JP5317055B2 - Drugs for delaying the onset or progression of movement disorders due to rare sugar amyotrophic lateral sclerosis - Google Patents

Abstract

[PROBLEMS] To provide a drug or a food for specified health uses aiming at slowing the onset or progress of mobility impairment relating to amyotrophic lateral sclerosis. [MEANS FOR SOLVING PROBLEMS] An agent containing D-allose as the active ingredient and aiming at slowing the onset or progress of mobility impairment relating to amyotrophic lateral sclerosis. A composition in the form of a food, a drink or a drug which contains the agent for slowing the onset or progress as described above. The above-described composition wherein the daily dose of D-allose is from 0.5 to 50 g. A food or a drink containing D-allose as the active ingredient which is indicated as being used for slowing the onset or progress of mobility impairment relating to amyotrophic lateral sclerosis. A method of slowing the onset or progress of mobility impairment relating to amyotrophic lateral sclerosis in a human subject which comprises administering or feeding D-allose in an efficacious amount to the subject. A method of treating a human subject diagnosed as suffering from amyotrophic lateral sclerosis which comprises administering or feeding to the subject D-allose in an efficacious amount for slowing the progress of mobility impairment.

Description

  The present invention relates to a pharmaceutical product or a food for specified health use that contains D-allose as an active ingredient and delays the onset or progression of a movement disorder associated with amyotrophic lateral sclerosis. The present invention also relates to a method for delaying the onset or progression of movement disorders associated with amyotrophic lateral sclerosis in a subject by administering to the subject a therapeutically effective amount of D-allose.

  Amyotrophic lateral sclerosis (ALS) mainly develops from hand or foot weakness or bulbar palsy after middle age, and weakness of the limbs and muscle atrophy progress over the course of several years, resulting in paralysis of respiratory muscles It is a neurodegenerative disease that leads to death. In ALS, upper and lower motor neurons are selectively impaired, and usually do not involve sensory impairment or dementia. Pathologically, anterior spinal horn and anterior root atrophy, degeneration and loss of motor neurons in the spinal cord and brainstem motor nucleus, and loss of large pyramidal cells in the motor cortex are observed. To date, hypotheses such as (1) oxidative stress caused by free radicals, (2) glutamate neurotoxicity, and (3) impaired axonal transport have been estimated as motor neuron degeneration mechanisms. It has not yet been elucidated. In addition, the mechanism by which motor neurons are selectively impaired is unclear.

  Most people who develop ALS are sporadic, but 5-10% are familial and many are known to have an autosomal dominant inheritance, and are called familial ALS (FALS). In 1991, it was revealed that some FALS families were linked to the long arm of chromosome 21, and in 1993 the copper / zinc superoxide dismutase (Cu / Zn SOD) gene was identified as the causative gene. The Cu / Zn SOD gene is 11.5 kb in length and consists of 5 exons. The Cu / ZnSOD protein is a dimer of about 32 kDa consisting of two 153 amino acid and about 16 kDa constituent proteins. Each constituent unit contains one copper ion and one zinc ion, and is an enzyme that mediates a reaction that disproportionates superoxide, which is one of free radicals, into hydrogen peroxide.

  Cu / Zn SOD gene abnormalities have been observed in about 20% of FALS patients, and about 60 gene mutations have been reported so far, most of which are point mutations. It has been found from previous reports that the onset age and disease duration differ depending on the type of mutation. For example, the 46th amino acid of Cu / Zn SOD reported in Japanese families is a histidine to arginine mutation (H46R mutation). ) Patients with FALS are characterized by a very long duration of 16.8 years on average. Initially, due to the nature of Cu / Zn SOD as a free radical scavenger, it was thought that the pathogenesis was caused by the increase in intracellular free radicals due to a decrease in enzyme activity due to gene mutation, and the degeneration of neurons. However, the age of onset and the degree of symptom progression do not correlate with the Cu / Zn SOD enzyme activity of the onset, and transgenic mice (Tg mice) introduced with human normal Cu / Zn SOD gene have no change in clinical symptoms. Tg mice introduced with mutant Cu / Zn SOD develop ALS-like symptoms of limb muscle atrophy and muscle weakness, and conversely, Cu / Zn SOD knockout mice do not show ALS-like symptoms. The newly acquired neurotoxicity of Cu / Zn SOD protein is considered to be a disease state.

  What is currently envisaged as the mechanism by which the mutated Cu / Zn SOD protein degenerates the nerve is: (1) The mutated Cu / Zn SOD either structurally changes or releases copper, so (2) Mutant Cu / Zn SOD promotes the generation of radical peroxynitrite and damages cells, (3) Mutant Cu / Zn SOD aggregates, which damages cells and so on. So far, three strains of Tg mice introduced with the human mutant Cu / Zn SOD gene have been prepared, and these mice are known to develop ALS-like symptoms, although the changes in symptoms and pathology are different. There are various hypotheses about the pathogenesis of ALS as described above, but only the mutation of the Cu / Zn SOD gene has been established as the primary pathogenesis.

  Tohoku University Department of Neurology searched the Cu / Zn SOD gene of FALS patients and reported a new mutation. Among them, the 46th histidine is located in the active center to which the copper ion of Cu / Zn SOD binds. Cu / Zn SOD enzyme activity is hardly observed when there is a gene mutation in. Compared to normal Cu / Zn SOD, the H46R mutation has a different copper ion fraction and is a good model for considering the role of copper ions involved in neurodegeneration. Furthermore, clinically, the onset of a family with the H46R mutation is characterized by a very long morbidity with no variation in symptoms (Non-patent Document 1). I have made it. Two Tg mice with different promoters have been prepared so far. One is the expression vector pCXN using the chicken b-actin promoter for the purpose of strongly expressing Cu / Zn SOD throughout the body (non-patented) The other was using the human Cu / ZnSOD promoter as in the existing Tg mouse for the purpose of comparison with the existing Tg mouse. Previous studies have shown that newly produced human H46R-mutated Tg mice cause motor neuron damage in strains in which Cu / Zn SOD is frequently expressed in the spinal cord.

  In addition, a novel transgenic rat “Amyotrophic lateral sclerosis (ALS) or a substantially equivalent symptom can be developed, which is useful as an ALS animal model for the search for anti-ALS drugs according to Patent Document 1. And a method of use thereof. By using the transgenic rat of the invention, it is possible to efficiently search for therapeutic agents for ALS diseases and confirm their effects. In addition, ALS model rats of the invention, for example, Tg rats introduced with the human mutant Cu / Zn SOD gene, reproduce the pathology of human ALS well in their symptoms and pathological picture, and future pathological conditions as ALS model animals. Useful for elucidation and development of treatments.

JP2002-142610 Nat. Genet., 5, 323-324 (1993) J, Gene, 108, 193-199 (1991)

  An object of the present invention is to provide a pharmaceutical product or a food for specified health use that contains D-allose as an active ingredient and delays the onset or progression of a movement disorder associated with amyotrophic lateral sclerosis. The present invention also provides a method for delaying the onset or progression of movement disorders associated with amyotrophic lateral sclerosis in a subject by administering to the subject a therapeutically effective amount of D-allose. With the goal.

  The present invention supplements and / or enhances the preventive, therapeutic and / or symptom progression-suppressing effects of existing drugs in delaying the onset or progression of movement disorders associated with amyotrophic lateral sclerosis. Onset or progression of movement disorders associated with amyotrophic lateral sclerosis, which has the effect of improving pharmacokinetics / absorption or reducing the dose / side effects of the drug and further preventing the development of drug resistance The purpose is to provide pharmaceuticals or foods for specified health use that will delay the treatment.

The gist of the present invention is the following pharmaceuticals for delaying the onset or progression of movement disorders caused by amyotrophic lateral sclerosis (1) to (3).
(1) To delay the onset or progression of movement disorders caused by amyotrophic lateral sclerosis, wherein D-allose is an active ingredient and the effective amount of D-allose per day is 0.5 to 50 g . Pharmaceuticals .
(2) Presence of genetic mutations that are positively correlated with amyotrophic lateral sclerosis and amyotrophic lateral sclerosis, which are at risk of suffering from a positive family history of amyotrophic lateral sclerosis Is diagnosed as amyotrophic lateral sclerosis at risk of suffering, amyotrophic lateral sclerosis at risk of suffering due to environmental exposure, or amyotrophic The pharmaceutical product according to (1) above, for delaying the onset or progression of movement disorders caused by lateral sclerosis.
(3) Amyotrophic lateral sclerosis, which is at risk of suffering from the presence of a genetic mutation that is positively correlated with amyotrophic lateral sclerosis , the genetic mutation is a gene that encodes superoxide dismutase. The pharmaceutical as described in said (2) which exists.

INDUSTRIAL APPLICABILITY The present invention can provide a pharmaceutical product or a food for specified health use that contains D-allose as an active ingredient and delays the onset or progression of a movement disorder associated with amyotrophic lateral sclerosis. The present invention also provides a method for delaying the onset or progression of movement disorders associated with amyotrophic lateral sclerosis in a subject by administering to the subject a therapeutically effective amount of D-allose. I can do it.
The present invention supplements and / or enhances the preventive, therapeutic and / or symptom progression-suppressing effects of existing drugs in delaying the onset or progression of movement disorders associated with amyotrophic lateral sclerosis. Onset or progression of movement disorders associated with amyotrophic lateral sclerosis, which has the effect of improving pharmacokinetics / absorption or reducing the dose / side effects of the drug and further preventing the development of drug resistance Drugs or foods for specified health use can be provided.

It is a figure which shows the effect of the release of glutamate and the effect of D-allose during ischemia using H46R spinal cord slices. The left side of the figure is untreated, and the right side is D-allose-administered glutamic acid, which is released in brown. It is a figure which shows the effect of the release of hydrogen peroxide at the time of recirculation | reflux, and D-allose on it using the H46R spinal cord slice. The figure on the left shows no treatment, and the figure on the right shows D-allose administration. The liberated hydrogen peroxide has a brown color.

  D-allose (D-allohexose) is a D-form of allose classified as aldose (aldohexose), and is a hexose (C6H12O6) with a melting point of 178 ° C. In the present invention, “D-allose” is a term that means D-allose and / or a derivative thereof. The D-allose derivative will be described. A compound obtained by converting the structure of a molecule from a certain starting compound by a chemical reaction is called a derivative of the starting compound. Derivatives of hexose containing D-psicose include sugar alcohols (when monosaccharides are reduced, aldehyde groups and ketone groups become alcohol groups and polyhydric alcohols with the same number of carbon atoms) and uronic acids (monosaccharides) This is an oxidized version of the alcohol group. Naturally, D-glucuronic acid, galacturonic acid, and mannuronic acid are known. Amino sugar (the OH group of the sugar molecule is replaced with NH2 group, glucosamine, chondrosamine, coordination The same applies to D-allose derivatives, but is not limited thereto.

  This D-allose can be produced by reducing D-alonic acid lactone with sodium amalgam, or by isomerizing D-psicose with L-rhamnose isomerase and separating D-allose from the mixture. Can be produced. As described in JP-A-2004-298106, a rare sugar D-allose can be mass-produced from D-psicose using L-rhamnose isomerase (L-RhI). In order to produce a mixture of D-allose and D-psicose, a method of preparing a mixture of D-psicose and D-allose by allowing L-rhamnose isomerase to act on D-psicose and isomerization can be advantageously performed. . D-psicose and D-allose can be obtained as mixed crystals without separation. Although the proportion of D-allose in the solution before crystallization is 50% or less than that of D-psicose, the amount of D-allose is equal or higher than that of D-psicose in the crystals. On the other hand, when D-psicose and D-allose are mixed at a ratio of 1: 1, the composition ratio of crystals is approximately 2: 3 for D-psicose and D-allose, and a large amount of D-allose is contained in the crystals. In other words, when the mixed sugar of D-psicose and D-allose is crystallized, the ratio of D-psicose to D-allose is considered to be a stable crystal structure between about 1: 1 and 2: 3. (PCT / JP2006 / 304151).

  The present invention relates to an onset or progression retarder of movement disorder associated with amyotrophic lateral sclerosis, comprising D-allose as an active ingredient, and a composition in the form of a food or drink or the medicament containing the progression retarder The present invention relates to a food / beverage product containing D-allose as an active ingredient and labeled as being used to delay the onset or progression of movement disorders associated with amyotrophic lateral sclerosis. Therefore, the pharmaceutical product or food for specified health use targeted by the present invention is characterized in that the blended D-allose is contained as an active ingredient.

When in the form of a pharmaceutical, a composition that delays the onset or progression of movement disorders associated with amyotrophic lateral sclerosis, including D-allose, with one or more pharmaceutically acceptable carriers . The pharmaceutical composition comprises a therapeutically effective amount of a pharmacologically active compound of the present invention alone or in combination with one or more pharmaceutically acceptable carriers.
When D-allose is used as the above-mentioned preparation, it can be carried out by a known method. Specifically, for example, it can be carried out as described below.

  The preparation of the present invention comprises tablets, pills, capsules (including hard capsules, soft capsules, microcapsules), powders, granules, fine granules, troches, liquids (syrups) with sugar coating or coating as necessary , Emulsions, suspensions, etc.).

  The preparation of the present invention can be mixed with a physiologically acceptable carrier or the like as long as the effects of the present invention are not inhibited. As physiologically acceptable carriers, various organic or inorganic carrier substances commonly used as pharmaceutical materials are used. Excipients, binders, disintegrants, lubricants in solid formulations; solvents in liquid formulations, dissolution aids Agents, suspending agents, buffering agents, thickeners, emulsifiers and the like. In addition, formulation additives such as coloring agents, sweetening agents, and antioxidants can be used as necessary. Furthermore, you may coat the formulation of this invention.

  Examples of the excipient include lactose, sucrose, D-mannitol, D-sorbitol, starch, pregelatinized starch, dextrin, crystalline cellulose (for example, microcrystalline cellulose), low-substituted hydroxypropylcellulose, sodium carboxymethylcellulose, Examples include gum arabic, dextrin, pullulan, light anhydrous silicic acid, synthetic aluminum silicate and magnesium aluminate metasilicate. Examples of the binder include pregelatinized starch, sucrose, gelatin, macrogol, gum arabic, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, sucrose, D-mannitol, trehalose, dextrin, pullulan, hydroxypropylcellulose ( HPC), hydroxypropylmethylcellulose (HPMC), polyvinylpyrrolidone (PVP), and the like. Examples of the disintegrant include lactose, sucrose, starch, carboxymethylcellulose, carboxymethylcellulose calcium, crosslinked polyvinylpyrrolidone, carmellose sodium, croscarmellose sodium, sodium carboxymethyl starch, light anhydrous silicic acid, low-substituted hydroxypropylcellulose, Examples include cation exchange resin, partially pregelatinized starch, and corn starch. Examples of the lubricant include stearic acid, magnesium stearate, calcium stearate, talc, waxes, colloidal silica, DL-leucine, sodium lauryl sulfate, magnesium lauryl sulfate, macrogol, and aerosil.

  Examples of the solvent include water for injection, physiological saline, Ringer's solution, alcohol, propylene glycol, polyethylene glycol, medium chain fatty acid triglyceride (MCT), vegetable oil (for example, safflower oil, sesame oil, corn oil, olive oil, cottonseed oil, soybean Lecithin, etc.). Examples of solubilizers include polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, sodium acetate, and the like. can give. Examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glyceryl monostearate; for example, polyvinyl alcohol, polyvinylpyrrolidone, Hydrophilic polymers such as sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose; polysorbates, polyoxyethylene hydrogenated castor oil, and the like. Examples of the buffer include buffer solutions of phosphate, acetate, carbonate, citrate, and the like. Examples of the thickener include natural gums and cellulose derivatives. Examples of emulsifiers include fatty acid esters (eg, sucrose fatty acid ester, glycerin fatty acid ester, sorbitan fatty acid ester, propylene glycol fatty acid ester), wax (eg, beeswax, rapeseed hydrogenated oil, safflower hydrogenated oil, palm Examples thereof include hydrogenated oil, sitosterol, stigmasterol, campesterol, brush casterol, cacao butter powder, carnauba wax, rice wax, molasses, paraffin, and the like, and lecithin (for example, egg yolk lecithin and soybean lecithin).

Examples of the colorant include water-soluble edible tar dyes (eg, edible red Nos. 2 and 3, edible yellow Nos. 4 and 5, edible blue Nos. 1 and 2 and the like, water-insoluble lake dyes (eg, Examples of the water-soluble edible tar pigment include aluminum salts, natural pigments (eg, β-carotene, chlorophyll, bengara, etc.) Examples of the sweetener include sucrose, lactose, sodium saccharin, dipotassium glycyrrhizinate, Examples include aspartame, stevia, etc. Examples of the antioxidant include sulfite, ascorbic acid, and alkali metal salts and alkaline earth metal salts thereof.

  Tablets, granules, fine granules and the like may be coated by a usual method using a coating substrate for the purpose of masking taste, improving light stability, improving appearance or enteric properties. Examples of the coating base include sugar coating base, water-soluble film coating substrate, enteric film coating substrate and the like.

  Examples of the sugar coating base include sucrose, and one or more kinds selected from talc, precipitated calcium carbonate, gelatin, gum arabic, pullulan, carnauba wax and the like may be used in combination.

  Examples of the water-soluble film coating base include cellulose polymers such as hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), ethylcellulose, hydroxyethylcellulose, methylhydroxyethylcellulose; polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer Synthetic polymers such as E (Eudragit E (trade name), Rohm Pharma) polyvinylpyrrolidone; and polysaccharides such as pullulan. Examples of enteric film coating bases include cellulose polymers such as hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, and cellulose acetate phthalate; methacrylic acid copolymer L (Eudragit L (trade name)) Acrylic polymers such as Rohm Pharma), methacrylic acid copolymer LD (Eudragit L-30D55 (trade name) Rohm Pharma), methacrylic acid copolymer S (Eudragit S (trade name) Rohm Pharma), etc. Examples include natural products. These coating bases may be coated singly or in combination of two or more at an appropriate ratio, or two or more may be coated sequentially.

  In the case of a composition in the form of a food or drink, or a food or drink with an indication of function or efficacy, the food composition or food or drink of the present invention is a functional food, health food, food for specified health use, or for the sick It may be prepared as a food, supplement or the like, and is preferably prepared as a functional food. Examples of the shape of the food composition or food or drink of the present invention include a tablet shape, a round shape, a capsule shape (including hard capsules, soft capsules, and microcapsules), a powder shape, a granular shape, a fine granular shape, a troche shape, Liquids (including syrups, milks, and suspensions) are included, and tablets and capsules are preferred.

  The food composition of the present invention is particularly preferably tablet-like or capsule-like, and particularly preferably a tablet-like functional food or a capsule-like functional food.

  The food composition of the present invention can be produced, for example, by including D-allose in food by a known method. Specifically, for example, a tablet-like food composition is added and mixed with, for example, D-allose and raw materials such as excipients (eg, lactose, sucrose, mannitol, etc.), sweeteners, and flavoring agents. And it can manufacture by shape | molding into a tablet shape, applying a pressure with a tableting machine etc. Other materials (for example, vitamins such as vitamin C, minerals such as iron, dietary fiber, etc.) can be added as necessary. Capsule-like food compositions are, for example, filled with a liquid, suspension, paste, powder or granule food composition containing D-allose, or encapsulated with a capsule base. Can be manufactured.

  As long as the effects of the present invention are not impaired, the food composition of the present invention can be used in addition to commonly used food materials, food additives, various nutrients, vitamins, flavor substances (for example, cheese and chocolate), and physiological May be blended with an acceptable carrier. As physiologically acceptable carriers, various conventional organic or inorganic carrier materials are used, and excipients, binders, disintegrants, lubricants, coloring agents, sweeteners, preservatives, antioxidants, Examples include thickeners and emulsifiers. Examples of food additives include colorants, sweeteners, preservatives, antioxidants, and flavoring agents. Furthermore, other materials, for example, minerals such as iron, dietary fibers such as pectin, carrageenan, and mannan may be contained.

  Excipients, binders, disintegrants, lubricants, solvents, solubilizers, suspending agents, buffers, thickeners, colorants, sweeteners, preservatives, and antioxidants are described above. The thing similar to what is used for the formulation of this invention is mention | raise | lifted.

  Vitamins may be water-soluble or fat-soluble, such as retinol palmitate, tocopherol, bisbenchamine, riboflavin, pyridoxine hydrochloride, cyanocobalamin, sodium ascorbate, cholecalciferol, nicotinamide, pantothene. Examples include calcium acid, folic acid, biotin, and choline bitartrate.

  For tablet-like, granule-like, and fine-grained food compositions, etc., coating is carried out by a known method using a coating substrate for the purpose of masking taste, improving light stability, improving appearance, or enteric properties. May be. Examples of the coating substrate include those similar to those used in the preparation of the present invention described above, and can be carried out in the same manner.

  In the present invention, D-allose is safe and may be administered and / or fed to any general person as a preventive measure against the possibility that an individual may develop ALS in the future. In a preferred embodiment of the present invention, D-allose may be administered and / or fed to an individual suspected of being at risk for ALS, an example of the cause of risk being a higher incidence of ALS than normal. Or a certain genetic tendency as a result of a mutation in the SOD gene, for example. In a preferred embodiment of the present invention, another category of subjects that may be treated prophylactically with D-allose includes environmental exposures (e.g., pesticides, herbicides, organic solvents, mercury, Those who have been exposed to lead, manganese, or selenium), smokers, or trauma to the nervous system.

  Furthermore, D-allose may be administered to a subject at an early stage of ALS, preferably after receiving a determination that the diagnosis of ALS is likely. For purposes of definition, the period considered “early stage” is one year from the onset of symptoms.

  In a further embodiment, D-allose is used to delay the onset of symptoms (especially the motor system), for example to delay vocal disturbances, and / or to the respiratory musculature associated with cranial motor nerve dysfunction. It may be administered at a later stage of ALS to delay the disorder. For the sake of definition, patients suffering from ALS for more than one year are at a later stage of the disease.

  When D-allose and / or its derivatives are ingested by humans, the dosage should be determined by the individual's age, weight, symptoms, etc., but in many cases the effective dose is D-allose and / or its derivatives When used, 0.01 to 100 g per day, preferably 0.5 to 50 g, is taken in portions before meals, after meals or with meals.

  In preferred embodiments of the present invention, D-allose is administered orally and / or fed, but other routes of administration, including subcutaneous, inhalation, intravenous, subarachnoid, rectal, or any other suitable route of administration. Can also be used. Formulations containing D-allose can vary using standard techniques and compounds, depending on the mode of administration.

  Details of the present invention will be described in the examples. The present invention is not limited to these examples.

There are many unclear parts regarding the pathology of ALS, but at least in familial ALS, it is known that reactive oxygen species are overproduced and processed poorly due to SOD point mutations.
The generation of reactive oxygen species is a kind of neurotransmitter, but it is thought to be due to glutamic acid that exhibits strong neurotoxicity when secreted in large quantities.
It is well known that reactive oxygen species are produced by glucose and oxygen in the case of glutamate toxicity.
The present inventors have already clarified that D-allose suppresses the generation of active oxygen during cerebral ischemia / reperfusion and has a function of preventing delayed neuronal cell death (WO2003 / 097820).

In this study, we investigated the effect of D-allose on the ALS model.
[experimental method]
1. Transgenic mice use species distributed by the Tohoku University Department of Neurology, and continue to cross at the Kagawa University Animal Experiment Facility to preserve the species.
2. A 5 mm portion of the H46R mouse tail was cut and dissolved in a lysate, and then DNA was extracted. Using this DNA, PCR was performed to confirm whether or not the target gene was introduced.
3. Since paralysis of H46R mice occurred from around 130 days, 2 g / kg of D-allose dissolved in physiological saline at 9 am was orally administered once a day at 9 am from 100 days after birth. In the control group, glucose dissolved in physiological saline was orally administered similarly at 2 g / kg.
4). The behavior was analyzed using visual observation and a motion analysis device (rotary basket motion measurement device). At the same time, video was recorded.
5. As part of the mechanism of action analysis, glutamate release experiments from the spinal cord were performed. Slices were prepared using an 80-day-old spinal cord of H46R, an acrylic self-made chamber was placed under a microscope, and glutamate release was observed in the presence or absence of D-allose during ischemia / reperfusion.

[Experimental result]
1. Therapeutic effect of D-allose on ALS
The average life span of H46R mice is 163 ± 16.4 days, whereas the D-allose administration group significantly prolongs survival at 189 days ± 8.0 days. This mouse develops at 151 ± 16.8 days, progresses from both lower limb paralysis to both sides, further into the upper limb, and eventually dies due to respiratory muscle paralysis. The number of days from onset to death is 12.3 ± 2.6 days. During this time, the progression of paralysis is continuous, and the pathology progresses such as paralysis, progress, and stiffness of the lower limbs. On the other hand, in the D-allose administration group, the period until onset tends to be delayed by 160.0 ± 6.8 days. Furthermore, the time from onset to death in the D-allose administration group is 30.8 ± 4.8 days, and the period from onset to death in the non-administration group is significantly prolonged. This is thought to be due to a delay in the progression of each symptom. The results for ALS of D-allose are shown in Table 1.

  These results have almost the same effect at the experimental animal level as riluzole, which is currently the only approved treatment for ALS. Moreover, it has the same effect as the recently reported gene therapy for insulin-like growth factor, and it is surprising that D-allose, a monosaccharide, has the same effect.

2. Analysis of effects and mechanism of action of D-allose on ALS As part of the working mechanism analysis, glutamate release experiments from the spinal cord were performed.
D-allose suppresses the release of glutamic acid having neurotoxicity in ischemia / reperfusion (FIG. 1). Glutamic acid is specifically released in gray matter and develops brown in this method. The right side of FIG. 1 shows release in the presence of D-allose, but is significantly suppressed. It had almost the same effect as riluzole. In addition, 2-deoxyglucose, an antimetabolite of glucose, exhibited the same action.
Furthermore, the generation of hydrogen peroxide (H ₂ O ₂ ) that was released upon reperfusion and had neurotoxicity was also suppressed (FIG. 2). Hydrogen peroxide is specifically liberated in gray matter and turns brown in this method. The right side of FIG. 2 shows release in the presence of D-allose, but it is significantly suppressed.
Thus, the mechanism of action of D-allose has been elucidated specifically, such as suppression of glutamate release and suppression of hydrogen peroxide production.

[Conclusion]
1. D-allose was found to have a life-prolonging effect by delaying the onset of familial ALS model mice H46R and significantly delaying the progression.
2. As one of the mechanism of action, it has been clarified that the release of glutamic acid having motor neurotoxicity is suppressed.
3. Moreover, it became clear as a 2nd action mechanism that it suppresses the production | generation of hydrogen peroxide which is a reactive oxygen species which has a motor neurotoxicity.
4). From the above, it is considered that D-allose has an effect on ALS by suppressing both the release of glutamic acid and the generation of reactive oxygen species, thereby suppressing the death of spinal motor neurons.

  The present invention provides a method for delaying the onset or progression of a movement disorder associated with ALS in a subject comprising administering to the subject a therapeutically effective amount of D-allose. This is based at least in part on the finding that D-allose was able to delay the onset of movement disorders in H46R mutant Cu / ZnSOD transgenic ALS model mice. Thus, D-allose prophylactically treats the general population and more specifically individuals who are considered to be at risk of developing ALS (eg, due to a positive family history of the disease and / or the presence of a genetic defect) Can be used for. Moreover, D-allose has already been combined with ALS to delay the progression of preexisting movement disorders and / or to delay the onset of movement disorders in motor systems that are not yet affected by the disease. Can be used to treat a diagnosed individual. A great impact and demand can be expected for these medicines or special health foods.

Claims (3)

A pharmaceutical product containing D-allose as an active ingredient and having an effective daily dose of D-allose of 0.5 to 50 g for delaying the onset or progression of movement disorders caused by amyotrophic lateral sclerosis . Due to the positive family history of amyotrophic lateral sclerosis, affected by the presence of genetic mutations that are positively correlated with amyotrophic lateral sclerosis, at risk of suffering from amyotrophic lateral sclerosis Amyotrophic lateral sclerosis at risk, diagnosed as amyotrophic lateral sclerosis at risk, or amyotrophic lateral sclerosis due to environmental exposure The pharmaceutical of Claim 1 for delaying the onset or progress of the movement disorder resulting from a disease. Amyotrophic lateral sclerosis, which is at risk of suffering from the presence of a genetic mutation that is positively correlated with amyotrophic lateral sclerosis , the genetic mutation is present in the gene encoding superoxide dismutase, The pharmaceutical product according to claim 2.