WO1992010200A1 - Interactions fonctionnelles entre un glial s-100b et des neurones serotoninergiques du systeme nerveux central - Google Patents

Interactions fonctionnelles entre un glial s-100b et des neurones serotoninergiques du systeme nerveux central Download PDF

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WO1992010200A1
WO1992010200A1 PCT/US1991/009383 US9109383W WO9210200A1 WO 1992010200 A1 WO1992010200 A1 WO 1992010200A1 US 9109383 W US9109383 W US 9109383W WO 9210200 A1 WO9210200 A1 WO 9210200A1
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subject
neurons
antibody
agonist
serotonergic
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PCT/US1991/009383
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Efrain C. Azmitia
Patricia M. Witaker-Amitia
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New York University
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    • 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
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • 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
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/48—Ergoline derivatives, e.g. lysergic acid, ergotamine
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/475—Growth factors; Growth regulators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/286—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against neuromediator receptors, e.g. serotonin receptor, dopamine receptor
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the invention in the field of neuroscience and medicine relates to a cortical growth factor produced by astroglial cells which is trophic for cortical and serotonergic neurons in the brain.
  • Serotonergic neurons which release serotonin (5- hydroxytryptamine, 5-HT) as a neurotransmitter, play a key role in the general maturation of the brain. Changes in the innervation density of serotonergic nerve fibers would be expected to induce changes in the maturation of "target" neurons with which the serotonergic fibers communicate.
  • SGF brain serotonergic growth factor
  • a high speed supernatant prepared from 5,7-DHT-lesioned hippocampus could stimulate fetal serotonergic neurons both in culture (Azmitia et al.. Soc. Neurosci. Abstr. 12 (1986)) and upon transplantation into the adult cerebellum (Zhou et al.. Brain Res. 507:301-308 (1990)), suggesting that the trophic substance is a soluble protein.
  • Binding studies with appropriately labelled ligands initially revealed the existence of two major types of serotonin receptors in the brain, termed 5-HT j and 5-HT 2 , and later pointed to the existence of further subtypes, such as 5-HT and 5-HT lb (Peroutka, S.J. et al. , Feder.
  • 5-HT receptors e.g., 5-HT 3 and 5- HT 4
  • Whitaker- Azmitia P.M. et al. , Eds., Ann. N.Y. Acad. Sci. volume 600 (1990)
  • Serotonin neurons have been shown to regulate their own development, i.e. to "autoregulate" (Whitaker- Azmitia, P.M. et al. , Neurosci. Lett. 67:307-312 (1986)), due in part to release of growth factors by stimulation of 5-HT la receptors on astrocytes ( hitaker-Azmitia, P.M. et al. , J. Neurochem. 4 ⁇ :1186-91 (1986)).
  • Glial cells such as astrocytes, have 5-HT receptors ( hitaker et al.. ibid...
  • Nerve growth factor appears to act as a CNS cholinergic growth factor (Hefti, J. Neurosci. 6 . :2155-2162 (1986)).
  • Epidermal growth factor (EGF) has trophic effects on neuron-like PC-12 cells .Leonard et al.. Mol. Cell. Biol. 7:3156-3167 (1987); Isobe, T. et al. , J. Neurochem. 43 . :1.494-1496 (1984)). Insulin has been shown to mediate growth of cultured fetal neurons (Heindenreich, K.A. et al.
  • the protein S-100 B which is composed of two ⁇ - subunits, stimulates neurite extension in cultured chick cortical neurons, hence its designation as a "cortical" growth factor (Kligman D., et al.. Proc. Natl. Acad. Sci. U.S.A. £32 . :7136-7139 (1985)). Calmodulin has been shown to have substantial structural homology and a similar Ca 2+ binding profile to S-100 B (Isobe, T. , et al.. Endocrinology 125.:1451-1457 (1989))
  • S-100 A family of proteins named S-100 was first isolated nearly 25 years ago (Moore, B.W. , Biochem. Biophys. Res. Co mun. 19_:739-742 (1965)). The member of this family designated S-100 B was known to promote neurite extension in chick embryo cultures (Klig an, D. et al. , Proc. Natl. Acad. Sci. USA 82 . :7136-39 (1985)). S-100 production was stimulated in cultures of the rat astroglioma line, C6, by dibutyryl cyclic AMP (Labourdette, G. et al.. Biochem. Biophvs. Res. Comm. 96:1702-09 (1965)). Furthermore, S-100 may be releasable from brain tissue (Shashoua, V.E. et al. , J. Neurochem. 42:1536-41 (1984)).
  • NGF neurotrophic factor
  • S-100 B shows an intense yet transient rise in the midline raphe region, where the serotonergic neurons are developing (Van Hartesveldt, C.J. et al.. J. Comp. Neurol. 253:175-184 (1986)).
  • the human gene for the ⁇ subunit of S-100 has been mapped to the distal half of the long arm of chromosome 21, a candidate region associated with the pathology of Down ⁇ s Syndrome and Alzheimer's Disease (Allore, R. et al. , Science 239:1311-1313 (1988)).
  • This gene was recently shown to contain the cAMP responsive element, CRE, on the promoter region (Allore, R. et al. , _____ Biol. Chem. 265:15537-15543 (1990)).
  • recent studies have shown an increase in S-100 immunoreactivity in postmortem Alzheimer's Disease and Down's Syndrome brains (Griffin, W.S.T. et al. , Proc. Natl. Acad. Sci. USA 86:7611- 7615 (1989)). Therefore, greater understanding of the physiological actions of S-100 and knowledge of which factors regulate its release are believed to be important for the understanding and treatment of both disorders.
  • S-100 B is the protein released by astroglial cells upon stimulation of their 5-HT la receptors which promotes the growth of serotonergic and cortical neurons. Therefore, they have developed methods for manipulating S100 B , and through it, serotonergic and cortical neuronal growth and maintenance.
  • the present invention is directed to a method for stimulating the production of S-100 B in a subject, comprising administering an effective amount of an agonist acting on the 5-HT la receptor.
  • the 5HT la agonists useful in the present invention include 5-hydroxytryptamine, 5-methoxytryptamine, buspirone, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH- DPAT) , ipsaspirone, gepirone, SM23997, lysergic acid diethylamide, and agonistic antibodies.
  • the present invention is further directed to a method for stimulating growth of central serotonergic neurons in a subject comprising administering to the subject an effective amount of S-100 B/ a functional derivative thereof, or an agonist acting at the 5-HT la receptor, such as those described above.
  • the present invention includes a method for stimulating the growth of central serotonergic neurons in vitro or in vivo by contacting the neurons with S100 B or a functional derivative thereof.
  • a method for stimulating the growth of central serotonergic neurons in vitro or in vivo by contacting the neurons with S100 B or a functional derivative thereof.
  • _____ vivo contacting is preferred.
  • the present invention involves a method for inhibiting the growth of central serotonergic neurons comprising contacting the neurons with an effective amount of an inhibitor of S-100terrorism production or action.
  • the inhibitor may be an antibody specific for S-100 B or a 5-HT la receptor antagonist, such as spiperone and spiroxatine.
  • the present invention relates to a method for treating a disease associated with decreased central serotonergic innervation or activity in a subject comprising administering an effective amount of S-100 B , a functional derivative thereof or a 5-HT agonist.
  • Diseases for which this method is useful include autism, depression, anxiety, biological rhythm-based sleep disorder, and cortical brain damage, as well as the treatment of neuronal loss associated with normal aging.
  • the present invention is directed to a method for treating a disease associated with increased central serotonergic innervation or activity in a subject comprising administering an effective amount of an inhibitor of S-100 B production or action.
  • Such inhibitors include an antibody specific for S-100 B and a 5-HT la receptor antagonist.
  • the invention is directed to a method for stimulating cortical neuronal growth in a subject having Alzheimer's disease comprising the steps of:
  • Figure 1 is a histogram showing the effects of EGF (0.5 ⁇ g/ml) , NGF (10 ⁇ g/ml) , S-100 B (10 ⁇ g/ml) and insulin (100 ⁇ g/ml) added daily in 5-fold serial dilutions (most concentrated dose at right) on serotonin uptake.
  • EGF 0.5 ⁇ g/ml
  • NGF 10 ⁇ g/ml
  • S-100 B 10 ⁇ g/ml
  • insulin 100 ⁇ g/ml
  • Figure 3 is a histogram showing a morphometric analysis of the total neurite length for individual 5-HT- im unoreactive neurons after 30 h of stimulation. The bars represent the mean + S.E.M. for 10 neurons in each well (number shown under bars) .
  • Figure 4 is a graph showing effects of native bovine S-100 and of media from astroglial cells stimulated with the selective 5-HTj. agonist ipsapirone (GCM-IPS) on the growth of serotonergic neurons in culture as determined by selective uptake of 3 H-serotonin. Hatched bars indicate the effects of S-100 and GCM-IPS in the presence of an antibody to S-100 (final dilution 1/10,000) . Each bar represents the mean ⁇ S.E.M. of 4 cultures, derived from different litters. S-100, GCM-IPS and the antibody were all added at time of plating and the growth assessed 3 days later.
  • S-100 B is a serotonergic growth factor (SGF) . Since this protein has no effect on cholinergic and noradrenergic neurons, nor on cells in the peripheral nervous system, it can be said to be specific for central serotonergic nerves.
  • SGF serotonergic growth factor
  • Serotonin neurons have been shown to autoregulate their own development (Whitaker-Azmitia, P.M. et al. , Neurosci. Lett. 67:307-312 (1986)).
  • the present inventors first discovered that this autoregulatory circuit involves the release of a growth factor or factors induced by stimulation of 5-HT la receptors on astrocytes (Whitaker- Azmitia, P.M. et al. , J. Neurochem. 46:1186-91 (1986)).
  • the present invention is based on the discovery by the present inventors that the growth factor released in response to 5-HT la receptor stimulation is S-100 B . Therefore, the present invention is directed to the use of 5-HT la agonists or antagonists as therapeutics, acting via the regulation of S-100 B production and/or release from astroglial cells.
  • the present invention is directed to methods involving the use of the S-100 B protein, which is a dimer of two ⁇ chains, and is found exclusively in the brain, in contrast to ⁇ -o: or a- ⁇ dimers, which are also found outside the brain. Also included within the scope of the present invention are functional derivatives of the S-100 B protein.
  • мем ⁇ онент is meant a “fragment,” “variant,” “analog,” or “chemical derivative” of S-100 B , which terms are defined below.
  • a functional derivative retains at least a portion of the function of the S-100 B whic permits its utility in accordance with the present invention, namely serotonergic or cortical growth factor activity.
  • a “fragment” of the S-100 relief refers to any subset of the molecule, or of the ⁇ chain, such as a shorter peptide.
  • a "variant" of the S-100 B refers to a molecule substantially similar to either the entire peptide or a fragment thereof. Variant peptides may be conveniently prepared by direct chemical synthesis of the variant peptide, using methods well-known in the art or by recombinant DNA technology. Amino acid sequence variants of the S-100 B molecule can also be prepared by mutations in the DNA. Such variants include, for example, deletions from, or insertions or substitutions of, residues within the amino acid sequence. Any combination of deletion, insertion, and substitution may also be made to arrive at the final construct, provided that the final construct possesses the desired activity, without placing the sequence out of reading frame and preferably not creating complementary regions that could produce secondary mRNA structure (see EP Patent Application Publication No.
  • these variants ordinarily are prepared by site- directed mutagenesis of nucleotides in the DNA encoding the S-100 B molecule, thereby producing DNA encoding the variant, and thereafter expressing the DNA in recombinant cell culture.
  • the variants typically exhibit the same qualitative biological activity as the naturally occurring analog.
  • An “analog” of S-100 B refers to a non-natural molecule substantially similar to either the entire molecule or a fragment thereof.
  • a "chemical derivative" of S-100 B contains additional chemical moieties not normally a part of the protein or peptide.
  • Covalent modifications of the protein are included within the scope of this invention. Such modifications may be introduced into the molecule by reacting targeted amino acid residues with an organic derivatizing agent that is capable of reacting with selected side chains or terminal residues.
  • salts of the proteins and peptides of the invention refers to both salts of carboxyl groups and to acid addition salts of amino groups of the protein or peptide molecule.
  • Salts of a carboxyl group may be formed by means known in the art and include inorganic salts, for example, sodium, calcium, ammonium, ferric or zinc salts, and the like, and salts with organic bases such as those formed for example, with amines, such as triethanolamine, arginine, or lysine, piperidine, procaine, and the like.
  • Acid addition salts include, for example, salts with mineral acids such as, for example, hydrochloric acid or sulfuric acid, and salts with organic acids such as, for example, acetic acid or oxalic acid.
  • agonist is intended any chemical or biological substance capable of binding to a particular receptor, such as the 5-HT la receptor according to the present invention, and stimulating a biological response associated with the receptor.
  • the term is intended to include an endogenous molecule which exerts its physiological action by receptor binding and triggering of a signal to a cell, as well as an exogenous agent which mimics the action of such an endogenous agonist.
  • a receptor is linked to a second messenger system that signals a positive response, such as, for example, the increased production and/or secretion of a protein growth factor
  • an agonist will induce production and/or secretion of the growth factor.
  • a receptor is linked to a second messenger system which signals a negative response, such as a termination of cell growth, an agonist for that receptor will inhibit cell growth.
  • Agonists for 5-HT la receptors include, but are not limited to, 5-hydroxytryptamine (serotonin), 5-methoxytryptamine, buspirone (U.S. Patent 3,717,634), 8-hydroxydipropylamineotetralin, ipsaspirone (EPO Publication 129,128A), gepirone (U.S. Patent 4,423,049), SM23997 (U.S. Patent 4,507,303), MDL 72832 (U.S. Patent 4,612,312) and lysergic acid diethylamide.
  • newer polycyclic aryl- and heteroarylpiperazinyl imides with 5-HT -binding and activating properties such as WY-47,846 (cpd. 34) and other disclosed in Abou-Gharbia, M. et al. , J. Med. Che . 31:1382-1392 (1988), may be useful in the present invention. (All of the above references to agonists are hereby incorporated by reference) .
  • an antibody to the 5-HT la receptor which by virtue of its epitope specificity stimulates a response, rather than inhibiting the binding of an agonist, termed an "agonistic antibody,” is also an agonist as intended herein.
  • the present invention is intended to encompass additional 5-HT la receptor agonists, including those not yet discovered.
  • antagonist is intended a substance which is itself devoid of intrinsic phar acologic activity and stimulates no biological response when bound to a receptor, but has the capacity to bind to a receptor and thereby inhibit binding of, or action of, an agonist.
  • antagonists act by competing for agonist binding to a receptor.
  • Antagonists for 5-HT la receptors include, but are not limited to, spiperone and spiroxatine.
  • an antibody specific for the 5- HT Ja receptor which does not have agonist activity, but inhibits binding or action of an agonist, is also an antagonist, as intended herein.
  • newer polycyclic aryl- and heteroarylpiperazinyl imides with 5- HT la -binding properties which would inhibit binding of endogenous agonists (Abou-Gharbia, M. et al. , supra. may be useful as antagonists in the present invention.
  • the antibodies of the present invention are those which are specific for, and interact with, S-100 B or with 5THla receptors and modulate the action of the S-100 B - serotonergic neuron autoregulatory system.
  • antibody is meant to include polyclonal antibodies, monoclonal antibodies (mAbs) , chimeric antibodies, and anti-idiotypic (anti-Id) antibodies.
  • mAbs monoclonal antibodies
  • chimeric antibodies chimeric antibodies
  • anti-Id anti-idiotypic antibodies.
  • Polyclonal antibodies are heterogeneous populations of antibody molecules derived from the sera of animals immunized with an antigen.
  • Monoclonal antibodies are a substantially homogeneous population of antibodies to specific antigens.
  • MAbs may be obtained by methods known to those skilled in the art. See, for example Kohler and Milstein, Nature 256:495-497 (1975) and U.S. Patent No. 4,376,110.
  • Such antibodies may be of any immunoglobulin class including IgG, IgM, IgE, IgA, GILD and any subclass thereof.
  • the hybridoma producing the mAbs of this invention may be cultivated in vitro or in vivo. Production of high titer ⁇ of mAbs in vivo production makes this the presently preferred method of production.
  • MAbs of isotype IgM or IgG may be purified from such ascites fluids, or from culture supernatants, using column chromatography methods well known to those of skill in the art.
  • Chimeric antibodies are molecules different portions of which are derived from different animal species , such as those having variable region derived from a murine mAb and a human immunoglobulin constant region. Chimeric antibodies and methods for their production are known in the art (Cabilly et al. Proc. Natl. Acad. Sci. USA 81:3273-3277 (1984) ; Morrison et al.. Proc. Natl. Acad. Sci. USA 81:6851-6855 (1984); Boulianne et al.. Nature 312:643-646 (1984); Neuberger _______ Nature 314:268-270 (1985);
  • An anti-idiotypic (anti-Id) antibody is an antibody which recognizes unique determinants generally associated with the antigen-binding site of an antibody.
  • An Id antibody can be prepared by immunizing an animal of the same species and genetic type (e.g. mouse strain) as the source of the mAb with the mAb to which an anti-Id is being prepared. The immunized animal will recognize and respond to the idiotypic determinants of the immunizing antibody by producing an antibody to these idiotypic determinants (the anti-Id antibody) .
  • the anti-Id antibody may also be used as an "immunogen" to induce an immune response in yet another animal, producing a so-called anti-anti-Id antibody.
  • the anti-anti-Id may be epitopically identical to the original mAb which induced the anti-Id.
  • antibodies to the idiotypic determinants of a mAb it is possible to identify other clones expressing antibodies of identical specificity.
  • mAbs generated against S-100 B may be used to induce anti-Id antibodies in suitable animals, such as BALB/c mice.
  • Spleen cells from such immunized mice are used to produce anti-Id hybridomas secreting anti-Id mAbs.
  • the anti-Id mAbs can be coupled to a carrier such as keyhole limpet hemocyanin (KLH) and used to immunize additional BALB/c mice.
  • KLH keyhole limpet hemocyanin
  • Sera from these mice will contain anti-anti-Id antibodies that have the binding properties of the original mAb specific for a S- 100 B epitope.
  • the anti-Id mAbs thus have their own idiotypic epitopes, or "idiotopes" structurally similar to the epitope being evaluated, such as an S-100 B epitope, and possessing biological activity of S-100 B .
  • antibody is also meant to include both intact molecules as well as fragments thereof, such as, for example, Fab and F(ab') 2 , which are capable of binding antigen.
  • Fab and F(ab') 2 fragments lack the Fc fragment of intact antibody, clear more rapidly from the circulation, and may have less non-specific tissue binding than an intact antibody fWahl et al.. J. Nucl. Med. 24:316-325 (1983)).
  • Fab and F(ab'), and other fragments of the antibodies useful in the present invention may be used according to the methods disclosed herein for intact antibody molecules.
  • Such fragments are typically produced by proteolytic cleavage, using enzymes such as papain (to produce Fab fragments) or pepsin (to produce F(ab•) 2 fragments) .
  • an antibody is said to be “capable of binding” a molecule if it is capable of specifically reacting with the molecule to thereby bind the molecule to the antibody.
  • epitope is meant to refer to that portion of any molecule capable of being bound by an antibody which can also be recognized by that antibody. Epitopes usually consist of chemically active surface groupings of molecules such as amino acids or sugar side chains and have specific three dimensional structural characteristics as well as specific charge characteristics.
  • an "antigen” is a molecule or a portion of a molecule capable of being bound by an antibody which is additionally capable of inducing an animal to produce antibody capable of binding to an epitope of that antigen.
  • An antigen may have one, or more than one epitope. The specific reaction referred to above is meant to indicate that the antigen will react, in a highly selective manner, with its corresponding antibody and not with the multitude of other antibodies which may be evoked by other antigens.
  • the preferred animal subject of the present invention is a mammal.
  • mammal an individual belonging to the class Mammalia.
  • the invention is particularly useful in the treatment of human subjects.
  • treating is " intended the administering to subjects of S-100 B , a functional derivative thereof, or an agonist or antagonist of the 5-HT receptor, for purposes which may include prevention, amelioration, or cure of the diseases discussed below.
  • administration may be by parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, or buccal routes.
  • Preferred routes for administration of substances which do not cross the blood- brain barrier (such as proteins and larger peptides) to subjects with fully developed blood-brain barriers include intracranial and intracerebroventricular (i.e.v.) routes.
  • administration may be by the oral route.
  • the dosage administered will be dependent upon the age, health, and weight of the recipient, kind of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired.
  • an antibody to S-100 B or to a 5-HT la receptor is administered prenatally, neonatally or to an adult.
  • the antibody is given systemically to the pregnant female or is introduced in utero. for example, into the amniotic cavity.
  • an antibody is administered systemically, for example, by intravenous or intraperitoneal injection.
  • the antibody can cross the blood-brain barrier and enter the brain from the circulation in a young individual in whom the blood-brain barrier is not completely formed, as is well-known to those of skill in the art.
  • the antibody In an individual with a fully formed blood-brain barrier, as in an adult, in order to be effective, the antibody, according to the present invention, must be administered intracranially (i.e.), preferably into the cerebral ventricles (i.e.v.) via a cannula, using methods well-known in the art.
  • the S-100 B protein or a functional derivative thereof is administered prenatally, neonatally, or to an adult as described above for an antibody or fragment thereof.
  • the present invention contemplates pharmaceutical preparations which may contain suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically.
  • the preparations particu ⁇ larly those preparations which can be administered orally and which can be used for the preferred type of administration, such as tablets, dragees, and capsules, and also preparations which can be administered rectally, such as suppositories, as well as suitable solutions for administration by injection or orally, contain from about 0.01 to 99 percent, preferably from about 20 to 75 percent of active compound(s) , together with the excipient.
  • Suitable excipients are, in particular, fillers such as saccharides, for example, lactose or sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example, tricalcium phosphate or calcium hydrogen phosphate, as well as binders such as starch paste, using, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/or polyvinyl pyrrolidone.
  • fillers such as saccharides, for example, lactose or sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example, tricalcium phosphate or calcium hydrogen phosphate, as well as binders such as starch paste, using, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl
  • disintegrating agents may be added such as the above-mentioned starches and also carboxymethyl-starch, cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate.
  • Auxiliaries are, above all, flow- regulating agents and lubricants, for example, silica, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and/or polyethylene glycol.
  • a number of major developmental disorders involve central serotonergic systems. Autism and Down's Syndrome (DS) are associated with altered serotonergic forebrain innervation, as seen upon postmortem examination of brains from patients with this disorder (Anderson, G.M. et al.. Ann. N.Y. Acad. Sci. 600:331-342 (1990)). Hyperserotonine ia has been observed in autistic children and an antibody specific for the human cortical 5-HT receptor has been identified in an autistic patient (Anderson, G.M. et al. , supra) .
  • the present invention provides a means for treating an individual affected by autism or DS in early developmental stages, for example, while in utero. Thus, for example, S-100 electron, a functional derivative thereof, or 5-HT la agonist is administered to a pregnant woman carrying a fetus diagnosed as having autism or DS.
  • AD Alzheimer's Disease
  • the present invention provides a method for treating AD by manipulating the serotonergic system to cause release of S-100 B to stimulate growth of cortical neurons.
  • the method is directed to first up-regulating the astroglial 5HT la receptors in order to render them sensitive to 5HT or exogenous agonists, and then to treating with the agonists in order to stimulate S-100 B release.
  • Up-regulation of the 5HT la receptors is accomplished by any of a number of means known in the art for depleting central 5HT or blocking its action.
  • Such means include depleting stored serotonin from nerve terminals by agents such as reserpine, fenfluramine or methylene deoxymethamenpetamine (MDMA) (Whitaker-Azmitia, P.C.
  • Such treatment must be performed for a period of time ranging from about 3 days to about 4 weeks.
  • a period of time ranging from about 3 days to about 4 weeks.
  • the treatment method of the present invention involves providing to the brain a 5HTj a receptor agonist such as those described above, preferably by the oral route, in a dose range of about 1 ⁇ g/kg to about 10 mg/kg, for a duration of about 3 days to about 4 weeks, in order to release the S-100 B accumulating in the astroglia.
  • the released S-100 B then acts as a cortical growth factor to stimulate growth of cortical neurons deficient in AD.
  • any pathological process associated with loss of cortical neurons, or serotonergic neurons or their activity, or lack of normal maintenance of serotonergic innervation can be treated according to the methods of the present invention.
  • Such neuronal loss may accompany normal aging.
  • the present invention is thus directed to a method of treating neuronal loss in an aging individual with S-100 radical, a functional derivative thereof, or a 5-HT la agonist which stimulates S-100 B production by astroglial cells in situ. If necessary, as described for AD, prior treatment may be used to up-regulated 5HT la receptors in order to allow stimulation of S-100 B release.
  • Affective disorders in particular depression, are diseases with an important serotonergic component.
  • the mode of action of many effective antidepressant drugs is considered to occur via inhibition of 5HT re-uptake, thus prolonging the availability of 5HT to act on post-synaptic 5HT receptors.
  • uptake blockade can occur within minutes of treatment, therapeutic benefits are typically seen only after prolonged (e.g. 3 weeks) of antidepressant therapy (see, for example, Gilman et al.. supra) .
  • stimulation of serotonergic neuronal growth by treatment with S-100 tone, a functional derivative thereof, or a 5-HT la agonist which stimulates endogenous S-100 B production can be used to treat depression.
  • a subject in need of treatment is administered an effective amount of S-100 jail, a functional derivative thereof, or a 5-H ⁇ a agonist.
  • the treatment with S-100 B , or functional derivatives which do not cross the blood-brain barrier is by i.e.v. infusion.
  • the protein or derivative may be administered systemically.
  • 5-HT agonists most of which readily cross the blood-brain barrier, are administered systemically.
  • Antidepressant agents have also been useful in the treatment of anxiety and obsessive-compulsive disorders (Gilman et al. , supra) , indicating the involvement of the serotonergic system in these states.
  • 5HT is involved in synchronization of biological rhythms, and dysregulation may result in sleep disorders (Wauquier, A. et al.. Ann. N.Y. Acad. Sci. 600:447-459 (1990)).
  • S-100 B a functional derivative thereof, or a 5-HT la agonist may be used to treat anxiety and sleep disorders due to its action as an inducer of central serotonergic neuronal growth, as described above for treatment of depression.
  • Schizophrenia a major psychiatric illness, is increasingly looked upon as a developmental disorder of the dopaminergic (DA) system wherein central DA activity is increased (Seene, P., Pharmaco1. Rev. (1982)).
  • the DA system appears to interact physiologically with serotonergic neurons in a way that stimulation of 5HT results in decrease in DA.levels. Therefore, stimulation of growth of serotonergic neurons by administration of S-100 B or a functional derivative thereof according to the present invention may be useful in preventing or reversing the effects of enhanced dopaminergic activity, and thus the development of schizophrenia.
  • S- 100 B or a 5-HT la agonist which stimulates astroglial production and/or secretion of S-100 B is administered to a pregnant female carrying a fetus at risk for schizophrenia, either systemically or by intrauterine introduction.
  • S- 100 B Due to its action as a cortical growth factor, S- 100 B promotes the growth and maintenance of cortical neurons, most of which utilize glutamate as their neurotransmitter. According to the present invention, S-100 B , a functional derivative thereof, or a 5-HT la receptor agonist may be used to induce repair of cortical neurons following cortical brain damage, such as that associated with traumatic head injury or stroke. Treatment of a subject in need of repair of cortical neurons is performed as described above for other diseases.
  • the amounts and regimens for the administration of S-100 B and functional derivatives thereof, 5-HT, a agonists and antagonists, and anti-S-100 B agonistic and antagonistic antibodies can be determined readily by those with ordinary skill in the clinical art of treating the particular disease. While individual needs vary, determination of optimal ranges of effective amounts of each component is within the skill of the art. Typical dosages comprise about 0.001 to 100 g/kg body wt. The preferred dosages comprise 0.1 to 10 mg/kg body wt.
  • the present invention also contemplates the implantation or transplantation of an astroglial cell capable of producing S-100 B to a subject having a deficit in such cells or having a genetic lesion rendering such cells non-functional, for example, non-responsive to 5-HT la receptor stimulation.
  • implanted cells may be derived from fetal or adult brain or may be a long term cell line, such as the C6 cell line (Labourdette, G. et al.. supra) , which is maintained in culture.
  • Such cells can be implanted in specific target regions in the brain in order to stimulate serotonergic cell growth or cortical cell growth, as discussed above. (See, also: Azmitia, E.C. ________ , Eds., Ann. N.Y. Acad. Sci.., vol.495 (1987)).
  • S-100 B is an SGF.
  • EGF, insulin and calmodulin were not found to produce any stimulation, indicating that the SGF activity of S-100 B was not a byproduct of its Ca 2+ binding potential nor was it due to a general mitogenic potential.
  • S-100 in the brain is an astroglial specific protein (Isobe, T. et al.. supra) .
  • Recent results have shown that the SGF properties of 5-HT ⁇ a - ⁇ timulated, glial cell conditioned medium is blocked by treatment with an anti-S-100 antibody (see Example II, below) .
  • astroglial cells were stimulated in primary culture with 100 nM ipsaperone (IPS) , a 5-HT ia receptor agonist, and collected the conditioned media (GCM- IPS) .
  • IPS ipsaperone
  • GCM- IPS conditioned media
  • the growth-promoting properties of native bovine S- 100 (10-1000 ng/ml and of GCM-IPS (diluted 1 to 500) were compared.
  • the S-100 was obtained from East Acres Biological ⁇ , Southbridge, MA (guaranteed >99% homogenous by SDS-PAGE) .
  • S-100 or GCM-IPS or each of these in the presence of a polyclonal antibody to S-100 (Accurate Chemical, Westbury, NY; final dilution 1/10,000) were added at the time of neuronal plating.
  • the polyclonal antibody had been characterized in our laboratory and shown to be positive for immunocytochemical staining of astrocytes in culture and brain) .
  • astroglial cultures After exposure to serum-free media with or without 100 nM ipsapirone, cultures were rinsed twice with Tris-buffered saline (TBS) at 4°C before incubation with a polyclonal antibody to a specific astroglial marker, glial fibrillary acidic protein (GFAP) (Accurate Chemicals; final dilution 1/800 in TBS with 0.2% Triton and 0.1% normal swine serum) for 2 hrs at 37°C. After rinsing with TBS, the cultures were stained using the avidin/biotin method prepared as Vectastain (Vector Labs) with final visualization using diaminobenzidine.
  • TBS Tris-buffered saline
  • GFAP glial fibrillary acidic protein
  • S-100 provides at least one means by which serotonin can autoregulate development of serotonergic nerves.
  • S-100 shows an intense yet transient rise in the midline raphe region, where the serotonin cells are developing (Van Hartesveldt, C.J. et al. , J. Comp. Neurol. 253:175-184 (1986)). Since in the process of producing and/or releasing S-100, the astroglial cells attain a mature morphology, the present results suggest a functional interaction between astrocytes and neurons during development, whereby both cell types mature through the action of the astroglial 5-HT, a receptor.
  • Stimulation of astroglial 5-HT receptor causes astroglial cells to acquire a more mature morphology and to release a factor (or factors) which promotes growth of serotonergic neurons.
  • a factor or factors which promotes growth of serotonergic neurons.
  • S-100 the astroglial-specific protein S-100. This may be a particularly important observation, in view of studies implicating S-100 in both Down's Syndrome and Alzheimer's Disease, as discussed above.

Abstract

La production de S-100B chez un sujet est stimulée par l'administration d'une dose efficace d'un agoniste agissant sur le récepteur de 5HT1a, la croissance de neurones sérotoninergiques centraux est stimulée par mise en contact des neurones avec une dose efficace de S-100B, et la croisance de neurones sérotoninergiques centraux est inhibée par mise en contact des neurones avec une dose efficace d'un inhibiteur de la production ou de l'action de S-100B. De plus, on peut traiter par lesdits procédés des maladies associées à une innervation ou à une activité sérotoninergique centrale diminuée, parmi lesquelles l'autisme, la dépression, l'anxiété, les troubles du sommeil basés sur le rythme biologique, ainsi que la détérioration du cortex. Des maladies associées à une innervation sérotoninergique centrale accrue et à une libération inefficace de S-100B astroglial, telles que la trisomie 21 et la maladie d'Alzheimer peuvent être traitées par régulation positive des récepteurs de 5HT1a sur des cellules astrogliales, suivie d'une stimulation de la production ou de la libération de S-100B à l'aide d'un agoniste de récepteur de 5HTa.
PCT/US1991/009383 1990-12-14 1991-12-13 Interactions fonctionnelles entre un glial s-100b et des neurones serotoninergiques du systeme nerveux central WO1992010200A1 (fr)

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US5990080A (en) * 1995-10-17 1999-11-23 A+ Science Invest Ab Use of protein S-100-b in medicines containing the protein S-100b
US6903188B2 (en) 1999-09-10 2005-06-07 Prolifia Inc. Neurogenic compositions and methods
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