograde FluoroGold Markierung von Pyramidalneuronen im sensomotorischen Kortex des Rattenhirns. Figur 2 zeigt den neuroprotektiven Ferneffekt auf primäre Motorneurone im Rattenhirn durch lokale Applikation des Eisenchelators BPY-DCA und/oder cAMP (8Br-cAMP) im verletzten Rückenmark.FIG. 1 shows a retrograde fluoro-gold marker of pyramidal neurons in the sensorimotor cortex of the rat brain. FIG. 2 shows the neuroprotective long-term effect on primary motor neurons in the rat brain by local application of the iron chelator BPY-DCA and / or cAMP (8Br-cAMP) in the injured spinal cord.
Durch retrograde axonale Markierung von Motoneuronen im sensomotorischen Kortex der Ratte mit dem Fluoreszenzfarbstoff FluoroGold konnte gezeigt werden, dass nach Verletzung einer motorischen Faserbahn im Rückenmark (z.B. der Kortikospinaltrakt, CST) ca. 25-30% der betroffenen Nervenzellen im Gehirn (hier:By retrograde axonal labeling of motoneurons in the sensorimotor cortex of the rat with the fluorescent dye FluoroGold it could be shown that after injury of a motor fiber tract in the spinal cord (for example the corticospinal tract, CST), approximately 25-30% of the affected nerve cells in the brain (here:
Pyramidalneurone im primär motorischen Kortex) untergehen. Der Zelluntergang kann durch ein Regeneration-Promoting-Treatment (RPT) unter Verwendung eines Eisenchelators wie Bipyridine dicarboxylic acid (BPY-DCA), verhindert werden. Das RPT bietet eine umfassende neuronale Schutzwirkung und fördert diePyramidal neurons in the primary motor cortex). Cell depletion can be prevented by a Regeneration Promoting Treatment (RPT) using an iron chelator such as bipyridine dicarboxylic acid (BPY-DCA). The RPT provides a comprehensive neural protective effect and promotes the
Regeneration verletzter Axone wodurch die funktionelle Erholung möglich wird. Die Erfindung wird anhand der folgenden Beispiele näher erläutert. Beispiel 1Regeneration of injured axons allowing functional recovery. The invention will be explained in more detail with reference to the following examples. example 1
Markierung zerebraler Projektionsneurone der Ratte und Gewebeaufarbeitung zur quantitativen Auswertung der Zellen inLabeling of rat cerebral projection neurons and tissue processing for the quantitative evaluation of cells in
Hirnschnitten Hydroxystilbamidine (FluoroGold) ist ein geeigneter axonaler Tracer für die retrograde Markierung primärer Motoneurone im sensomotorischen Kortex der Ratte.Cerebral sections Hydroxystilbamidine (FluoroGold) is a suitable axonal tracer for the retrograde labeling of primary motor neurons in the sensorimotor cortex of the rat.
2 x 0.5 μl einer 3%-igen Lösung des Tracers in aqua bidest über eine Dauer von 2 min wird unmittelbar nach der Läsion einer Faserbahn im Rückenmark, z. B. des CST, auf der Höhe des Thorakalsegments2 x 0.5 .mu.l of a 3% solution of the tracer in double-distilled water over a period of 2 min is immediately after the lesion of a fibrous web in the spinal cord, z. B. the CST, at the level of the thoracic segment
Th7 ins Rückenmark injiziert.Th7 injected into the spinal cord.
Fig. 1 zeigt die retrograde FluoroGold Markierung von Pyramidalneuronen in einem Schnittpräparat (20 μm) aus dem sensomotorischen Kortex (Schicht V) des Rattenhirns (Sham-Kontrolle).1 shows the retrograde fluoro gold labeling of pyramidal neurons in a section preparation (20 μm) from the sensorimotor cortex (layer V) of the rat brain (sham control).
Histologie: Intrakardiale Perfusion der Ratte mit PBS (pH 7.4) und 4%Histology: Intracardiac perfusion of the rat with PBS (pH 7.4) and 4%
Paraformaldehyd (PFA) in PBS (pH 7.4). Postfixierung in PFA (24h) und Kryopreservierung. Herstellung von 20 μm koronaren Serienschnitten aus dem sensomotorischen Kortex.Paraformaldehyde (PFA) in PBS (pH 7.4). Postfixing in PFA (24h) and cryopreservation. Production of 20 μm coronal serial sections from the sensorimotor cortex.
Beispiel 2Example 2
Retrogrades axonales Tracing zerebraler Projektionsneurone unter verschiedenen Behandlungsbedingungen nach Verletzung des Rückenmarks.Retrograde axonal tracing of cerebral projection neurons under different treatment conditions after spinal cord injury.
Testparameter: Darstellung überlebender Kortexneurone durch retrogradeTestparameter: Presentation of surviving cortical neurons by retrograde
Tracerfüllungtracer filling
Läsionstyp: Drahtmesser-Läsion des Rückenmarks in Höhe Thorakalseegment Th8 Tiergruppen : Sham, Läsion ohne Behandlung (Kontrolle mit Injektion einer Pufferlösung), Läsion mit RPT-Behandlung Zeitpunkte: 1 Woche, 4 Wochen Tracer: FluoroGold (retrograd) Standard ("Scouten" Drahtmesser)-LäsionLesion type: wire-knife lesion of the spinal cord at the height of the thoracic segment Th8 Animal groups: sham, lesion without treatment (control with injection of a buffer solution), lesion with RPT treatment Time points: 1 week, 4 weeks Tracer: FluoroGold (retrograde) Standard ("Scouten" wire knife) lesion
(a) Sham Kontrolle(a) Sham control
(b) Läsion ohne Behandlung (Pufferlösung)(b) lesion without treatment (buffer solution)
(c) Läsion mit Eisenchelator (BPY-DCA)(c) Lesion with iron chelator (BPY-DCA)
(d) Läsion mit cAMP (8Br-cAMP) (e) Läsion mit Eisenchelator plus cAMP (RPT)(d) lesion with cAMP (8Br-cAMP) (e) lesion with iron chelator plus cAMP (RPT)
Zeitpunkte : Iw, 4wTimes: Iw, 4w
Es wurde eine Drahtmesser-Läsion mit dem sog. "Scouten" Drahtmesser ausgeführt (Hermanns et al ., 2001). Unmittelbar nach Axotomie im Rückenmark wurden die proximalen Stümpfe der verletzten CST-Axone mit Fl uoroGold retrograd markiert. Untersucht wurden die folgendenA wire-knife lesion was made with the so-called "scouting" wire-knife (Hermanns et al., 2001). Immediately after axotomy in the spinal cord, the proximal stumps of the injured CST axons were retrograded with FluoroGold. The following were investigated
Tiergruppen : (a) Sham, (b) Puffer-Läsionskontrolle, (c) Läsion mit Eisenchelator (BPY-DCA), (d) Läsion mit cAMP (8Br-cAMP) und (e) Läsion mit Eisenchelator plus cAMP (RPT).Animal groups: (a) sham, (b) buffer lesion control, (c) lesion with iron chelator (BPY-DCA), (d) lesion with cAMP (8Br-cAMP) and (e) lesion with iron chelator plus cAMP (RPT).
Beispiel 3Example 3
Fluoreszenzmikroskopische Dokumentation und quantitative Auswertung retrograd markierter Neurone an ausgewähltenFluorescence microscopy documentation and quantitative evaluation of retrograde labeled neurons at selected
Hirnschnittenbrain slices
Für die fluoreszenzmikroskopische Dokumentation retrograd markierter Pyramidalneurone wurden koronare Kryo-Serienschnitte (20 μm) aus dem sensomotorischen Kortex (Schicht V) der Versuchstiere ausgewertet.Coronary cryose serial sections (20 μm) from the sensorimotor cortex (layer V) of the test animals were evaluated for the fluorescence microscopy documentation of retrogradely marked pyramidal neurones.
Koronarschnitte wurden über den Koordinatenbereich von Bregma +0,9 bis -2, 1 gewonnen . Jeder 10. H irnschn itt wurde u nter fl uoreszenzmikroskopischer Beobachtung fotografiert und retrograd markierte Kortexneurone in beiden Hemispheren ausgezählt. 16 Schnitte (32 Hemispheren) von jeweils 3 Tieren pro Versuchsbedingung wurden ausgezählt und statistisch ausgewertet (siehe Auswertung in der Anlage).Coronal sections were obtained over the coordinate range of Bregma +0.9 to -2.1. Each 10th scan was photographed by fluorescence microscopic observation and retrograde labeled cortical neurons were counted in both hemispheres. 16 Sections (32 hemispheres) of 3 animals per test condition were counted and statistically evaluated (see evaluation in the annex).
Fig. 2 zeigt beispielhaft die unterschiedlichen Dichten retrograd markierter Pyramidalneurone im sensomotorischen Kortex im intakten TierFIG. 2 shows, by way of example, the different densities of retrogradely marked pyramidal neurons in the sensorimotor cortex in the intact animal
(Fig. 2A: Sham-Kontrolle), nach Verletzung des CST im Rückenmark der Ratte (Fig. 2B, Läsionskontrolle) und nach Applikation des RPT nach Rückenmarkverletzung (Fig. 2C). Die lokale Applikation von BPY-DCA und/oder 8Br-cAMP ins Rückenmark hat einen neuroprotektiven Effekt auf kortikale Pyramidalneurone der Schicht V im sensomotorischen Kortex(Fig. 2A: sham control), after injury of CST in rat spinal cord (Fig. 2B, lesion control) and after application of RPT after spinal cord injury (Fig. 2C). Local application of BPY-DCA and / or 8Br-cAMP to the spinal cord has a neuroprotective effect on cortical pyramidal neurons of layer V in the sensorimotor cortex
(zwischen Bregma -1.1 und -2.1) nach Durchtrennung des Kortikospinaltraktes im Rückenmark. Beispielhaft dargestellt sind FluoroGold markierte Pyramidalneurone in den Tiergruppen (A) Sham- Kontrollen, (B) Läsion ohne Behandlung und (C) Läsion plus RPT- Behandlung 4 Wochen nach dem chirurgischen Eingriff. (D) Histogramm mit quantitativer Auswertung. In seriellen Hirnschnitten der Versuchstiere (n = 3 Tiere in jeder Gruppe) wurden die retrograd markierten Zellen gezählt. Dargestellt sind die Mittelwerte (schwarze Balken) mit der jeweiligen Standardabweichung. Die ermittelten Zellzahlen für Sham- Kontrollen und die behandelten Tiere sind signifikant unterschiedlich von den unbehandelten Läsionstieren (* P<0.05, ** P<0.01, *** P<0.001).(between Bregma -1.1 and -2.1) after transection of the corticospinal tract in the spinal cord. Exemplified are fluoroGold-labeled pyramidal neurones in the animal groups (A) sham controls, (B) lesion without treatment, and (C) lesion plus RPT treatment 4 weeks after surgery. (D) Histogram with quantitative evaluation. In serial brain sections of the experimental animals (n = 3 animals in each group), the retrograde labeled cells were counted. Shown are the mean values (black bars) with the respective standard deviation. The determined cell counts for Sham controls and the treated animals are significantly different from the untreated lesion animals (* P <0.05, ** P <0.01, P <0.001).
Gegenüber der Sham-Kontrolle (Fig. 2A) zeigt die Läsionskontrolle mit Trispuffer (Fig. 2B) vier Wochen nach Rückenmarkverletzung eine deutlich erkennbare Abnahme markierter Pyramidalneurone in Schicht V. Durch dasCompared to the sham control (FIG. 2A), the lesion control with Tris buffer (FIG. 2B) shows a clearly recognizable decrease of labeled pyramidal neurons in layer V four weeks after spinal cord injury
RPT kann dieser Zellverlust verhindert werden (Fig. 2C).RPT, this cell loss can be prevented (Figure 2C).
Die retrograde Markierung der kortikalen Pyramidalneurone in Zellschicht V mit FluoroGold ergibt eine sehr verlässliche, definierte, homogene und hoch reproduzierbare Markierung der sensomotorischen Hirnregion in sämtlichen untersuchten Tieren. Das Hirngebiet der retrograd markierten Neurone erstreckt sich über ca. 4,4 mm in rostrocaudaler Ausrichtung und ist symmetrisch über beide Hemispheren verteilt. Die markierte Zellschicht erscheint als Streifen m it einer Höhe von ca . 0.5 mm und einer mediolateralen Weite von 0,8 bis 2 mm je nach rostrocaudalem Abstand vom Bregma. Die läsionsbedingten Zellverluste liegen nach 4 Wochen in einerThe retrograde labeling of the cortical pyramidal neurones in cell layer V with fluoro gold gives a very reliable, defined, homogeneous and highly reproducible marking of the sensorimotor brain region in all the animals examined. The brain area of the retrograde labeled neurons extends over approximately 4.4 mm in rostrocaudaler Alignment and is distributed symmetrically over both Hemispheren. The marked cell layer appears as a strip with a height of approx. 0.5 mm and a medio-lateral width of 0.8 to 2 mm, depending on the rostrocaudal distance from the bregma. The lesion-related cell losses are after 4 weeks in one
Größenordnung von ca. 25-30%. Nach Hains et al. (2003) sind die Verluste der primären Motoneurone im Kortex nach Verletzung des CST auf apoptotischen Zelluntergang in der 2.-4. Woche nach Läsion zurückzuführen. Fig. 2 zeigt auch, dass durch die Behandlung mit dem RPT die neuronalen Zellverluste praktisch komplett aufgehoben werden können . Der durch die Erfindung gewährleistete neuroprotektive Effekt, der sich vom Läsionsort im Rückenmark über eine weite Distanz bis in den zerebralen Kortex erstreckt, ist von höchstem Interesse. Der neuroprotektive Effekt sowohl von Eisen chelatisierenden Verbindungen als auch von CASEV ist gegenüber der Tris-Läsionskontrolle statistisch signifikant (Fig. 2D). Zwischen den Sham-Kontrolltieren und den mit Eisenchelator plus cAMP behandelten verletzten Tieren lässt sich kein sign ifikanter Untersch ied meh r in der Anza h l markierter Pyramidalneuronen feststellen. Die Analyse der BPY-DCA bzw. cAMP-Tiere ergab, dass beide Moleküle unabhängig von einander einen signifikantenMagnitude of about 25-30%. According to Hains et al. (2003) are the losses of the primary motor neurons in the cortex after injury of the CST on apoptotic cell death in the 2-4. Attributed week after lesion. FIG. 2 also shows that treatment with RPT virtually eliminates neuronal cell loss. The neuroprotective effect provided by the invention, which extends from the lesion site in the spinal cord over a long distance to the cerebral cortex, is of highest interest. The neuroprotective effect of both iron chelating compounds and CASEV is statistically significant over Tris lesion control (Figure 2D). No significant difference in the number of labeled pyramidal neurons can be detected between the sham controls and the injured animals treated with the iron chelator plus cAMP. Analysis of the BPY-DCA and cAMP animals, respectively, showed that both molecules independently of each other had a significant
Beitrag zur Neuroprotektion nach Rückenmarkverletzung leisten. Durch BPY-DCA können je nach Kortexareal ca. 60-74% der betroffenen Zellen erhalten werden, während mit cAMP ca. 66-98% der Zellen überleben. Die individuellen neuroprotektiven Effekte von BPY-DCA und cAMP sind, für sich betrachtet, jeweils signifikant (p=0.05 bzw. p=0.01). Die Unterschiede zwischen den Effekten des Chelators und cAMP sind hingegen nicht signifikant.Contribute to neuroprotection after spinal cord injury. Depending on the cortical area, about 60-74% of the affected cells can be obtained by BPY-DCA, whereas with cAMP about 66-98% of the cells survive. The individual neuroprotective effects of BPY-DCA and cAMP are, by themselves, significant (p = 0.05 and p = 0.01, respectively). The differences between the effects of the chelator and cAMP are not significant.
In der Kurzzeitanalyse nach einer Woche konnten keine läsionsbedingten Zelluntergänge festgestellt werden . Beispiel 4In the short-term analysis after one week, no lesion-related cell subsidence could be detected. Example 4
Korrelation der neuronalen Protektion mit dem Ausmaß axonaler Regeneration (anteroqrades BDA-Tracinq) Die neuronale Protektion korreliert im Fall der Eisen chelatisierendenCorrelation of neuronal protection with the extent of axonal regeneration (anteroqrades BDA-Tracinq) The neuronal protection correlates in the case of iron chelating
Verbindungen mit der axonalen Regeneration. Ausschließlich unter den Bedingungen der Verfahrensweise gemäß WO-A-98/51708 wird eine Regeneration verletzter Axone im ZNS beobachtet, die schließlich zur funktionellen Erholung führt. Die Einzelkomponente cAMP kann zwar mehr als 50% der unter Kontrollbedingungen (Tris) absterbenden primärenCompounds with axonal regeneration. Only under the conditions of the procedure according to WO-A-98/51708 a regeneration of injured axons in the CNS is observed, which finally leads to the functional recovery. Although the individual component cAMP can be more than 50% of the primary dying under control conditions (Tris)
Motorneurone erhalten (siehe oben), jedoch findet unter diesen Bedingungen nach Rückenmarkverletzung keine Axonregeneration statt. Das bedeutet, dass die Neuroprotektion durch die Eisen chelatisierende Verbindung gemäß der Erfindung eine von der Axonregeneration unabhängige Erhaltungsfunktion für verletzte Neurone darstellt. Durch die unerwartete protektive Fernwirkung kann der Pool regenerationsfähiger Neurone um ca. 25-30% gegenüber unbehandelten Kontrolltieren vergrößert werden. Motor neurons are obtained (see above), but under these conditions after spinal cord injury no axon regeneration takes place. This means that the neuroprotection by the iron-chelating compound according to the invention represents an axon regeneration-independent maintenance function for injured neurons. Due to the unexpected long-term protective effect, the pool of regenerative neurons can be increased by approximately 25-30% compared to untreated control animals.
Literaturzitatereferences
Hains BC, Black JA, Waxman SG (2003) Primary cortical motor neurons undergo apoptosis after axotomizing spinal cord injury. J Comp NeurolHains BC, Black JA, Waxman SG (2003) Primary cortical motor neurons undergoing apoptosis after axotomizing spinal cord injury. J Comp Neurol
462, 328-341.462, 328-341.
Hermanns, S., Klapka, N. and Müller, H.W. (2001 ) The collagenous lesion scar - an obstacle for axonal regeneration in brain and spinal cord injury. Restor. Neurol. Neurosci. 19, 139-148. Hermanns, S., Klapka, N. and Müller, H.W. (2001) The collagenous lesion scar - an obstacle for axonal regeneration in brain and spinal cord injury. Restor. Neurol. Neurosci. 19, 139-148.

Claims

Patentansprüche claims
1. Verwendung von Zellimplantaten und/oder mindestens einer pharmazeutisch akzeptablen Verbindung ausgewählt aus der Gruppe bestehend aus Eisenchelatoren, zyklischen Adenosinmonophosphat- Spiegel erhöhenden Verbindungen (CASEV), Axonwachstum fördernden Verbindungen, Inhibitoren des intrazellulären Rho-Signalweges oder Kombinationen davon zur Herstellung eines Arzneimittels zur Protektion von durch axonale Läsion verletzten Neuronen im ZNS vor ihrem damit verbundenem Untergang.Use of cell implants and / or at least one pharmaceutically acceptable compound selected from the group consisting of iron chelators, cyclic adenosine monophosphate level increasing compounds (CASEV), axon growth promoting compounds, intracellular Rho signaling pathway inhibitors or combinations thereof for the manufacture of a medicament for protection neurons in the CNS injured by axonal lesion before their associated demise.
2. Verwendung nach Anspruch 1, wobei die Protektion vor apoptotischen Prozessen erfolgt.2. Use according to claim 1, wherein the protection takes place before apoptotic processes.
3. Verwendung nach Anspruch 1 und/oder 2, wobei die axonale Läsion durch traumatische Einwirkungen und/oder entzündliche Prozesse hervorgerufen wird.3. Use according to claim 1 and / or 2, wherein the axonal lesion is caused by traumatic effects and / or inflammatory processes.
4. Verwendung nach einem der Ansprüche 1 bis 3, wobei die traumatischen Einwirkungen durch Quetschung und/oder Durchtrennung von Axonen erfolgt. 4. Use according to any one of claims 1 to 3, wherein the traumatic effects by crushing and / or transection of axons occurs.
5. Verwendung nach einem der Ansprüche 1 bis 3, wobei die entzündlichen5. Use according to any one of claims 1 to 3, wherein the inflammatory
Prozesse im Verlauf von neuro-degenerativen Prozessen ablaufen.Processes proceed in the course of neuro-degenerative processes.
6. Verwendung nach einem der Ansprüche 1 bis 4, wobei als Eisenchelator N-Oxaloglycin; Zn-Salze; Pyridinderivate, wie 5-Arylcarbonyamino- oder 5-Arylcarbamoylderivate, 2-Carboxylat, 2,5 Dicarboxylate, ihre Ethylester oder Ethylamide oder -5-Acyl Sulfonamide, 2,4 Dicarboxylate, ihre6. Use according to any one of claims 1 to 4, wherein as an iron chelator N-oxaloglycine; Zn salts; Pyridine derivatives, such as 5-arylcarbonyamino or 5-arylcarbamoyl derivatives, 2-carboxylate, 2.5 dicarboxylates, their ethyl esters or ethylamides or -5-acyl sulfonamides, 2,4 dicarboxylates, their
Ethylester oder Ethylamide oder Dimethoxyethylamide; 3,4'-Bipyridine, wie 5 Amino-6-(lH)-one, l,6-Dihydro-2-methyl-6-oxo-5-carbonitril; 2,2'- Bipyridine, wie 5,5'-Dicarbonsäure oder ihre pharmazeutisch annehmbaren Salze, 4,4'-Dicarbonsäureethylester oder -ethylamide; 3,4'- Dihydroxybenzoate, wie die Diethylester; Prolin und strukturelle und funktionelle Analoga; ß-Aminopropionitril; Desferrioxamine; Deferasirox; Deferiprone; Anthracyclines; 2,7,8-Trihydroxy Anthrachinone, Fibrosta- tin-C; Coumalinsäure ihre pharmazeutisch annehmbaren Salze; 5- Oxaproline, ß-Lactam Antibiotika eingesetzt werden.Ethyl esters or ethylamides or dimethoxyethylamides; 3,4'-bipyridines, such as 5-amino-6- (1H) -one, 1,6-dihydro-2-methyl-6-oxo-5-carbonitrile; 2,2'-bipyridines such as 5,5'-dicarboxylic acid or its pharmaceutically acceptable salts, 4,4'-dicarboxylic acid ethyl ester or ethylamides; 3,4 ' Dihydroxybenzoates, such as the diethyl esters; Proline and structural and functional analogs; .beta.-aminopropionitrile; desferrioxamine; deferasirox; deferiprone; anthracyclines; 2,7,8-trihydroxy anthraquinones, fibrostatin-C; Coumalic acid their pharmaceutically acceptable salts; 5- oxaprolines, ß-lactam antibiotics are used.
7. Verwendung nach einem der Ansprüche 1 bis 6, wobei die axonales Wachstum fördernden Verbindungen ausgewählt sind aus der Gruppe bestehend aus wachstumsfördernden Proteinen wie neurotrophe Faktoren, Fibroblasten Wachstumsfaktoren, Chemokine wie SDF-I, Neuralzellen Adhäsions Moleküle wie Ll (NILE), mit Wachstum assoziierteUse according to any one of claims 1 to 6, wherein the axonal growth promoting compounds are selected from the group consisting of growth promoting proteins such as neurotrophic factors, fibroblast growth factors, chemokines such as SDF-I, neural cell adhesion molecules such as L1 (NILE), with growth associated
Proteine wie GAP43 und anti-apoptotischen Proteinen wie bcl-2 stimuliert.Proteins like GAP43 and anti-apoptotic proteins like bcl-2 are stimulated.
8. Verwendung nach einem der Ansprüche 1 bis 7, wobei der Eisenchelator, die Axonwachstum fördernde Verbindung, CASEV und/oder ein Inhibitor des Rho-Signalweges intrathekal (intraparenchymal, intraventrikulär, intraläsional oder intramedullär) oder systemisch (oral oder intravenös) appliziert wird.8. Use according to any one of claims 1 to 7, wherein the iron chelator, the axon growth promoting compound, CASEV and / or an inhibitor of the Rho signaling pathway is administered intrathecally (intraparenchymal, intraventricular, intralesional or intramedullary) or systemically (orally or intravenously).
9. Verwendung nach einem der Ansprüche 1 bis 8, wobei CASEV zyklische Nukleotidanaloga, Phosphodiesterase Inhibitoren und Kombinationen davon sind. Use according to any one of claims 1 to 8, wherein CASEV are cyclic nucleotide analogues, phosphodiesterase inhibitors and combinations thereof.
10. Verwendung nach einem der Ansprüche 1 bis 8, wobei als Inhibitoren des Rho-Signalweges Derivate der Exoenzym C3-Transferase und/oder Antikörper gegen das Nogo-Protein und/oder Antikörper gegen Nogo- Rezeptoren eingesetzt werden.10. Use according to any one of claims 1 to 8, wherein as inhibitors of the Rho signaling pathway derivatives of the exoenzyme C3 transferase and / or antibodies to the Nogo protein and / or antibodies to Nogo receptors are used.
11. Verwendung nach einem der Ansprüche 1 bis 8, wobei als Zellimplantat Makrophagen, OEC (olfactory ensheathing cells) oder Stammzellen eingesetzt werden.11. Use according to one of claims 1 to 8, wherein as a cell implant macrophages, OEC (olfactory ensheathing cells) or stem cells are used.
12. Verwendung nach einem der Ansprüche 1 bis 11, wobei die Eisenchelatoren, CASEV, Axonwachstum fördernde Verbindungen und/oder Inhibitoren des Rho-Signalweges in therapeutisch wirksamen Mengen, wie 1 ng/kg bis 1 mg/kg Körpergewicht verabreicht werden. 12. Use according to any one of claims 1 to 11, wherein the iron chelators, CASEV, axon growth promoting compounds and / or inhibitors of the Rho signaling pathway are administered in therapeutically effective amounts, such as 1 ng / kg to 1 mg / kg of body weight.
PCT/EP2006/067878 2005-10-27 2006-10-27 Use of iron-chelating compounds, cyclic adenosine monophosphate-increasing compounds or combinations thereof for treating axonal lesions in the cns WO2007048846A1 (en)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
EP05110090 2005-10-27
EP05110090.7 2005-10-27
EP06110266.1 2006-02-22
EP06110266 2006-02-22
US78304206P 2006-03-17 2006-03-17
US60/783,042 2006-03-17

Publications (1)

Publication Number Publication Date
WO2007048846A1 true WO2007048846A1 (en) 2007-05-03

Family

ID=37717752

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2006/067878 WO2007048846A1 (en) 2005-10-27 2006-10-27 Use of iron-chelating compounds, cyclic adenosine monophosphate-increasing compounds or combinations thereof for treating axonal lesions in the cns

Country Status (1)

Country Link
WO (1) WO2007048846A1 (en)

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5563048A (en) * 1993-10-14 1996-10-08 Ono Pharmaceutical Co., Ltd. Human stromal derived factor 1α and 1β, and DNAs encoding the same
EP0878480A1 (en) * 1997-05-14 1998-11-18 H.W. Prof. Dr. Müller A method for the improvement of neuronal regeneration
WO1999029279A2 (en) * 1997-12-05 1999-06-17 The Board Of Trustees Of The Leland Stanford Junior University Long-term survival and regeneration of central nervous system neurons
WO2000074664A2 (en) * 1999-06-07 2000-12-14 Yeda Research And Development Co. Ltd. Novel iron chelators and pharmaceutical compositions comprising iron chelators for the treatment of neurodegenerative disorders
WO2001072326A1 (en) * 2000-03-31 2001-10-04 Smithkline Beecham Plc Use of crf receptor agonists for the treatment or prophylaxis of diseases, for example neurodegenerative diseases
WO2002045749A2 (en) * 2000-11-02 2002-06-13 Research Foundation Of City University Of New York Methods for stimulating nervous system regeneration and repair by inhibition phosphodiesterase type 4
US20040047843A1 (en) * 2002-02-12 2004-03-11 Uab Research Foundation Method for spinal cord reconnection
WO2004033498A2 (en) * 2002-10-10 2004-04-22 Centre National De La Recherche Scientifique-Cnrs- .pharmaceutical composition comprising ht4d100a receptors, and therapeutic uses thereof
WO2005061458A2 (en) * 2003-12-11 2005-07-07 Memory Pharmaceuticals Corporation Phosphodiesterase 4 inhibitors, including n-substituted diarylamine analogs

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5563048A (en) * 1993-10-14 1996-10-08 Ono Pharmaceutical Co., Ltd. Human stromal derived factor 1α and 1β, and DNAs encoding the same
EP0878480A1 (en) * 1997-05-14 1998-11-18 H.W. Prof. Dr. Müller A method for the improvement of neuronal regeneration
WO1999029279A2 (en) * 1997-12-05 1999-06-17 The Board Of Trustees Of The Leland Stanford Junior University Long-term survival and regeneration of central nervous system neurons
WO2000074664A2 (en) * 1999-06-07 2000-12-14 Yeda Research And Development Co. Ltd. Novel iron chelators and pharmaceutical compositions comprising iron chelators for the treatment of neurodegenerative disorders
WO2001072326A1 (en) * 2000-03-31 2001-10-04 Smithkline Beecham Plc Use of crf receptor agonists for the treatment or prophylaxis of diseases, for example neurodegenerative diseases
WO2002045749A2 (en) * 2000-11-02 2002-06-13 Research Foundation Of City University Of New York Methods for stimulating nervous system regeneration and repair by inhibition phosphodiesterase type 4
US20040047843A1 (en) * 2002-02-12 2004-03-11 Uab Research Foundation Method for spinal cord reconnection
WO2004033498A2 (en) * 2002-10-10 2004-04-22 Centre National De La Recherche Scientifique-Cnrs- .pharmaceutical composition comprising ht4d100a receptors, and therapeutic uses thereof
WO2005061458A2 (en) * 2003-12-11 2005-07-07 Memory Pharmaceuticals Corporation Phosphodiesterase 4 inhibitors, including n-substituted diarylamine analogs

Non-Patent Citations (17)

* Cited by examiner, † Cited by third party
Title
ANDREWS M R ET AL: "STUDIES OF OEC - MEDIATED REGENERATION AFTER PARTIAL SPINAL INJURY IN ADULT RAT; A PROGRESS REPORT.", SOCIETY FOR NEUROSCIENCE ABSTRACT VIEWER AND ITINERARY PLANNER, vol. 2002, 2002, & 32ND ANNUAL MEETING OF THE SOCIETY FOR NEUROSCIENCE; ORLANDO, FLORIDA, USA; NOVEMBER 02-07, 2002, pages Abstract No. 133.3 URL - http://sf, XP009079211 *
BERTRAND ET AL: "Application of Rho antagonist to neuronal cell bodies promotes neurite growth in compartmented cultures and regeneration of retinal ganglion cell axons in the optic nerve of adult rats", JOURNAL OF NEUROSCIENCE, vol. 25, no. 5, 2 February 2005 (2005-02-02), pages 1113 - 1121, XP002421722 *
BERTRAND J ET AL: "Inactivation of Rho increases retinal ganglion cells survival and promotes regeneration after optic nerve axotomy", IOVS, vol. 46, no. Suppl. S, 2005, & ANNUAL MEETING OF THE ASSOCIATION-FOR-RESEARCH-IN-VISION-AND-OPHTHALM OLOGY; FT LAUDERDALE, FL, USA; MAY 01 -05, 2005, pages 174, XP009079205, ISSN: 0146-0404 *
CUI L ET AL: "Embryonic stem cell transplantation promotes Schwann cell and axonal regeneration and enhances functional recovery following sciatic nerve axotomy in rats.", SOCIETY FOR NEUROSCIENCE ABSTRACT VIEWER AND ITINERARY PLANNER, vol. 2003, 2003, & 33RD ANNUAL MEETING OF THE SOCIETY OF NEUROSCIENCE; NEW ORLEANS, LA, USA; NOVEMBER 08-12, 2003, pages Abstract No. 152.9 URL - http://sf, XP009079208 *
CUI QI ET AL: "Intraocular elevation of cyclic AMP potentiates ciliary neurotrophic factor-induced regeneration of adult rat retinal ganglion cell axons.", MOLECULAR AND CELLULAR NEUROSCIENCE, vol. 22, no. 1, January 2003 (2003-01-01), pages 49 - 61, XP002421717, ISSN: 1044-7431 *
CUI QI; SO KWOK-FAI: "Involvement of cAMP in neuronal survival and axonal regeneration", ANATOMICAL SCIENCE INTERNATIONAL, vol. 79, no. 4, December 2004 (2004-12-01), pages 209 - 212, XP002359976 *
IWASAKI YASUO ET AL: "Effect of transforming growth factor beta-1 on spinal motor neurons after axotomy", JOURNAL OF THE NEUROLOGICAL SCIENCES, vol. 147, no. 1, 1997, pages 9 - 12, XP002421716, ISSN: 0022-510X *
KAWANO HITOSHI ET AL: "Inhibition of collagen synthesis overrides the age-related failure of regeneration of nigrostriatal dopaminergic axons", JOURNAL OF NEUROSCIENCE RESEARCH, vol. 80, no. 2, April 2005 (2005-04-01), pages 191 - 202, XP002421718, ISSN: 0360-4012 *
KLAPKA N; HERMANNS S; MUELLER H W: "TRANSIENT SUPPRESSION OF FIBROUS SCAR AFTER ACUTE SPINAL CORD INJURY IN RAT LEADS TO MASSIVE AXONAL REGENERATION", SOCIETY FOR NEUROSCIENCE ABSTRACT VIEWER AND ITINERARY PLANNER, 2002, pages 203.16, XP009058874 *
LI LINXI ET AL: "Neurotrophic agents prevent motoneuron death following sciatic nerve section in the neonatal mouse", JOURNAL OF NEUROBIOLOGY, vol. 25, no. 7, 1994, pages 759 - 766, XP002421720, ISSN: 0022-3034 *
REGAN RAYMOND F ET AL: "Delayed treatment of hemoglobin neurotoxicity.", JOURNAL OF NEUROTRAUMA, vol. 20, no. 1, January 2003 (2003-01-01), pages 111 - 120, XP009079160, ISSN: 0897-7151 *
RIOS-MUNOZ WILSON ET AL: "Fibroblast growth factor 2 applied to the optic nerve after axotomy increases Bcl-2 and decreases Bax in ganglion cells by activating the extracellular signal-regulated kinase signaling pathway", JOURNAL OF NEUROCHEMISTRY, vol. 93, no. 6, June 2005 (2005-06-01), pages 1422 - 1433, XP002421721, ISSN: 0022-3042 *
SAGOT Y ET AL: "BCL-2 OVEREXPRESSION PREVENTS MOTONEURON CELL BODY LOSS BUT NOT AXONAL DEGENERATION IN A MOUSE MODEL OF A NEURODEGENERATIVE DESEASE", JOURNAL OF NEUROSCIENCE, NEW YORK, NY, US, vol. 15, no. 11, November 1995 (1995-11-01), pages 7727 - 7733, XP002044575, ISSN: 0270-6474 *
SHIBATA M ET AL: "Single injections of a DNA plasmid that contains the human Bcl-2 gene prevent loss and atrophy of distinct neuronal populations after spinal cord injury in adult rats.", NEUROREHABILITATION AND NEURAL REPAIR 2000, vol. 14, no. 4, 2000, pages 319 - 330, XP009079165, ISSN: 1545-9683 *
TAKAHASHI KOSEI ET AL: "DNA plasmid that codes for human Bcl-2 gene preserves axotomized Clarke's nucleus neurons and reduces atrophy after spinal cord hemisection in adult rats", JOURNAL OF COMPARATIVE NEUROLOGY, vol. 404, no. 2, 8 February 1999 (1999-02-08), pages 159 - 171, XP002421719, ISSN: 0021-9967 *
YOUDIM MOUSSA B H; FRIDKIN MATI; ZHENG HAILIN: "Bifunctional drug derivatives of MAO-B inhibitor rasagiline and iron chelator VK-28 as a more effective approach to treatment of brain ageing and ageing neurodegenerative diseases", MECHANISMS OF AGEING AND DEVELOPMENT, vol. 126, no. 2, February 2005 (2005-02-01), pages 317 - 326, XP002359975 *
ZHOU LINQIU ET AL: "Red nucleus neurons of Bcl-2 over-expressing mice are protected from cell death induced by axotomy", NEUROREPORT, vol. 10, no. 16, 8 November 1999 (1999-11-08), pages 3417 - 3421, XP009079157, ISSN: 0959-4965 *

Similar Documents

Publication Publication Date Title
DE69317578T2 (en) USE OF RILUZOLE FOR TREATING TRAUMATIC NEUROLOGICAL DAMAGES
DE3528979C2 (en)
DE69715862T2 (en) USE OF A K-252A DERIVATIVE TO TREAT PERIPHERAL OR CENTRAL NERVOUS DISEASES AND EXCESSIVE CYTOKINE FORMATION
DE69106586T2 (en) Use of baclofen for the manufacture of medicaments for the treatment of angina pectoris.
DE69132797T2 (en) Use of vincristine to evaluate active substances in the central nervous system
DE69224069T2 (en) PHARMACEUTICAL COMBINATION PRODUCT CONTAINING A URICOSURIC AGENT AND AN EXCITATORIC AMINO ACID ANTAGONIST
DE60118953T2 (en) FARNESYL PROTEIN TRANSFERASE HEMMER FOR THE TREATMENT OF INFLAMMATORY ENDURANCE
DE60012230T2 (en) USE OF OLIGOSACCHARIDE-CONTAINING DERMATOLOGIC PREPARATION FOR THE TREATMENT OF SKIN DISEASES
DE60106026T2 (en) 2-ARACHIDONYLGLYCEROL (2-AG) - AN INHIBITOR OF TUMOR NECROSIS FACTOR ALFA AND NEUROPROTEKTOR OF BRAIN IN CLOSED HEAD BREAKDOWNS
EP0083600B1 (en) Use of alkaloid derivatives for the manufacture of a medicament for the strengthening of the immune system and for the treatment of viral, bacterial and fungal infections
DE60210101T2 (en) Treatment of hair follicles especially against hair loss
EP0856312A1 (en) Use of trospium chloride for the manufacture of a medicament for the treatment of diseases of the bladder
DE60026491T2 (en) MELAGATRAN FOR THE TREATMENT OF INFLAMMATION
DE69008853T2 (en) Use of a derivative of 1,3,7-trimethylxanthine for the treatment of memory disorders, intellectual disorders in old age, and in Alzheimer&#39;s disease.
DE69232516T2 (en) Treatment of neurological conditions by an interleukin-i inhibitory compound
EP3747454B9 (en) Amyloid-beta binding peptides and these peptides for use in the therapy and diagnosis of alzheimer&#39;s dementia
DE69932834T2 (en) New peptides
DE2608079A1 (en) DRUG PREPARATION IN THE FORM OF A DRY PREPARATION FOR THE PREPARATION OF INJECTIONS
WO1999042088A2 (en) Method for the treatment of diseases or disorders of the inner ear
EP0493662B1 (en) Use of superoxide dismutase for the preparation of drugs for the prophylaxis and/or treatment of organ failure in risk patients having a polytrauma due to an accident
DE60125955T2 (en) BIOACTIVE FRACTION OF EURYCOMA LONGIFOLIA
DE69814089T2 (en) USE OF A DRAFLAZINE ANALOGUE FOR TREATMENT
DE60206169T2 (en) COMBINATION CONTAINING A P-GP INHIBITOR AND AN ANTI-PILEPTIC ACTIVE
WO2007048846A1 (en) Use of iron-chelating compounds, cyclic adenosine monophosphate-increasing compounds or combinations thereof for treating axonal lesions in the cns
DE69326188T2 (en) Use of N-acyl derivatives of amino alcohols for the manufacture of a medicament for the treatment of neurogenic endoneural edema of the peripheral nerves

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 06807622

Country of ref document: EP

Kind code of ref document: A1