JP6764233B2 - Eye disease treatment drug - Google Patents

Description

This patent application claims priority with respect to Japanese Patent Application No. 2015-024439, which is incorporated herein by reference in its entirety.

The present invention provides therapeutic and / or prophylactic agents for eye diseases that include branched chain amino acids (BCAAs) as active ingredients. The present invention also provides an agent for suppressing cell degeneration and / or cell death of retinal cells containing BCAA as an active ingredient. The present invention further provides an inhibitor of visual function deterioration containing BCAA as an active ingredient. The present invention further provides a food containing BCAA as an active ingredient for reducing the risk of eye diseases or maintaining or improving visual function.

Glaucoma is a disease characterized by visual field defects due to degeneration or shedding of retinal ganglion cells, which can even cause blindness without aggressive treatment. The prevalence in Japan is 5% over 40 years of age, and was the most common cause of premature blindness in 2005 (24.6%). Although high intraocular pressure is mentioned as the cause of glaucoma, the number of patients with glaucoma without high intraocular pressure, that is, normal-tension glaucoma, is 60% of all glaucoma patients in Japan, for example. Current treatments for glaucoma, whether drug administration or surgery, are by reducing intraocular pressure. Decreasing intraocular pressure in patients with normal-tension glaucoma may stop or delay the progression of glaucoma, but lowering intraocular pressure does not adequately delay or delay the progression of glaucoma in some patients. .. In addition, since the intraocular pressure of patients with normal-tension glaucoma is normal in the first place, it may not be possible or sufficient to reduce the intraocular pressure. In addition, even in glaucoma accompanied by high intraocular pressure, the progression of glaucoma may not be sufficiently delayed by the intraocular pressure lowering therapy, or the intraocular pressure lowering may be difficult.

Retinitis pigmentosa is a progressive disease characterized by visual field defects and night blindness due to degeneration or shedding of photoreceptor cells. Retinitis pigmentosa is hereditary in about half of the cases, but sporadic in the other half. Currently, gene therapy, neuroprotective therapy and regenerative medicine are being attempted, but the therapeutic method for retinitis pigmentosa has not been sufficiently established and there is no preventive method. Therefore, there is no way to prevent the patient from developing visual field defects and vision loss, which often leads to blindness. The number of patients is estimated to be 50,000 in Japan, and it was the third cause of premature blindness in 2005.

Age-related macular degeneration is an eye disease with symptoms such as difficulty in seeing the center and distortion, and is the leading cause of blindness in the elderly in developed countries. In the United States, in 2000, about 15% of older people over the age of 80 suffered from age-related macular degeneration. In Japan as well, the number of age-related macular degeneration patients has been increasing in recent years due to the aging of the population and the westernization of food culture, which is the fourth cause of premature blindness (2005).

In age-related macular degeneration, drusen, a waste product mainly composed of lipids, accumulates subcutaneously under the retinal pigment. After that, in wet age-related macular degeneration, subchoroidal neovascularization is formed, and visual loss occurs due to subretinal hemorrhage, retinal edema, and the like. Currently, as effective treatment methods, vascular retraction treatment (intravenous administration of anti-VEGF agent, photodynamic therapy) for formed new blood vessels and steroid treatment that suppresses leakage from new blood vessels are used. Once new blood vessels are formed, the visual prognosis is poor even with such treatment. In order to maintain good visual acuity, it is important to perform progression-suppressing treatment during the drusen format, but there is currently no such treatment. In atrophic age-related macular degeneration, after the accumulation of drusen, the retinochoroid gradually atrophies without neovascularization, resulting in decreased visual acuity. There is currently no effective treatment for atrophic age-related macular degeneration. It may shift from wet age-related macular degeneration to atrophic age-related macular degeneration.

Branched-chain amino acids are essential nutrients for the human body as essential amino acids, so they are extremely safe compared to synthetic compounds. So far, it has been known that branched-chain amino acids are used as agents for suppressing the development and progression of liver cancer, agents for improving hypoalbuminemia in patients with decompensated liver cirrhosis, and the like. However, it has not been reported to be used in the treatment or prevention of eye diseases including glaucoma, retinitis pigmentosa and age-related macular degeneration.

International Publication No. 2012/043891 International Publication No. 2012/147901 International Publication No. 2014/12495 Japanese Patent No. 4419390 Japanese Patent No. 5067160 Japanese Patent No. 5074661 Japanese Patent No. 5516654 Japanese Patent No. 5555401 Special table 2013-527222

An object of the present invention is to provide a treatment and / or a preventive agent for eye diseases. An object of the present invention is also to provide an agent for suppressing retinal cell degeneration and / or cell death. An object of the present invention is further to provide an agent for suppressing deterioration of visual function. An object of the present invention is further to provide a food for reducing the risk of eye diseases or maintaining or improving visual function.

As a result of diligent research in view of the above problems, the present inventors have found that branched-chain amino acids show therapeutic and preventive effects in models of glaucoma, retinitis pigmentosa and age-related macular degeneration. We also found that branched-chain amino acids protect retinal cells, including photoreceptor cells, retinal pigment epithelial cells and retinal ganglion cells, suppress their degeneration and / or cell death, and suppress the decline in visual function. .. The present inventors have completed the present invention based on these findings.

The present invention provides a treatment and / or preventive agent for eye diseases containing at least one selected from the group consisting of isoleucine, leucine and valine as an active ingredient.

The present invention also provides an agent for suppressing retinal cell degeneration and / or cell death, which comprises at least one selected from the group consisting of isoleucine, leucine and valine as an active ingredient.

The present invention also provides an inhibitor of visual function deterioration containing at least one selected from the group consisting of isoleucine, leucine and valine as an active ingredient.

The present invention also provides foods for reducing the risk of eye diseases or maintaining or improving visual function, which contain at least one selected from the group consisting of isoleucine, leucine and valine as an active ingredient.

The agent of the present invention suppresses retinal cell degeneration and / or cell death and suppresses deterioration of visual function. Therefore, the present invention can provide new treatments and / or preventive methods for diseases caused by retinal cell degeneration and / or cell death.

FIG. 1 shows the results of full-thickness network thickness measurement of 13-month-old and 19-month-old retinitis pigmentosa model mice rd12. FIG. 2 shows the results of measurement of photoreceptor layer thickness of 13-month-old and 19-month-old retinitis pigmentosa model mice rd12. FIG. 3 shows the results of light adaptation electrocardiography of a 19-month-old retinitis pigmentosa model mouse rd12. FIG. 4 shows the results of retinal tissue staining and cell number counting of 19-month-old retinitis pigmentosa model mouse rd12. FIG. 5 shows the results of Western blotting of the extraretinal tissue and retina of 19-month-old retinitis pigmentosa model mouse rd12 with anti-CHOP antibody and anti-cleaving caspase-3 antibody. FIG. 6 shows the number of retinal ganglion cells measured by a retinal flat mount of a 12-month-old normal tension glaucoma model mouse. FIG. 7 shows the optic disc diameter of an 18-month-old normal tension glaucoma model mouse. FIG. 8 is a representative fundus photograph of 9-month-old and 15-month-old age-related macular degeneration model mice. FIG. 9 shows the increase / decrease in the number of drusen in the age-related macular degeneration model mouse. FIG. 10 shows the results of dark-adapted electroretinography of 15-month-old age-related macular degeneration model mice. FIG. 11 is a hematoxylin-eosin (HE) stained photograph of retinal tissue of a 15-month-old age-related macular degeneration model mouse. FIG. 12 is a retinal electron micrograph of a 15-month-old age-related macular degeneration model mouse. FIG. 13 shows the results of dark-adapted electroretinography of 9-month-old age-related macular degeneration model mice. FIG. 14 shows the results of full-thickness network thickness measurement of the 37-day-old retinitis pigmentosa model mouse rd10. FIG. 15 shows the results of measuring the thickness of the photoreceptor cell layer of the 37-day-old retinitis pigmentosa model mouse rd10. FIG. 16 shows a typical optical interference tomography image of a 37-day-old retinitis pigmentosa model mouse rd10. FIG. 17 shows the results of dark-adapted electroretinography of a 24-day-old retinitis pigmentosa model mouse rd10. FIG. 18 shows the results of light adaptation electrocardiography of a 30-day-old retinitis pigmentosa model mouse rd10. FIG. 19 shows a typical light-adapted electroretinography waveform of a 30-day-old retinitis pigmentosa model mouse rd10.

The present invention is an agent for treating and / or preventing eye diseases, which comprises at least one selected from the group consisting of isoleucine, leucine and valine as an active ingredient (in the present specification, "the agent of the present invention". (Sometimes referred to as).

Isoleucine, leucine and / or valine, which are the active ingredients of the agent of the present invention, can be used in any of L-form, D-form and DL-form, respectively, but preferably L-form and DL-form. , And more preferably the L-form.

In addition, isoleucine, leucine and / or valine in the present invention can be used not only in the form of free form but also in the form of salt. Isoleucine, leucine and / or valine in the present invention also include such salt forms. Examples of the salt form include a salt with an acid (acid-added salt), a salt with a base (base-added salt), and the like, but it is preferable to select a pharmaceutically acceptable salt.

Examples of the acid added to isoleucine, leucine and / or valine and forming a pharmaceutically acceptable acid addition salt include inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid and phosphoric acid; acetic acid, lactic acid and citrus. Examples thereof include organic acids such as acids, tartaric acids, maleic acids, fumaric acids and monomethylsulfuric acid.

Examples of the base added to isoleucine, leucine and / or valine and forming a pharmaceutically acceptable base addition salt include hydroxides or carbon oxides of metals such as sodium, potassium and calcium, and inorganic substances such as ammonia. Bases: Organic bases such as ethylenediamine, propylenediamine, propylenediamine, ethanolamine, monoalkylethanolamine, dialkylethanolamine, diethanolamine, triethanolamine and the like can be mentioned.

The agent of the present invention is at least one selected from the group consisting of three branched chain amino acids, isoleucine, leucine and valine (ie, one (isoleucine, leucine or valine)) and two (isoleucine and leucine, isoleucine and It contains valine, or leucine and valine) or three types (isoleucine, leucine and valine) as active ingredients. The agent of the present invention preferably contains at least isoleucine as an active ingredient (that is, three kinds of isoleucine, leucine and valine, two kinds of isoleucine and leucine, two kinds of isoleucine and valine, or only isoleucine as an active ingredient. contains). The agent of the present invention contains three kinds of isoleucine, leucine and valine as active ingredients, or contains only isoleucine as an active ingredient (that is, isoleucine is contained as an active ingredient and leucine and valine are contained as active ingredients. No) is more preferable. The agent of the present invention most preferably contains three kinds of isoleucine, leucine and valine as active ingredients. The agent of the present invention may be a pharmaceutical composition containing at least one selected from the group consisting of three branched-chain amino acids of isoleucine, leucine and valine as an active ingredient.

When the agent of the present invention contains three types of branched-chain amino acids, isoleucine, leucine and valine as active ingredients, the compounding ratio of these three types of amino acids is usually 1: 1.5 to 2. It is in the range of 5: 0.8 to 1.7, particularly preferably in the range of 1: 1.9 to 2.2: 1.1 to 1.3, and most preferably in the range of 1: 2: 1.2. is there.

When the agent of the present invention contains isoleucine and leucine, isoleucine and valine, or two branched chain amino acids of leucine and valine as active ingredients, the compounding ratio of the two amino acids is the compounding ratio of the above three amino acids. It may be the compounding ratio of the two kinds of amino acids in.

When the drug of the present invention contains only isoleucine, only leucine, or only valine as an active ingredient, the blending amount thereof can be determined based on the dose described later and formulated.

As used herein, "prevent" or "prevention" prevents the development of an eye disease in a subject, especially in a subject who is more likely to have an eye disease but has not yet. It also means reducing the chances of getting an eye disease. Subjects who may have eye disease but have not yet suffered include, for example, subjects who have no subjective symptoms but have retinal abnormalities, and subjects who may have retinal damage. ..

As used herein, "treating" or "treating" means reducing or eliminating the cause of an eye disease, delaying or stopping the progression of the eye disease in a subject suffering from the eye disease. , And / or means reducing, alleviating, ameliorating or eliminating the symptoms of eye disease.

Eye diseases treated and / or prevented by the agents of the invention include all eye diseases caused or associated with retinal cell degeneration and / or cell death, such as glaucoma, retinitis pigmentosa, age-related macular degeneration. Includes degeneration. Glaucoma includes normal-tension glaucoma and glaucoma refractory to intraocular pressure-lowering therapy. Age-related macular degeneration includes wet age-related macular degeneration and atrophic age-related macular degeneration.

The intraocular pressure of a normal person is 10 to 21 mmHg, but it is considered that retinal ganglion cells degenerate or drop out when the intraocular pressure rises above this range, typically 25 mmHg or more for some reason, causing glaucoma. Has been done. However, in recent years, there have been a large number of cases in which glaucoma develops despite normal intraocular pressure (10 to 21 mmHg), and intraocular pressure lowering therapy may not be applicable or effective for such patients. , Or may be inadequate. In addition, even in glaucoma patients with high intraocular pressure, intraocular pressure lowering therapy may not be effective or inadequate. Since the agent of the present invention can suppress degeneration or shedding of retinal ganglion cells independently of intraocular pressure, it is also useful for treating normal-tension glaucoma and glaucoma refractory to intraocular pressure-lowering therapy. .. Subjects in the prevention of glaucoma include subjects with abnormalities on visual field tests and subjects with enlarged optic disc depression, thinning of the nerve fiber layer and / or ganglion cell layer.

The agents of the present invention can treat glaucoma independently of intraocular pressure, but this is not intended to exclude the combination of the agents of the present invention and intraocular pressure lowering therapy. The intraocular pressure-lowering therapy that can be used in combination with the agent of the present invention includes, but is not limited to, administration of a drug for treating glaucoma or ocular hypertension or an intraocular pressure-lowering agent, laser surgery or surgery.

Retinitis pigmentosa is a disease caused by cell death of photoreceptor cells, which are a type of nerve cell, especially rod cells. It is caused by degeneration and shedding of photoreceptor cells due to abnormalities in genes that work in photoreceptor cells. Retinitis pigmentosa is hereditary and is inherited by autosomal dominant inheritance, autosomal recessive inheritance, and X chromosome recessive inheritance. About 50 causative gene mutations are known. The agents of the invention can treat and / or prevent retinitis pigmentosa regardless of the type of causative gene and whether the causative gene is known. Targets for the prevention of retinitis pigmentosa are those who have a gene mutation that causes retinitis pigmentosa, and genetically expected to develop retinitis pigmentosa regardless of whether the causative gene is clear. The subject is included.

Age-related macular degeneration is divided into exudative and atrophic types. The exudative type is a disease whose main condition is choroidal neovascularization (CNV) generated by changes in retinal pigment epithelial cells-Bruch's membrane-choroid in the macula and its proliferative changes. CNV develops subcutaneously under the retinal pigment and then under the retina. It presents with retinal pigment epithelial detachment and retinal detachment due to bleeding and exudation, and after they are absorbed, atrophy and scarring occur, resulting in a high degree of permanent visual loss, which progresses rapidly. In the atrophic type, retinal pigment epithelium-geographic atrophy lesions of the choroidal capillary plate are formed in the macula, but the progression is slow.

Retinal pigment epithelial cells play an important role in maintaining the environment of the neural retina, including the phagocytic function of the outer segment of photoreceptor cells, but as a change with age, the accumulation of lipofuscin as a digestive residue occurs. An abnormal structure called drusen is formed. In addition, with aging, the Bruch membrane under the pigment subepithelium thickens, and the physiological environment between the photoreceptor cells, the retinal pigment epithelium, and the Bruch membrane changes. Chronic inflammation and ischemia caused by these changes are thought to cause new blood vessels from the choroid, and vascular endothelial growth factor (VEGF) is a physiologically active substance that has the greatest effect on the development and development of new blood vessels. Can be mentioned. CNV extends from the damaged part of Bruch's membrane to the subepithelial retinal pigment, subretinal, and in some cases into the retina.

At present, there is no effective treatment for atrophic age-related macular degeneration. For wet age-related macular degeneration, the only effective treatment method is vascular retraction treatment (anti-VEGF treatment, photodynamic therapy) for the formed new blood vessels. The agents of the present invention treat and / / atrophic and exudative age-related macular degeneration by a mechanism of action different from that of vascular involution therapy by removing drusen or suppressing the formation or increase of drusen. Or it can be prevented. Targets for the prevention of age-related macular degeneration include subjects with abnormalities such as drusen formation on fundus examination, subjects with abnormalities such as CNV or drusen formation in only one eye, and age-related macular degeneration by examination of genetic polymorphism. Subjects with a high risk of developing degeneration and subjects with a family history of age-related macular degeneration are included.

The agents of the present invention can treat and / or prevent atrophic and exudative age-related macular degeneration by a mechanism of action different from that of the treatment of vascular involution, which is the same as the agents of the present invention and the treatment of vascular involution, steroids. , It is not intended to exclude the combined use with surgery. Treatment of vascular involution that can be used in combination with the agent of the present invention includes, but is not limited to, intravitreal administration of an anti-VEGF agent and photodynamic therapy. Surgery that can be used in combination with the agents of the present invention includes those aimed at removing CNV, removing intravitreal bleeding, and moving subretinal bleeding.

The application target of the agent of the present invention includes animals, typically mammals (for example, humans, mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, etc.). When applied to animals other than humans, the dose of the drug of the present invention may be appropriately adjusted according to the weight or size of the animal.

The administration method of the drug of the present invention is not particularly limited, but a general administration route such as oral administration, rectal administration, injection, infusion, eye drop, and intravitreal injection can be used.

Dosage forms for oral administration include granules, fine granules, powders, coated tablets, tablets, suppositories, powders, (micro) capsules, chewables, syrups, juices, liquids, suspensions, emulsions, etc. Can be mentioned. As the dosage form for administration by injection, general dosage forms of pharmaceutical preparations such as those for direct intravenous injection, those for infusion, those for vitreous injection, and those that prolong the release of active substances can be adopted.

These dosage forms are produced by formulating them by a conventional method. Further, various pharmaceutically acceptable preparation substances can be blended as required in the preparation. The substance for formulation can be appropriately selected depending on the dosage form of the formulation, and for example, excipients, diluents, additives, disintegrants, binders, coating agents, lubricants, gliding agents, lubricants, flavoring agents. , Sweeteners, solubilizers and the like. Further, concrete examples of the substances for preparation include magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk protein, gelatin, starch, cellulose and derivatives thereof, animal and vegetable oils, polyethylene glycol, and solvents. For example, sterile water and monohydric or polyhydric alcohols such as glycerol can be mentioned.

The agents of the present invention can also be administered in the form of eye drops. The eye drops are isotonic agents such as sodium chloride and concentrated glycerin; buffering agents such as sodium phosphate and sodium acetate; surfactants such as polyoxyethylene sorbitan monooleate, polyoxyl 40 stearate, and polyoxyethylene hydrogenated castor oil. Agents; Stabilizers such as sodium citrate and sodium edetate; Preservatives such as benzalkonium chloride and paraben can be used as needed for production. The pH may be in the range acceptable for ophthalmic preparations, but is usually in the range of 4-8. In addition, the eye ointment can be produced by using a general-purpose base such as white petrolatum and liquid paraffin.

Injections for intravitreal administration include isotonic agents such as sodium chloride; buffering agents such as sodium phosphate; surfactants such as polyoxyethylene sorbitan monooleate; thickeners such as methylcellulose, etc. as necessary. Can be used and manufactured.

The dose of the agent of the present invention varies depending on the age, body weight or pathological condition of the target patient, the dosage form or administration method of the drug, and isoleucine 0.005 g / kg body weight to 5 g / kg body weight per adult. Leucine 0.01 g / kg body weight 10 g / kg body weight, valine 0.005 g / kg body weight ~ 5 g / kg body weight as a guide.

In the case of a general adult, preferably, isoleucine 0.01 g / kg body weight ~ 1 g / kg body weight, leucine 0.02 g / kg body weight ~ 2 g / kg body weight, valine 0.01 g / kg body weight ~ 1 g / kg body weight per day. It is kg body weight, more preferably isoleucine 0.02 g / kg body weight ~ 0.2 g / kg body weight, leucine 0.04 g / kg body weight ~ 0.4 g / kg body weight, valine 0.02 g / kg body weight ~ 0.2 g. / Kg weight. The total amount of amino acids is preferably about 0.01 g / kg body weight to 2 g / kg body weight per day. The daily dose can be administered at one time or in several divided doses. The time of administration is not particularly limited, and may be, for example, before meals, after meals, or between meals. Moreover, the administration period is not particularly limited.

When calculating the dose of branched-chain amino acid, which is the active ingredient of the drug of the present invention, the value is different from the action intended by the present invention (for example, from the necessity of a normal diet or different). Branched-chain amino acids that are ingested or administered (for the purpose of treating the disease of) need not be included in the above calculation. For example, it is not necessary to deduct the amount of branched chain amino acids ingested from a normal diet from the daily dose of the active ingredient in the present invention.

Isoleucine, leucine and / or valine, which are the active ingredients of the agents of the present invention, may be contained in the preparation individually or in any combination, or all of them may be contained in one preparation. .. When they are separately formulated and administered, their administration routes and dosage forms may be the same or different, and the timing of administration of each may be simultaneous or different. Therefore, the dosage form, administration time, administration route, etc. can be appropriately determined. That is, the drug of the present invention may be a preparation containing a plurality of branched-chain amino acids, or may be a concomitant drug in which each is separately formulated and used in combination. The agents of the present invention include all these forms of formulations. In particular, a form containing all branched-chain amino acids in the same preparation is preferable because it can be easily administered.

In the present invention, the "weight ratio" indicates the weight ratio of each component in the preparation. For example, when the active ingredients of isoleucine, leucine and valine are included in one formulation, they are the ratio of individual weights, and each of each active ingredient is included in multiple formulations alone or in any combination. In the case of, it is the ratio of the total weight of each active ingredient contained in each formulation.

Further, in the present invention, the ratio of the actual dose is the ratio of the single dose or the daily dose of each active ingredient per administration subject (that is, the patient). For example, when each active ingredient of isoleucine, leucine and valine is contained in one preparation and administered to an administration subject, the weight ratio corresponds to the dose ratio. When each active ingredient is administered alone or in any combination in a plurality of formulations, the ratio of the total weight of each active ingredient in each formulation administered once or daily corresponds to the dose ratio.

Isoleucine, leucine, and valine are already widely used in the pharmaceutical and food fields, and their safety has been established. For example, the acute toxicity (LD ₅₀ ) of a preparation containing these amino acids in a weight ratio of 1: 2: 1.2 is 10 g / kg or more even when orally administered to mice.

The agents of the invention can be used alone or in combination with one or more additional active ingredients, in particular the active ingredient for the treatment and / or prevention of eye diseases.

With respect to the present invention, "combination" of ingredients not only involves the use of dosage forms containing all ingredients and the use of combinations of dosage forms containing each ingredient separately, as well as the prevention and / of prevention of the same disease. Alternatively, as long as it is used for treatment, it also means that each component is administered at the same time or one of the components is delayed. It is also possible to use two or more additional active ingredients in combination.

When the eye disease is glaucoma, active ingredients suitable for concomitant use include, for example, sympathomimetics (non-selective stimulants such as epinephrine and dipibefurin, α ₂ stimulants such as apraclonidine and brimonidin), and sympathomimetics. (Β-blockers such as timolol, befnorol, carteolol, betaxolol, nipradilol, levobnorol, α ₁ blockers such as bunazosin), parasympathomimetics (pyrocarpine, dystigmin, etc.), carbonate dehydration enzyme inhibitors (acetazolamide, brinzoramide, dolzolamide) Etc.), prostaglandins (isopropylunoprost, latanoprost, travoprost, bimatoprost, tafluprost, etc.), Rho kinase inhibitors (lipasdyl hydrochloride, etc.) and other tonological pressure-lowering agents, in particular, latanoprost, travoprost, etc. And prostaglandins such as tafluprost, beta blockers, carbonate dehydratase inhibitors and glaucomadin.

If the eye disease is age-related macular degeneration, active ingredients suitable for concomitant use include, for example, anti-VEGF agents (ranibizumab, pegaptanib, aflibercept, bevacizumab, etc.), anti-angiogenic agents, and steroids (triamcinolone acetonide, etc.). Includes, in particular pegaptanib and ranibizumab.

Other active ingredients suitable for concomitant use include, for example, vitamins such as vitamin 12 and carotenoids such as lutein.

In addition to the administration of the agent of the present invention, treatments for eye diseases other than drug therapy can also be implemented. Suitable treatments include, for example, surgery, photodynamic therapy, gene therapy, regenerative medicine, artificial retinal transplantation, laser therapy.

In another aspect, the invention provides an inhibitor of retinal cell degeneration and / or cell death containing at least one selected from the group consisting of isoleucine, leucine and valine as an active ingredient. In a preferred embodiment, retinal cells include photoreceptor cells, retinal pigment epithelial cells and retinal ganglion cells.

The retinal cell degeneration and / or cell death inhibitor of the present invention can be produced and used in the same manner as the above-mentioned treatment and / or preventive agent for eye diseases. In the present invention, retinal cell degeneration and / or cell death, and suppression thereof, can be confirmed by methods known in the art, for example, by optical interference tomography or adaptive optics scanning laser ophthalmoscope. it can.

The retinal cell degeneration and / or cell death inhibitor of the present invention can treat and / or prevent eye diseases caused by retinal cell degeneration and / or cell death. In addition, the retinal cell degeneration and / or cell death inhibitor of the present invention can protect retinal cells by suppressing retinal cell degeneration and / or cell death. In addition, the agent for suppressing retinal cell degeneration and / or cell death of the present invention can suppress deterioration of visual function due to retinal cell degeneration and / or cell death.

In a further aspect, the present invention provides an inhibitor of visual impairment, which comprises at least one selected from the group consisting of isoleucine, leucine and valine as an active ingredient.

The inhibitor of visual function deterioration of the present invention can be manufactured and used in the same manner as the above-mentioned treatment and / or preventive agent for eye diseases. In the present invention, a decrease in visual function means a decrease in corrected visual acuity and / or an abnormality in visual field, an abnormality in color vision, and includes night blindness, visual field defect, tunnel vision, tunnel vision, blindness, and the like. Deterioration of visual function and its suppression are confirmed by methods known in the art, such as visual acuity test, visual field test, electroretinogram test, retinal sensitivity test, central flicker test, color vision test, visual evoked potential, etc. can do. In some embodiments, diminished visual function results from degeneration and / or cell death of retinal cells. In another aspect, diminished visual function results from eye disease.

Also, in some embodiments, the present invention provides the use of at least one selected from the group consisting of isoleucine, leucine and valine as active ingredients for the manufacture of a medicament for the treatment and / or prevention of eye diseases. To do.

In another aspect, the invention is at least selected from the group consisting of isoleucine, leucine and valine as active ingredients for producing a medicament for suppressing cell degeneration and / or cell death of the retina. Provide use of.

In another aspect, the present invention provides the use of at least one selected from the group consisting of isoleucine, leucine and valine as active ingredients for producing a medicament for suppressing visual dysfunction.

In these embodiments, at least one selected from the group consisting of isoleucine, leucine and valine as active ingredients is used for the manufacture of a pharmaceutical, according to the method for producing an eye disease treatment and / or preventive agent described above. Can be used.

Also, in some embodiments, the present invention provides at least one selected from the group consisting of isoleucine, leucine and valine for use in the treatment and / or prevention of eye diseases.

In another aspect, the invention provides at least one selected from the group consisting of isoleucine, leucine and valine for use in suppressing cell degeneration and / or cell death of the retina.

In another aspect, the invention provides at least one selected from the group consisting of isoleucine, leucine and valine for use in suppressing visual impairment.

In these embodiments, at least one selected from the group consisting of isoleucine, leucine and valine is used in accordance with the treatment and / or prophylactic agents for eye diseases described above.

In some embodiments, the present invention provides a method for treating and / or preventing an eye disease, which comprises administering to a subject at least one selected from the group consisting of isoleucine, leucine and valine as active ingredients. ..

In another aspect, the present invention comprises administering to a subject at least one selected from the group consisting of isoleucine, leucine and valine as active ingredients, a method for suppressing cell degeneration and / or cell death of the retina. I will provide a.

In another aspect, the present invention provides a method for suppressing visual dysfunction, which comprises administering to a subject at least one selected from the group consisting of isoleucine, leucine and valine as active ingredients.

In these aspects, at least one selected from the group consisting of isoleucine, leucine and valine as active ingredients can be administered to the subject according to the above-mentioned method of treating eye diseases and / or using preventive agents. ..

Furthermore, the branched chain amino acid, which is the active ingredient of the present invention, can be easily used in the form of a functional food having the effect of reducing the risk of eye diseases or maintaining or improving visual function. Therefore, the present invention provides foods for reducing the risk of eye diseases or maintaining or improving visual function, which contain at least one selected from the group consisting of isoleucine, leucine and valine as an active ingredient. The food of the present invention may be any general dietary form containing the active ingredient of the food of the present invention, that is, branched chain amino acids. For example, a drink agent, for example, a soft drink or a powdered drink, can be prepared by adding an appropriate flavor. Specifically, for example, it can be eaten as juice, milk, confectionery, jelly, yogurt, candy and the like. Further, for example, it may be in the form of a food additive that is added to other foods by the manufacturer or the consumer and ingested, or may be in the same form as a medicine for oral administration.

It is also possible to provide such foods as health foods or dietary supplements. This food with health claims also includes foods for specified health uses and foods with nutritional claims. Foods for specified health use are foods that can be labeled as having a specific health purpose, such as reducing the risk of eye diseases or maintaining or improving visual function. In addition, nutritionally functional foods are foods that can display the function of nutritional components when the amount of nutritional components contained in the daily intake guideline conforms to the upper and lower limit standards set by the government. is there. Dietary supplements include so-called dietary supplements or dietary supplements. In the present invention, the food for specified health use is a food labeled as being used for reducing the risk of eye diseases or maintaining or improving visual function, and further, for such purposes. Foods that include a document stating that there is a document (so-called Noh writing) as a package shall also be included.

The intake amount and the intake period of the food of the present invention can be appropriately set so that the food of the present invention exhibits a desired effect based on the description of the dose and the administration period of the drug of the present invention.

In another aspect, the invention uses at least one selected from the group consisting of isoleucine, leucine and valine to reduce the risk of eye disease or to produce foods for maintaining or ameliorating visual function. I will provide a. In another aspect, the invention provides the use of at least one selected from the group consisting of isoleucine, leucine and valine for reducing the risk of eye disease or maintaining or ameliorating visual function. In another aspect, the invention reduces the risk of eye disease or maintains or improves visual function by ingesting or administering a food containing at least one selected from the group consisting of isoleucine, leucine and valine. Provide a method. In another aspect, the invention reduces the risk of eye disease or maintains or improves visual function, comprising administering a food containing at least one selected from the group consisting of isoleucine, leucine and valine. Provide a non-therapeutic method of

The following examples explain the present invention, but do not limit the scope thereof.
In the following examples, a mixture of branched chain amino acids containing leucine, isoleucine and valine in a ratio of 2: 1: 1.2 was used as BCAA. BCAA was administered after dissolution in γ-cyclodextrin aqueous solution (CAVAMAX W8, Wacker fine chemicals).

Example 1: Pharmacological test in a relatively elderly retinitis pigmentosa model As a retinitis pigmentosa model, rd12 mice (The Jackson Laboratory) (Pang, JJ, Chang, B., Hawes, NL, et al. 2005. Retinal degeneration 12 (rd12): a new, spontaneously arising mouse model for human Leber congenital amaurosis (LCA). Molecular vision 11, 152-162) was used. In this mouse model, cell death of photoreceptor cells progresses slowly. Thirty-four 13-month-old rd12 mice were divided into two groups, a BCAA-administered group (17 mice) and a control group (17 mice). From 13 months of age, in the BCAA group, BCAA was orally administered by free drinking of water containing 7.5 g / l of BCAA (about 1.6 kg / kg / day). Control groups were fed only water in the same manner.

Optical coherence tomography (OCT) was performed at 13 and 19 months of age. Mice were anesthetized by intramuscular injection of ketamine 70 mg / kg + xylazine 14 mg / kg. Mice were mydriasis by instillation of tropicamide phenylephrine. For optical coherence tomography, Spectralis HRT + OCT (Heidelberg Engineering, Inc.) equipped with a 25D adapter lens was used. A contact lens made of polymethylmethacrylate was placed on the mouse cornea, and a range of 30 ° × 15 ° was continuously photographed around the optic nerve head. The full-thickness network thickness in the range of 366 μm at the center of the optic nerve head (excluding the range of 122 μm at the center) was measured.

The result of the full-thickness net film thickness measurement is shown in FIG. At 13 months of age, the average full-thickness retina thickness was 202.4 ± 9.0 μm in the control group and 203.0 ± 9.0 μm in the BCAA group, showing no significant difference (P = 0.40). At 19 months of age, the average full-thickness network thickness was 184.9 ± 10.2 μm in the control group and 194.4 ± 12.6 μm in the BCAA group, which was thicker in the BCAA group (P = 0.0043).

The photoreceptor layer thickness was measured by the same method. A 30-degree line scan was taken vertically around the optic disc. The thickness of the photoreceptor cell layer (the sum of the outer nuclear layer thickness and the inner and outer segment thicknesses of the photoreceptor cells) was measured at a site 244 μm above and below the optic nerve head. The result of the photoreceptor layer thickness measurement is shown in FIG. At 13 months of age, the mean photoreceptor layer thickness was 58.5 ± 6.3 μm in the control group and 59.7 ± 4.6 μm in the BCAA group, showing no significant difference (P = 0.20). At 19 months of age, the photoreceptor layer thickness was 39.4 ± 7.4 μm in the control group and 45.3 ± 6.8 μm in the BCAA group, which was thicker in the BCAA group (P = 0.007).

At 19 months of age, a light-adapted electroretinogram (ERG) was performed. The test was performed under general anesthesia (ketamine 70 mg / kg + xylazine 14 mg / kg intramuscular injection). Mice were mydriasis by instillation of tropicamide phenylephrine. Using a contact lens type LED electrode (Mayo), stimulate with LS-W (Mayo) with stimulating light of 10 cds / m ² , and record the waveform with PowerLab 2/25 (AD Instruments, New South Wales, Australia). Then, the b-wave amplitude of the light-adapted electroretinogram was measured. The results are shown in FIG. The amplitude of the b wave was 12.2 ± 5.0 μV in the control group and 14.9 ± 6.0 μV in the BCAA group, which was larger in the BCAA group (P = 0.046).

At 19 months of age, the eyeball was removed, fixed overnight with 4% paraformaldehyde, and the retina was stained with hematoxylin and eosin (HE). The number of cells in the outer nuclear layer in the range of 400-500 μm from the optic disc margin was measured using vertical slices passing through the optic nerve (n = 4 eyes each). As shown in FIG. 4, in males, the number of cells was 78.8 ± 5.0 in the control group and 100 ± 11.2 in the BCAA group, which was higher in the BCAA group (P = 0.007). .. Overall, the number of cells was 95.3 ± 20.0 in the control group and 101.1 ± 16.4 in the BCAA group, which was higher in the BCAA group (P = 0.26).

Extraretinal tissue (including retinal pigment epithelium, choroid and sclera) and neural retina were removed from the eyeball removed at 19 months of age, and CHOP: GADD153 (R-20) antibody (Santa Cruz Biotechnology), 1: 1000 dilution, Caspase-3: Western blot was performed using cleaved caspase-3 (D175) antibody (cell signaling), 1: 1000 dilution. As a control, actin: anti-actin antibody (Millipore), 1: 10000 dilution was used. The results are shown in FIG. CHOP, known as a endoplasmic reticulum stress marker, was suppressed in the BCAA group in extraretinal tissue. Cleaved caspase-3, a marker of apoptosis, was suppressed in the BCAA group in the retina.

These results indicate that BCAA suppressed photoreceptor degeneration and cell death and suppressed deterioration of visual function in relatively old rd12 mice, which is a model of advanced retinitis pigmentosa.

Example 2: Pharmacological test in a normal-tension glaucoma model A mouse model of slow-growing normal-tension glaucoma, a GLAST-deficient (hetero +/-) mouse (The Journal of Clinical Investigation, Volume 117, Number 7, July 2007) Mice B6.Cg-Tg (Thy 1-CFP) 23Jrs / J were crossed to obtain GLAST-deficient (+/-) and Thy 1-CFP mice, which were used as model mice for normal-tension glaucoma. Thirty 4-week-old model mice were divided into two groups, a control group (15 mice) and a BCAA-administered group (15 mice). In the BCAA group, 0.375 g / kg / day of BCAA was intraperitoneally administered 5 days a week from 4 to 8 weeks of age, and after 8 weeks of age, by free drinking of water containing 7.5 g / l BCAA. BCAA was orally administered (about 1.7 g / kg / day). The control group was intraperitoneally administered with physiological saline 5 days a week from 4 to 8 weeks of age, and after 8 weeks of age, BCAA-free water was given by free drinking water.

At 12 months of age, the eyeball was removed from the mouse, fixed with 4% paraformaldehyde for 1 hour, the retina was flat-mounted, and the cells having CFP fluorescence were placed at a position 1200 μm from the center of the optic nerve head and in a range of 250 μm × 250 μm. The number was measured (Fig. 6). These cells are considered to be retinal ganglion cells. The number of cells was 110 ± 9.6 in the control group and 124.8 ± 7.5 in the BCAA group, which was higher in the BCAA group (P = 0.016).

At 18 months of age, the eyeball was removed from the mouse, fixed overnight with 4% paraformaldehyde, embedded in paraffin, and the optic nerve cross section was photographed with a section vertically cut through the optic nerve behind the eyeball. The diameter was measured (Fig. 7). The optic disc diameter reflects the number of ganglion cells. The median nerve head diameter is 70637Myuemu ² in 45352Myuemu ^2, BCAA group in the control group, was higher BCAA administration group.

These results indicate that BCAA suppressed retinal ganglion cell degeneration and cell death in a normal tension glaucoma model.

Example 3: Pharmacological test in a relatively old age-related macular degeneration model As a model of age-related macular degeneration, CCR2 (monocyte activating factor (MCP-1) receptor) deficient mouse (The Jackson Laboratory) (Nat) Med. 2003 Nov; 9 (11): 1390-7. Epub 2003 Oct 19. An animal model of age-related macular degeneration in senescent Ccl-2- or Ccr-2-deficient mice. Ambati J1, Anand A, Fernandez S , Sakurai E, Lynn BC, Kuziel WA, Rollins BJ, Ambati BK) were used. 34 9-month-old CCR2-deficient mice were divided into two groups, a control group (24 mice) and a BCAA-administered group (10 mice). From 9 months of age, CCR2-deficient mice were orally administered BCAAs by free drinking of water containing BCAAs (7.5 g / l) dissolved in an aqueous solution of γ-cyclodextrin. Control mice were fed only water in the same manner.

Color photographs of the fundus centering on the optic nerve head were taken every month from 9 months to 15 months (Micron III, Phoenix Research Laboratories), and the number of drusen was evaluated. A typical photograph is shown in FIG. The white granular structure is drusen. In the figure, the white dotted line indicates a place with a lot of drusen. In the BCAA administration group, there were many that suppressed the increase in the number of drusen. FIG. 9 shows the increase / decrease in the number of drusen in each month from the number of drusen at the age of 9 months after the start of administration. In the BCAA-administered group (n = 14 eyes), the increase in drusen was significantly suppressed after 10 months of age as compared with the control group (n = 16 eyes) (P = 0.043 (10 months of age)). 0.015 (11 months old), 0.046 (12 months old), 0.015 (13 months old), 0.018 (14 months old), 0.016 (15 months old)).

At 15 months of age, a dark-adapted electroretinogram (ERG) was performed. Mice were dark-adapted 24 hours before ERG and tested under general anesthesia (70 mg / kg ketamine + 14 mg / kg xylazine intramuscular injection) and under mydriasis (0.5% phenylephrine, 5% neocinedin). Under dark adaptation, using a contact lens type LED electrode, stimulate with LS-W with stimulating light of 0.01 cds / m ² , record the waveform with PowerLab 2/25, and measure the amplitude of b wave. Similarly, the waveform was recorded by stimulating with a stimulating light of ³ cds / m ² , and the amplitude of the a wave was measured. The results are shown in FIG. The amplitude of the a wave was 163.6 ± 65.2 μV in the control group and 207.0 ± 47.4 μV in the BCAA group, which was larger in the BCAA group (P = 0.0026). The amplitude of the b wave was 223.1 ± 82.0 μV in the control group and 308.4 ± 56.8 μV in the BCAA group, which was larger in the BCAA group (P = 0.0016).

At 15 months of age, the eyeball was removed, fixed overnight with 4% paraformaldehyde, the retina was HE-stained, and retinal sections were observed. FIG. 11 shows a retinal section of a CCR2-deficient mouse at 15 months of age (upper row: 40 times, lower row: 100 times). In the control group to which only water was administered, vacuolar degeneration occurred in the retinal pigment epithelium (arrowhead), whereas in the BCAA-administered group, no vacuolar degeneration was observed (upper row). In addition, the Bruch membrane (basement membrane of retinal pigment epithelium) in the control group was significantly thickened as compared with the BCAA-administered group (lower row, arrow).

At 15 months of age, electron microscopy of the retina was performed. The eyeball was removed, fixed by the same method as HE staining, and then fixed with 1% osmium tetroxide. After ethanol dehydration and epoxy resin embedding, ultrathin sections were prepared, stained with uranyl acetate and lead citrate, and the stained sections were observed with a transmission electron microscope (H-7650, Hitachi, Ltd.). The results are shown in FIG. In FIG. 12, RPE shows retinal pigment epithelium. Subretinal deposits were lower in the BCAA-treated group compared to controls.

These results indicate that BCAA suppressed the increase in drusen and the decrease in visual function in relatively old age-related macular degeneration model mice.

Example 4: Pharmacological test in a relatively young age-related macular degeneration model 37 2-month-old CCR2-deficient mice were divided into two groups, a BCAA-administered group (11 mice) and a control group (26 mice). From 2 months of age, CCR2-deficient mice were administered BCAAs by free drinking of water containing BCAAs (7.5 g / l) dissolved in an aqueous solution of γ-cyclodextrin. Control mice were fed only water in the same manner.

At 9 months of age, a dark-adapted electroretinogram (ERG) was performed. Mice were dark-adapted 24 hours before ERG and tested under general anesthesia (70 mg / kg ketamine + 14 mg / kg xylazine intramuscular injection) and under mydriasis (0.5% phenylephrine, 5% neocinedin). Under dark adaptation, using a contact lens type LED electrode, stimulate with LS-W with stimulating light of 0.01 cds / m ² , record the waveform with PowerLab 2/25, and measure the amplitude of b wave. Similarly, the waveform was recorded by stimulating with a stimulating light of ³ cds / m ² , and the amplitude of the a wave was measured (control n = 43 eyes, BCAA n = 17 eyes). The results are shown in FIG. The amplitude of the a wave was 174.6 ± 69.6 μV in the control group and 251.1 ± 72.3 μV in the BCAA group, which was larger in the BCAA group (P = 0.0011). The amplitude of the b wave was 253.1 ± 113.2 μV in the control group and 386.7 ± 133.6 μV in the BCAA group, which was larger in the BCAA group (P = 0.0010).

These results indicate that BCAA suppressed the decline in visual function in relatively young age-related macular degeneration model mice.

Example 5: Pharmacological Test retinitis pigmentosa Model in retinitis pigmentosa Model, rd10 mice ^{(B6.CXB1-Pde6b rd10 / J (} Jackson Laboratory (Bar Harbor, ME) purchased from, Chang B. et al; Vision Res (2007 )) Was used. In this mouse model, photoreceptor cells rapidly degenerate by 2 months of age. 35 7-day-old rd10 mice were divided into 2 of the BCAA-administered group (17) and the control group (18). In the BCAA group, 1.5 g / kg / day of BCAA was intraperitoneally administered from 7 days to 23 days of age, and after 24 days of age, by free drinking of water containing 7.5 g / l BCAA. , BCAA was orally administered (about 1.7 g / kg / day). In the control group, physiological saline was intraperitoneally administered from 7 days to 23 days of age, and after 24 days of age, BCAA was contained by free drinking. Gave no water.

Optical coherence tomography (OCT) was performed at 24, 30 and 37 days of age. Mice were anesthetized by intramuscular injection of ketamine 70 mg / kg + xylazine 14 mg / kg. Mice were mydriasis by instillation of tropicamide phenylephrine. For optical coherence tomography, Spectralis HRT + OCT (Heidelberg Engineering, Inc.) equipped with a 25D adapter lens was used. A contact lens made of polymethylmethacrylate was placed on the mouse cornea, and a range of 30 ° × 15 ° was continuously photographed around the optic nerve head. The full-thickness network thickness in the range of 366 μm at the center of the optic nerve head (excluding the range of 122 μm at the center) was measured.

At 24 days of age, the average full-thickness retina thickness was 188.9 ± 21.8 μm in the control group and 187.2 ± 13.8 μm in the BCAA group, showing no significant difference (P = 0.36). At 30 days of age, the average full-thickness retina thickness was 153.7 ± 7.4 μm in the control group and 155.0 ± 6.3 μm in the BCAA group, showing no significant difference (P = 0.27). At 37 days of age, the average full-thickness network thickness was 144.2 ± 5.7 μm in the control group and 149.8 ± 3.3 μm in the BCAA group, which was thicker in the BCAA group (P <0.01). The result of the full-thickness network thickness measurement at 37 days old is shown in FIG.

The photoreceptor layer thickness was measured by the same method. A 30-degree vertical line scan was taken around the optic disc. The thickness of the photoreceptor cell layer (the sum of the outer nuclear layer thickness and the inner and outer segment thicknesses of the photoreceptor cells) was measured at a site 244 μm above and below the optic nerve head. At 24 days of age, the mean photoreceptor layer thickness was 50.4 ± 23.8 μm in the control group and 42.6 ± 19.1 μm in the BCAA group, showing no significant difference (P = 0.09). At 30 days of age, the mean photoreceptor layer thickness was 16.8 ± 3.6 μm in the control group and 18.9 ± 6.0 μm in the BCAA group, showing no significant difference (P = 0.09). At 37 days of age, the photoreceptor layer thickness was 10.1 ± 4.8 μm in the control group and 15.1 ± 3.3 μm in the BCAA group, which was thicker in the BCAA group (P <0.01). The result of the measurement of the thickness of the photoreceptor cell layer at the age of 37 days is shown in FIG. A photocoherent tomogram image of a 37-day-old mouse having a median photoreceptor layer thickness is shown in FIG. It can be seen that the continuity of the Ellipsoid zone, which is known to correlate with visual function, is maintained in the BCAA group more than in the control group.

At 24 days of age, a dark-adapted electroretinogram (ERG) was performed. Mice were dark-adapted overnight prior to ERG and tested under general anesthesia (70 mg / kg ketamine + 14 mg / kg xylazine intramuscular injection). Mice were mydriasis by instillation of tropicamide phenylephrine. Under dark adaptation, using a contact lens type LED electrode, stimulate with LS-W with stimulating light of 0.01 cds / m ² and 3.0 cds / m ² , and record the waveform with PowerLab 2/25. The amplitude of the b wave was measured. The results are shown in FIG. The amplitude of the b wave was 18.8 ± 16.8 μV in the control group and 40.1 ± 50.2 μV (P <0.01) in the BCAA group at a stimulus light intensity of 0.01 cds / m ² , which stimulated the stimulus. At a light intensity of 3.0 cds / m ² , the control group had 76.4 ± 61.3 μV and the BCAA group had 121.3 ± 115.9 μV (P = 0.02), both of which were larger in the BCAA group. It was.

Light-adapted electroretinography was performed at 30 and 37 days of age. The test was performed under general anesthesia (ketamine 70 mg / kg + xylazine 14 mg / kg intramuscular injection). Mice were mydriasis by instillation of tropicamide phenylephrine. Mice were wear contact lens mold LED electrodes were stimulated with the stimulating light LS-W at ^{3cds / m 2, 10cds / m} 2 and 30cds / ^{m 2,} to record the waveform at PowerLab 2/25, light adaptation The b-wave amplitude of the electroretinogram was measured. At 30 days of age, the amplitude of the b-wave was 10.0 ± 9.7 μV in the control group and 14.8 ± 11.0 μV (P = 0.03) in the BCAA group at a stimulus light intensity of 3 cds / m ² . Yes, at a stimulus light intensity of 10 cds / m ² , 15.7 ± 12.0 μV in the control group, 24.9 ± 21.2 μV (P = 0.01) in the BCAA group, and a stimulus light intensity of 30 cds / m ² . , 20.6 ± 16.3 μV in the control group and 36.3 ± 22.4 μV (P <0.001) in the BCAA group, both of which were larger in the BCAA group (FIG. 18). At 37 days of age, the amplitude of the b wave at a stimulus light intensity of 3 cds / m ² was 8.7 ± 4.0 μV in the control group and 9.3 ± 4.4 μV in the BCAA group, showing no significant difference. (P = 0.29). At a stimulus light intensity of 10 cds / m ² , 6.7 ± 3.1 μV in the control group, 15.6 ± 11.0 μV (P <0.0001) in the BCAA group, and at a stimulus light intensity of 30 cds / m ² , in the control group. It was 9.7 ± 5.5 μV and 20.5 ± 14.0 μV (P <0.0001) in the BCAA group, both of which were higher in the BCAA group. The results of the light-adapted electroretinogram of 30-day-old mice having the median b-wave amplitude are shown in FIG. It can be seen that the BCAA group has a more preserved waveform than the control group.

These results indicate that BCAA suppressed photoreceptor degeneration and cell death and suppressed deterioration of visual function in the retinitis pigmentosa model.

Claims (4)

A treatment and / or preventive agent for glaucoma, retinitis pigmentosa or age-related macular degeneration containing isoleucine, leucine and valine as active ingredients, the weight ratio of isoleucine, leucine and valine being 1: 1.5 to 2. .5: A treatment and / or preventive agent for glaucoma, retinitis pigmentosa or age-related macular degeneration, which is 0.8 to 1.7. The treatment of glaucoma, retinitis pigmentosa or age-related macular degeneration according to claim 1, wherein the weight ratio of isoleucine, leucine and valine is 1: 1.9 to 2.2: 1.1 to 1.3 and /. Or a preventive agent. The treatment and / or preventive agent for glaucoma, retinitis pigmentosa or age-related macular degeneration according to claim 1 or 2, wherein the weight ratio of isoleucine, leucine and valine is 1: 2: 1.2. A food containing isoleucine, leucine and valine as active ingredients for reducing the risk of glaucoma, retinal pigment degeneration or age-related macular degeneration , or maintaining or improving visual function by weight ratio of isoleucine, leucine and valine. Is 1: 1.5-2.5: 0.8-1.7, food.