KR20070019001A - Use of neurotrophic factor stimulators for the treatment of ophthalmic neurodegenerative diseases - Google Patents

Abstract

Disclosed are compositions and methods for the treatment of retina and optic head neuropathy. The compositions and methods relate to the use of neurological factor stimulants such as AIT-082 (neotropin) and the like, particularly in the treatment of glaucoma neuropathy.

Nerve factor stimulant, Neutropin, Retina, Optic head, Neuropathy, Glaucoma

Description

Nerve factor stimulant for the treatment of ocular neurodegenerative diseases {USE OF NEUROTROPHIC FACTOR STIMULATORS FOR THE TREATMENT OF OPHTHALMIC NEURODEGENERATIVE DISEASES}

The present invention relates to neurotrophic factor stimulants for the treatment of ocular neurodegenerative diseases.

Primary open-angle glaucoma (POAG) is a progressive disease that causes optic nerve damage and eventually blindness. The cause of the disease has not been fully understood, although it has been the subject of research for many years. Glaucoma causes neurodegeneration in the retina and optic nerve head, which is usually associated with progressive medical and surgical treatment of retinal neurons (retinal ganglion cells ("RGCs")). It does not stop the decline (Van Buskirk et al . , Predicted outcome from hypotensive therapy for glaucomatous optic neuropathy , Am . J. Ophthalmol . , volume 25, pages 636-640 (1993); Schumer et al . , The nerve of glaucoma ! , Arch . Ophthalmol . , volume 112, pages 37-44 (1994)).

Numerous theories have been proposed to explain the etiology of glaucoma. One theory suggests that excessive intraocular pressure (in some cases related to optic heads, RGCs, or genetic defects in the optic nerve) destroys the normal axonal transport function along the optic nerve. .

Crosstalk in the axon transport of the optic nerve impedes the movement of intracellular molecules between RGC cell bodies and their ends. Important intracellular molecules include neurological factors. Neuronal factors are peptide molecules that stimulate or maintain the growth of neural tissues, and the loss of psychotropic factors may induce neuronal apoptosis because the transport of these neuronal factors from the brain to RGC cell bodies is essential for RGC survival. Raff et al . , Programmed cell death and the control of cell survival : lessons from the nervous system , Science , volume 262, pages 695-700 (1993)).

The loss of neurological factors can be attributed to glaucoma-induced RGC killing, which may be supported by a lot of experimental evidence (Anderson et. al . , Effect of intraocular pressure on rapid axoplasmic transport in monkey optic nerve , Invest. Ophthalmol . , volume 13, pages 771-783 (1974); Quigley et al . , The dynamics and location of axonal transport blockade by acute intraocular pressure elevation in primate optic nerve , Invest . Ophthalmol . , volume 15, pages 606-616 (1976); Mansour-robaey et al . , Effects of ocular injury and administration of brain - derived neurotrophic factor on survival and regrowth of axotomized retinal ganglion cells , Proc . Natl . Acad . Sci . USA , volume 91, pages 1632-1636 (1994); Meyer-Franke et al . , Characterization of the signaling interactions that promote the survival and growth of developing retinal ganglion cells in culture , Neuron , volume 15, pages 805-819 (1995); And Cui et al . , NT -4/5 reduces naturally occurring retinal ganglion cell death in neonatal rats , Neuroreport, volume 5, pages 1882-1884 (1994)). These neurological factors include neurotrophin and some other cytokines.

Neurotrophin ("NT") family peptides include nerve growth factor (NGF), brain-derived neuronal factor (BDNF), NT-3, NT-4 / 5 and NT-6, and include TrkA, TrkB, TrkC And neuronal surface receptors such as p75NTR. Trk receptors are tyrosine kinase. TrkA is selective for NGF, TrkB is selective for BDNF and NT-4 / 5, while TrkC is selective for NT-3. After binding, the NT-receptor complex is internalized and transported to the body via axons. These receptors are ligand-induced phosphorylation and dimerization, activating a series of Ras protein-mediated signal transduction processes and affecting a variety of important functions of neurons (Lewin et. al . , Physiology of the neurotrophins , Ann . Rev. Neurosci . , volume 19, pages 289-317 (1997); Segal et al . Intracellular signaling pathways activated by neurotrophic factors , Ann . Rev. Neurosci . , volume 19, pages 463-489 (1996); Ebadi et al . , Neurotrophins and their receptors in nerve injury and repair , Neurochem . Int . , volume 30, pages 347-374 (1997); Kaplan et al . , Signal transduction by the neurotrophin receptors , Curr. Opin . Cell Biol . , volume 9, pages 213-221 (1997)). Thus, these receptors play a fundamental role in the regulation of survival and differentiation in the development of neurons and contribute to the maintenance of adult neural organs.

In the retina, mRNAs of TrkA and TrkB have been found in RGCs, dopaminergic amacrine cells and optic nerves ("ON"). Their expression is known to be tightly regulated during neural development (Jelsmaet al .,Different forms of the neurotrophin receptor trkB mRNA predominate in rat retina and optic nerve,J. Neurobiol ., volume 24, pages 1207-1214 (1993); Rickmanet al.,Expression of the protooncogene , trk , receptors in the developing rat retina,Vis . Neurosci ., volume 12, pages 215-222 (1995); Ugoliniet al .,TrkA, TrkB and p75 mRNAexpression is developmentally regulated in the rat retina,Brain Res ., volume 704, pages 121-124 (1995); Cellerinoet al .,Brain -derived neurotrophic factor Of neurotrophin -4 receptor TrkB is localized on ganglion cells and dopaminergic amacrine cells in the vertebrate retina,J. Comp. Neurol ., volume 386, pages 149-160 (1997)). The TrkB receptor-selective ligands BDNF and NT-4 / 5 have been shown to be effective for the detection of RGCs. In numerous studies, these NTs not only improve the growth of axons and cell survival in RGC culture, but also significantly reduce axonal cleavage-induced in vivo damage in ON and RGCs, and also regenerate axon branches by regenerating RGCs. Has been shown to stimulate growth (cited above, Andersonet al.; Quigleyet al .; Mansour-robaeyet al .; Meyer-Frankeet al .; And Cui et al). For example, within 5 days after injury, a single injection of 5 μg of BDNF into the vitreous body prevented the death of the axon cleaved RGC (Mansour-Robaey, above).et al.). About half of the axon-cut RGCs were lost in the untreated retina, whereas in the retina injected once with BDNF all RGCs that were present on day 0 were present after one week. After ON injury, mRNA expression of BDNF in the RGC layer of rats increased substantially (Gaoet al .,Elevated mRNA expression of brain - derived neurotrophic factor in retinal ganglion cell layer after optic nerve injury,Invest . Ophthalmol. Vis . Sci ., volume 38, pages 1840-1847 (1997)), further illustrating the potential importance of this NT in retinal repair.

In addition to the protective effect against mechanical damage on the retina and / or ON, neurotrophin may be protective against other forms of neuronal damage. By yet unclear mechanisms (but perhaps by inhibition of apoptosis), BDNF protects CNS neurons from glutamate neurotoxicity (Lindholm et al. al . , Brain-derived neurotrophic factor is a survival factor for cultured rat cerebellar granule neurons and protects them against glutamate-induced neurotoxicity, Eur . J. Neurosci. , volume 5, pages 1455-1464 (1993)); Rat Retina (Unoki et al . , Protection of the rat retina from ischemic injury by brain - derived neurotrophic factor , ciliary neurotrophic factor , and basic fibroblast growth factor , Invest . Ophthalmol . Vis . Sci . , volume 35, pages 907-915 (1994)), and hippocampus (Beck et al . , Brain - derived neurotrophic factor protects against ischemic cell damage in the rat hippocampus , J. cereb . Blood Flow Metab . , volume 14, pages 689-692 (1994)).

Ciliary neurotrophic factor (CNTF) is another neurological factor that supports neuron survival. It is a member of the cytokine family that is not structurally related to Neutropin. CNTF and its receptors are expressed by Muller glia during retinal nerve production and differentiation (Kirschet al .,Evidence for multiple , local functions of ciliary neurotrophic factor ( CNTF ) in retinal development : expression of CNTF and its receptors and in in vitro effects on target cells,J. Neurochem., volume 68, pages 979-990 (1997)). In addition, since this factor prevents injury-induced death of RGC, it may be useful in preventing glaucoma.et al ., Intravitreal injections of neurotrophic factors support the survival of axotomized retinal ganglion cells in adult rats in vivo,Brain Res ., volume 602, pages 304-317 (1993)), while less effective than BDNF, prevent ON axon degeneration (Weibel).et al .,Brain - derived neurotrophic factor ( BDNF prevents lesion - induced axonal die - back in young rat optic nerve,Brain Res ., volume 679, pages 249-254 (1995)).

Thus, neurological factors play a therapeutic role in the symptoms of glaucoma retinopathy and general retinal degeneration. However, these factors are peptide molecules, and in general, there is a problem in bioavailability at the time of administration, which makes it difficult to develop pharmaceuticals. Therefore, it is necessary to stimulate psychoactive activity in retinal tissues deteriorated with non-peptide molecules so as to avoid the bioavailability problem of natural peptides.

Many psychoactive agent stimulants have been reported in the scientific literature, for example AIT-082 (Graul & Castaner, AIT -082 , Drugs of the Future , volume 22, pages 945-947 (1997)), Idebenon (Nabeshima et al . , Oral administration of NGF synthesis stimulators recovers reduced brain NGF content in aged rats and cognitive dysfunction in basal - forebrain - lesioned rats , Gerontology , volume 40, supplement 2, pages 46-56 (1994)), ONO-2506 (Matsui et al . , Protective effects of ONO -2506 on neurological deficits and brain infarct volume following 1 week of permanent occlusion of middle cerebral artery in rats , Society for Neurosci . Abstracts , volume 24, pages 254 (1998)), NS521 (Gronborg et. al . , Neuroprotection by a novel compound , NS521 , Society for Neurosci. Abstracts , volume 24, page 1551 (1998), CB-1093 (Aimone et al . , The 1α, 25 ( OH ) ₂ D ₃ analog CB -1093 induces nerve growth factor in non - human primate brain , Society for Neurosci . Abstracts , volume 24, page 292, (1998)) and clenbuterol (Culmsee et al . , NGF antisense oligonucleotide blocks protective effects of clenbuterol against glutamate - induced excitotoxicity in vitro and focal cerebral ischemia in vivo , Society for Neurosci . Abstracts , volume 24, page 295 (1998)). However, the present disclosure discloses or suggests the use of neurological factor stimulants in the treatment of glaucoma or other ocular neuropathy.

The present invention relates to compositions and methods for treating glaucoma and retinal degenerative diseases. The compositions and methods include neurological factor stimulants for the treatment of retinal or optic nerve head tissue in a dysfunctional or dangerous condition.

 Psychotic factor stimulants are substances that stimulate the activity and production of neurological factors in the retina, and the intraocular stimulation of these psychotropic factors improves the status of glaucoma neuropathy and other retinal and optic head degenerative diseases.

 Preferred compositions and methods relate to neuronal factor stimulants, AIT-082 (neotropin) and idebenone.

The present invention relates to compositions and methods for treating glaucoma and other retinal or optic head degenerative diseases. The composition comprises one or more neurological stimulants present in a pharmaceutically acceptable carrier.

The "neurotrophic factor stimulators" used herein should be within the (in total of the neurotrophic factor in the retina situ ) to compounds that increase production or activity. As used herein, “neurogenic factor” refers to a factor that treats or improves NGF, BDNF, NT-3, NT-4 / 5, NT-6, CNTF or other retinal neuropathy. Examples of neurological factor stimulants include AIT-082 (neotropin), idebenone, ONO-2506, CB-1093, NS521 ((1- (1-butyl) -4- (2-oxoso-1-benzimidazolone) Piperidine) SS-701, KT-711 and clenbuterol etc. The most preferred neuronal factor stimulant of the present invention is AIT-082 (neotropin). And those that can be synthesized by methods known to those skilled in the art.

[ Example ]

(Example 1)

The following examples illustrate the protective efficiency of the neurological factor stimulant (propentofylline) against retinal cell injury.

Retinal ganglion cell survival analysis Retinal Ganglion Cell Survival Assay )

Techniques for isolation and culturing of RGCs have been reported by Takahashi et al. (Takahashi N. et. al . , Rat retinal ganglion cells in culture , Exp . Eye Res . volume 53, pages 565-572 (1991)). The method involves injecting the fluorescent dye, Di-I, into the superior colliculi to degenerate the ganglion cells. After 2-4 days retinal cells were isolated and cultured RGCs were identified by visually observing Di-I fluorescence using a fluorescence microscope.

Sprague-Dawley rats, 2-5 days old, were anesthetized by hypothermia, and a 2 mm midline opening was made in the scalp to the traverse sinus. The tip of the injection needle (30 gauge) was inserted 6 mm below the top of the skull and 3 mg / ml Di-I (1,1'-dioctadecyl-3,3,3 ', 3'-tetramethylindo-carbosi Perchlorate (Molecular Probes, Eugene, Oregon) was injected with 5 μl of a Di-I solution dissolved in 90% ethanol and 10% dimethylsulfoxide. A drop of Flexible Collodion (Amend Drug & Chemical, Irvington, NJ) was then applied to the wound, and the anesthetized, warmed rat was returned to the mother.

Two to four days after the Di-I injection, the rats were anesthetized by hypothermia, sacrificed by monocephalus, and the eye was extracted and extracted with Dulbecco's Modified Eagle's Medium: Nutrient Mixture F12 (1: 1; DMEM / F12, Gibco, Grand Ireland, New York State). Retinas from each eye were detached and 12 retinas separated and 10 mg papain (34 units / ml; Sigma Chemical, St. Louis, Missouri), 2 mg DL-cysteine (3.3 mM; Sigma) in 5 ml of DMEM / F12 solution. Retinal cells were isolated by reacting for 25 minutes at 37 ° C. in 5 ml of papain solution containing Chemicals, St. Louis, Missouri) and 2 mg bovine serum albumin (0.4 mg / ml; Sigma Chemicals, St. Louis, Missouri) It was. Cells were then placed in DMEM medium (Gibco, Grand Island, NY), 10% fetal bovine serum (Hyclone, Logan, Utah), 4 mM glutamine (Gibco, Grand Island, NY), 100 units / ml penicillin And three washes with 5 ml of RGC medium added with 100 μg / ml streptomycin (Sigma Chemical, St. Louis, Missouri). Additional RGC medium was added to the retinal pieces to bring the final total volume to 40 ml, and the solution was triturated by passing through the disposable pipette several times to obtain dispersed cells. Cell suspension (1.5 ml; containing about 4.5 × 10 ⁶ cells) was placed in a poly-D-lysine coated glass bottom culture dish and incubated at 37 ° C. with 95% air / 5% CO ₂ . It was.

Cells treated or untreated with various therapeutic agents were isolated and 3 days later fetal bovine serum was removed from the culture. After 3 days, cells were observed 200 times magnification with a fluorescence microscope, and Di-I labeled fluorescent cells were counted in 20 microscopic fields and the average value was calculated. The results are shown in Table 1 below:

Table 1: Effect of neuronal factor stimulants on RGC survival

Serum-containing culture Pharmaceutical RGC survival rate (%) Yes none 100.0 ± 4.9 * no none 46.4 ± 5.6 no BDNF (5 μM) + Paul's Choline (10 ng / ml) 79.9 ± 5.4 * no Propentophylline (100 μM) 96.9 ± 4.8 *

Note: Define RGC survival in the presence of serum as 100%. All values are expressed as mean and SEM (n = 6). * Indicates p <0.05 compared to the serum-free, drug-free treatment group, as determined by one-way ANOVA and Dunnett's test.

Table 1 shows that the survival rate of RGC is higher in the presence of fetal serum (and when intrinsic neurological factors are included in the serum). Neuronal factor BDNF was resistant to such injury in the presence of folscholine (ie removal of fetal bovine serum). Similarly, in cultured astrocytes (Shinoda et al. al . , Stimulation of nerve growth factor synthesis / secretion by propentofylline in cultured mouse astroglial cells , Biochem . Pharmacol . , volume 39, pages 1813-1816 (1990)), and in vivo in the aged rat brain (Nabeshima et al. al . , Impairment of learning and memory and the accessory symptom in aged rat as senile dementia model : oral administration of propentofylline produces recovery of reduced NGF content in the brain of aged rats , Jpn . J. Psychol . Pharmacol . , volume 13, pages 89-95 (1993)), propentophylline, which is known to stimulate the production of nerve growth factors, also protected cells from cell death due to serum depletion. It can be seen from these data that compounds that stimulate neuronal factor production and enhanced activity thereof can protect retinal cells, especially RGCs, from injury due to depletion of neuronal factors.

The methods of the present invention comprise administering one or more neurological factors to a patient for the treatment of retinal or optic head neuropathy.

The method of the present invention provides for glaucoma and other diseases and abnormalities of the external retina, in particular age-related macular degeneration, retinal ischemia, trauma-related acute retinopathy, postoperative complications, laser therapy-related injuries including photodynamic therapy (PDT), and It is particularly related to the use of neurological factor stimulants in the treatment of surgical photo-induced pseudopathy. As used herein, "retinal or optic nerve neuropathy" means any of the aforementioned diseases, or other retinal or optic nerve neurodegenerative diseases.

The neurological factor stimulant of the present invention may be contained in various forms of pharmaceutical compositions based on formulation techniques known to those skilled in the art. In general, neurological factor stimulants may be formulated in solutions or suspensions for topical ophthalmic administration or intraocular administration, or formulated in tablets, capsules or solutions for systemic administration (eg, oral or intravenous administration).

Oral formulations of neurotropin stimulants are preferred because of their ease of administration, which may be in liquid or solid form. In general, oral dosage forms will include active neurological factor stimulants and inactive excipients. In general, solid tablet or capsule formulations will contain various excipients, such as filling agents, binders, timed release coatings, or other agents known to those skilled in the art. Liquid formulations will contain carriers, buffers, tonicity agents, solubilizers, or other agents known to those skilled in the art.

The compositions of the present invention may be administered intraocularly following traumatic and / or other cases of acute ischemia to prevent ischemic injury or injury before or at the time of retina and optic head tissue or surgery. Compositions useful for intraocular administration will generally be intraocular injection compositions or surgical cleaning solutions. Intraocular injection compositions generally consist of a liquid solution, such as a balanced salt wash solution described below.

When the neurological factor stimulant is administered during intraocular surgery by methods such as posterior or peripheral eye injection and intraocular spray or injection, it is most preferred to use a balanced salt wash solution as a carrier. BSS ^® sterile cleaning solutions and BSS plus ^® sterile cleaning solutions (AlconLaboratories, Fort Worth, TX) are examples of physiologically balanced intraocular cleaning solutions. The latter solution is described in US Pat. No. 4,550,022 to Garabedian et al. , The entire contents of which are incorporated herein by reference. Ocular posterior and peripheral eye injections are known to those skilled in the art and are disclosed in many publications (eg, Ophthalmic Surgery : Principles of Practice , Ed., GL Spaeth, WBSanders Co., Philadelphia, PA, USA, pages 85-87 (1990)).

In general, dosages used for this purpose may vary, but are within the range of amounts effective to prevent, reduce or ameliorate retinal or optic head neuropathy. As used herein, "pharmaceutically effective amount" refers to the amount of neurological factor stimulant that prevents, reduces or ameliorates retinal or optic head neuropathy. Neurogenic factor stimulants are generally contained in topical or ocular internal formulations in the ranges of amounts expected from about 0.001 to about 10.0 weight / volume (“% W / V”) herein. Preferred concentrations are in the range of about 0.1 to about 5.0% (W / V). Topical formulations are generally administered to the eyes once to six times per day, at the discretion of the skilled clinician. Compositions for systemic administration generally comprise 10 to 1000 mg of neuronal factor stimulant and may be administered once to four times daily, at the discretion of the skilled clinician.

As used herein, the term "pharmaceutically acceptable carrier" refers to any formulation that is capable of adequately delivering an effective amount of at least one neurological factor stimulant via the desired route of administration and is safe.

The compositions of the present invention may comprise additional pharmaceutically active agents and may be administered with other pharmaceutical compositions. In particular, in the treatment of mammals for the prevention, treatment or amelioration of glaucoma retinopathy, the compositions of the present invention may comprise additional "anti-glaucoma" agents, or may be simultaneously or sequentially with the anti-glaucoma agent compositions. Can be administered. Examples of anti-glaucoma preparations include the following: prostaglandins or prostanoids, carbonic anhydrase inhibitors, beta adrenergic agonists and beta adrenergic antagonists anti-glaucoma agents known to an adrenergic antagonist, alpha-adrenergic agonist, or other skilled person.

(Example 2)

Topical compositions useful for the treatment of glaucoma neuropathy:

ingredient % (W / V) AIT-082 (neotropin) 0.1-2.0 Tyloxapol 0.01-0.05 HPMC 0.5 Benzalkonium Chloride 0.01 Sodium chloride 0.8 Edetate Disodium 0.01 NaOH / HCl Titrate to pH 7.4 Purified water Quantity

(Example 3)

Preferred topical compositions useful for the treatment of glaucoma

ingredient % (W / V) AIT-082 (neotropin) 0.5-1.0 Tyloxapol 0.01-0.05 HPMC 0.5 Benzalkonium Chloride 0.01 Sodium chloride 0.8 Edetate Disodium 0.01 NaOH / HCl Titrate to pH 7.4 Purified water Quantity

In order to form the above formulation, a predetermined amount of purified water was first placed in a beaker and heated to 90 ° C. Then hydroxypropylmethylcellulose (HPMC) was added to the heated water and mixed vigorously by vortex mixing until all the HPMC was dispersed. The resulting mixture was cooled in the course of mixing to hydrate HPMC. The resulting solution was sterilized by autoclaving in a container equipped with a liquid insertion port and a hydrophobic, sterile air inlet filter.

Thereafter, sodium chloride and edetate disodium were added and dissolved in another constant amount of purified water. Benzalkonium chloride was then added to the solution and the pH of the solution was titrated to 7.4 with 0.1 M NaOH / HCl. The solution was sterilized by passing through a filter.

AIT-082 was sterilized by dry heat or ethylene oxide. The use of ethylene oxide requires air injection at 50 ° C. for at least 72 hours. The sterile compound was aseptically weighed and placed in a pressurized ballmill vessel, to which thyroxaxol in the form of a sterile liquid solution was added. Sterile glass balls were placed in the vessel and the contents in the vessel were aseptically ground for 16 hours at 225 rpm so that all particle sizes were in the range of about 5 microns.

Under sterile conditions, the micron-sized pharmaceutical suspension formed in the above step was mixed while pouring into HPMC solution. Here the ball mill vessel and balls were washed with an amount of solution containing sodium chloride, edetate disodium and benzalkonium chloride, and the wash solution was aseptically added to the HPMC solution. The final volume of the solution was adjusted with purified water and the pH in the solution was adjusted to 7.4 with NaOH / HCl.

(Example 4)

Formulations for Oral Administration:

refine:

According to methods known to those skilled in the art of tablet formulation, it may be formulated by adding 1 to 1000 mg of neuronal factor stimulant with inactive ingredients such as starch, lactose and magnesium stearate.

(Example 5)

Preferred formulations for topical eye drops:

ingredient % (W / V) AIT-082 (neotropin) 0.5-1.0 Benzalkonium Chloride 0.01 HPMC 0.5 Sodium chloride 0.8 Sodium phosphate 0.28 Edetate Disodium 0.01 NaOH / HCl Titrate to pH 7.2 Purified water Quantity

(Example 6)

Preferred Formulations for Oral Administration:

refine:

According to methods known to those skilled in the art of tablet formulation, it can be formulated by adding 50-500 mg of AIT-082 (neotropin) with inert ingredients such as starch, lactose and magnesium stearate.

The invention in its broader aspects is not limited to the specific fields specified above. Modifications are possible within the scope of the following claims without departing from the principles of the present invention or impairing its advantages.

The present invention proposes the use of neurological factor stimulants as therapeutic agents for ocular neurodegenerative diseases, including retinal or optic nerve head neuropathy. The oral, topical ocular, or intraocular formulations, which are composed of a composition comprising one or more neurological factor stimulants and a pharmaceutically acceptable carrier, are of great medical use in the present invention.

Claims (7)

Comprising an effective amount of a non-peptide neurotrophic factor stimulator (s) and a pharmaceutically acceptable carrier, Composition for the treatment of retinal or optic nerve head neuropathy. The method of claim 1, wherein the non-peptide neuronal factor stimulant is 4-((3-1,6-dihydro-6-oxo-9H-purin-9-yl) -1-oxopropyl) amino) benzoic acid, Ide Benon, (R)-(-)-2-propyloctanoic acid, 20-epi-22 (S) -ethoxy-23-24α, 26α, 27α-trihomo-1a, 25-dihydroxy-vitamin D3 , (1- (1-butyl) -4- (2-oxo-1-benzimidazolinyl) piperidine, 4 '-(4-methylphenyl) -2,2': 6 ', 2-terpyridine : Trihydrochloride, selected from the group consisting of a compound of formula (1) and clenbuterol, Compositions for the treatment of retina or optic head neuropathy: Formula 1

. 3. The non-peptide neuronal factor stimulant of claim 2, wherein the non-peptide neuronal factor stimulant is 4-((3-1,6-dihydro-6-oxo-9H-purin-9-yl) -1-oxopropyl) amino) benzoic acid , Composition for the treatment of retinal or optic nerve head neuropathy. The composition according to claim 1, wherein the composition is an oral preparation. Composition for the treatment of retinal or optic nerve head neuropathy. The composition of claim 1, wherein the composition is a topical ocular or intraocular preparation, Composition for the treatment of retinal or optic nerve head neuropathy. The composition according to claim 3, wherein the composition is an oral preparation. Composition for the treatment of retinal or optic nerve head neuropathy. The composition of claim 3, wherein the composition is a topical ocular or intraocular agent. Composition for the treatment of retinal or optic nerve head neuropathy.