Agent for preventing or improving neuropathy

Abstract

To provide an agent for preventing or improving neuropathy caused by a decrease in neural function due to nerve injury.SOLUTION: An agent for preventing or improving neuropathy comprises a combination of gluconodeltalactone and monocaffeoylquinic acid or a salt thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to an agent for preventing or ameliorating nerve damage. [Background technology]

[0002] When nerve tissue is damaged, the effector organs innervated by the damaged nerves are impaired. The number of stroke patients, a typical example of neurological damage, is extremely high in Japan, at approximately 1.2 million, resulting in enormous social losses.

[0003] When nerve damage occurs due to a stroke, traffic accident, or other causes, rehabilitation is recommended to restore nerve function. However, the current rehabilitation method's effectiveness in restoring function is insufficient, and it has been reported that even after rehabilitation, patients often remain disabled or are unable to return to society. As such, there are limitations to the effectiveness of conventional rehabilitation in restoring nerve function, and there is a need for useful means that can promote the effects of rehabilitation.

[0004] Neuropathy is also a common complication of diabetes (diabetic neuropathy), which manifests as alternating constipation and diarrhea, autonomic neuropathy (e.g., erectile dysfunction, dizziness, and abnormal sweating), and sensory neuropathy (e.g., numbness and abnormal sensations). These symptoms are thought to be the result of peripheral nerve fiber loss and decreased nerve function, which can cause abnormalities in various parts of the body. In many cases, subjective symptoms such as numbness and pain in the feet gradually spread to the central nerves. Without appropriate treatment, the loss of sensory nerve fibers can lead to the inability to sense pain or heat. This can result in the formation of foot ulcers, which, if left untreated, can lead to gangrene and, in the worst case, lower limb amputation, significantly reducing the patient's quality of life (QOL).

[0005] It has also been reported that neurological decline contributes to the decline in muscle function associated with aging (Non-Patent Document 1), and in Japan, which is an ultra-aged society, it is important to create technologies to improve declined neurological function and technologies to prevent decline in neurological function.

[0006] Nerve damage is often perceived as pain (neuropathic pain). Pain can cause inconvenience and discomfort in daily life, reduce motivation to work, and reduce quality of life. Neuropathic pain occurs when damaged nerves remain excited, resulting in excessive release of pain-transmitting substances from the damaged nerves. As a result, even after the cause or source of pain is removed and the disease is cured, pain may persist for a long time, be severe with slight stimulation, be felt with changes in weather or climate, or be felt even without movement. Neuropathic pain often manifests as symptoms such as electric shock-like pain or severe numbness. Nerve disorders can also cause discomfort such as stiff shoulders and lower back pain. For example, patients with cervical nerve root compression may experience symptoms such as pain and stiffness in the neck and shoulders. It has been reported that nerve root block injections in such patients can relieve the compressed nerve roots and reduce pain and stiffness (Non-Patent Document 2).

[0007] Neuropathic pain is thought to be caused by calcium entering nerve cells through calcium channels, which excites the nerve cells and causes excessive release of neurotransmitters. Calcium channel blockers are often used for its treatment and prevention. Antidepressants and antiepileptic drugs may also be used. Furthermore, if pain persists with these drugs and interferes with daily activities, narcotic analgesics such as opioids may also be used.

[0008] On the other hand, it has been reported that sugarcane top extracts containing monocaffeoylquinic acids such as neochlorogenic acid and chlorogenic acid have a protective effect on nerve cells from amyloid beta and are useful in improving learning disabilities and memory disorders (Patent Document 1). However, it has not been known that monocaffeoylquinic acid, coffee bean extract or plum extract containing monocaffeoylquinic acid, or the combined use of these with a specific lactone compound, can have an improving effect on nerve disorders. [Prior art documents] [Patent documents]

[0009] [Patent Document 1] International Publication No. 2021 / 167012 [Non-patent literature]

[0010] [Non-Patent Document 1] Nutrition 28: 495-503, 2012 [Non-patent document 2] Eur Radiol. 25: 3405-3413, 2015 Summary of the Invention [Problem to be solved by the invention]

[0011] The present invention relates to providing an agent for preventing or ameliorating neuropathy caused by nerve damage or decreased nerve function due to diabetic neuropathy. [Means for solving the problem]

[0012] The present inventors have searched for materials that improve nerve function and have found that a combination of glucono-delta-lactone, monocaffeoylquinic acid or a salt thereof, and a plant extract containing the same has the effect of improving decreased nerve function due to nerve damage.

[0013] That is, the present invention relates to the following 1) to 21). 1) A preventive or ameliorating agent for nerve disorders comprising a combination of glucono-delta-lactone and monocaffeoylquinic acid or a salt thereof. 2) A nerve regeneration promoter comprising a combination of glucono-delta-lactone and monocaffeoylquinic acid or a salt thereof. 3) A promoter for recovery of motor function after nerve damage, comprising a combination of glucono-delta-lactone and monocaffeoylquinic acid or a salt thereof. 4) An agent for inhibiting muscle atrophy after nerve injury, comprising a combination of glucono-delta-lactone and monocaffeoylquinic acid or a salt thereof. 5) A prophylactic or ameliorative agent for neuropathic pain comprising a combination of glucono-delta-lactone and monocaffeoylquinic acid or a salt thereof. 6) An agent for preventing or improving nerve disorders comprising a combination of glucono-delta-lactone and plum or coffee beans, or extracts thereof. 7) A nerve regeneration promoter comprising a combination of glucono-delta-lactone and plum or coffee beans, or extracts thereof. 8) A promoter for recovery of motor function after nerve damage, comprising a combination of glucono-delta-lactone and plum or coffee beans, or extracts thereof. 9) An agent for inhibiting muscle atrophy after nerve injury, comprising a combination of glucono-delta-lactone and plum or coffee beans, or extracts thereof. 10) An agent for preventing or ameliorating neuropathic pain comprising a combination of glucono-delta-lactone and plum or coffee beans, or extracts thereof. 11) A food for preventing or improving nerve disorders, comprising a combination of glucono-delta-lactone and monocaffeoylquinic acid or a salt thereof. 12) A food for promoting nerve regeneration comprising a combination of glucono-delta-lactone and monocaffeoylquinic acid or its salt. 13) A food for promoting recovery of motor function after nerve damage, comprising a combination of glucono-delta-lactone and monocaffeoylquinic acid or its salt. 14) A food for inhibiting muscle atrophy after nerve damage, comprising a combination of glucono-delta-lactone and monocaffeoylquinic acid or its salt. 15) A food for preventing or improving neuropathic pain comprising a combination of glucono-delta-lactone and monocaffeoylquinic acid or a salt thereof. 16) A food for preventing or improving nerve disorders, comprising a combination of glucono-delta-lactone and plum extract or coffee bean extract. 17) A food for promoting nerve regeneration comprising a combination of glucono-delta-lactone and plum extract or coffee bean extract. 18) A food for promoting recovery of motor function after nerve damage, comprising a combination of glucono-delta-lactone and plum extract or coffee bean extract. 19) A food for inhibiting muscle atrophy after nerve injury, comprising a combination of glucono-delta-lactone and plum extract or coffee bean extract. 20) A food for preventing or improving neuropathic pain, comprising a combination of glucono-delta-lactone and plum extract or coffee bean extract. 21) A pharmaceutical or food composition containing glucono-delta-lactone and monocaffeoylquinic acid or a salt thereof. [Effects of the Invention]

[0014] According to the present invention, it is possible to provide a pharmaceutical, quasi-drug, food, or supplement for preventing or ameliorating nerve damage. According to the present invention, it is possible to promote recovery of nerve function and relieve pain associated with nerve damage using a food or supplement, and therefore it is possible to provide a new means for improving the quality of life for elderly people and patients receiving care at home due to nerve damage. [Brief explanation of the drawings]

[0015] [Figure 1] Improves nerve damage after spinal cord crush injury (neochlorogenic acid). [Figure 2] Coffee bean extract improves nerve damage after spinal cord crush injury. [Figure 3] Improves nerve damage after spinal cord crush injury (plum extract). [Figure 4] Improvement of nerve damage in an animal model of sciatic nerve crush injury (neurohistological analysis: g-ratio). A: Sham group, B: Control group, C: Neochlorogenic acid + GDL group, D: Neochlorogenic acid (10x) + GDL group, E: Coffee bean extract + GDL group. [Figure 5] Nerve damage improvement effect in an animal model of sciatic nerve crush injury (weight of extensor digitorum longus muscle). A: Sham group, B: Control group, C: Neochlorogenic acid + GDL group, D: Neochlorogenic acid (10x) + GDL group, E: Coffee bean extract + GDL group. DETAILED DESCRIPTION OF THE INVENTION

[0016] In the present invention, glucono-delta-lactone is an intramolecular ester formed by dehydrating one water molecule from gluconic acid. Glucono-delta-lactone of a quality used in the food industry can be obtained and used. In this specification, glucono-delta-lactone may be abbreviated as "GDL."

[0017] In the present invention, examples of monocaffeoylquinic acids include neochlorogenic acid (CAS No. 906-33-2), cryptochlorogenic acid (CAS No. 905-99-7), and chlorogenic acid (CAS No. 327-97-9). One or more of these can be used, but from the viewpoint of the effect of improving nerve damage, it is preferable to include neochlorogenic acid and / or chlorogenic acid, and it is more preferable to include at least neochlorogenic acid. In the present invention, neochlorogenic acid refers to 5-O-(trans-3,4-Dihydroxycinnamoyl)-D-quinic acid, which is formed by esterifying caffeic acid to the 5-position of quinic acid. The compound name (IUPAC) is Cyclohexanecarboxylic acid, 3-[[(2E)-3-(3,4-dihydroxyphenyl)-1-oxo-2-propen-1-yl]oxy]-1,4,5-trihydroxy-,(1R,3R,4S,5R)-(ACI). and its structure is shown below:

[0018] [ka]

[0019] Salts of monocaffeoylquinic acid include pharmaceutically acceptable salts, such as alkali metal salts (e.g., sodium, potassium, etc.), alkaline earth metal salts (e.g., magnesium, calcium, etc.), organic amine salts (e.g., monoethanolamine, diethanolamine, triethanolamine, etc.), basic amino acid salts (e.g., arginine, lysine, histidine, ornithine, etc.), and ammonium salts (e.g., ammonium chloride, tetraethylammonium, tetramethylammonium, etc.).

[0020] Monocaffeoylquinic acid is a type of chlorogenic acid and is contained in many plants. Therefore, the monocaffeoylquinic acid or a salt thereof of the present invention may be a chemically synthesized product, or may be a plant extract containing monocaffeoylquinic acid or a salt thereof, a concentrate thereof, or a purified product thereof. Examples of plants containing monocaffeoylquinic acid or a salt thereof include plants known to contain neochlorogenic acid, such as plum, coffee beans, cherry, rowan, sour cherry, loquat, burdock, and Peucedanum japonicum. In the present invention, plum and coffee beans are preferably used in view of their effect in improving nerve disorders.

[0021] "Plum" refers to Prunus domestica, a plant belonging to the genus Prunus in the family Rosaceae. The parts of the plum that are used may be, for example, the fruit, flowers, leaves, seeds, stems, roots, or a combination thereof, but the fruit is preferred. Dried plums are also called "prunes." The coffee beans may be derived from any of the Arabica, Robusta, Liberica and Arabusta trees. Decaffeinated beans may also be used. The above-mentioned parts of the plum can be dried and then used as is, or roasted, steam-dried, or powdered, but it is preferably used as an extract. The coffee beans may be either green or roasted, with green coffee beans being preferred, and decaffeinated beans may also be used. Whole beans or ground beans may be used as is, but it is preferred to use them as an extract. The production of the extract is not particularly limited, and can be obtained by extracting the above-mentioned plant parts by a known method. In the present invention, extracts produced by solvent extraction using various extraction solvents are preferably used.

[0022] The solvent used for extraction can be either polar or nonpolar. Specific examples of solvents include water; alcohols such as methanol, ethanol, propanol, and butanol; polyhydric alcohols such as propylene glycol and butylene glycol; ketones such as acetone and methyl ethyl ketone; esters such as methyl acetate and ethyl acetate; linear and cyclic ethers such as tetrahydrofuran and diethyl ether; polyethers such as polyethylene glycol; hydrocarbons such as squalane, hexane, cyclohexane, and petroleum ether; aromatic hydrocarbons such as toluene; halogenated hydrocarbons such as dichloromethane, chloroform, and dichloroethane; and supercritical carbon dioxide; pyridines; organic solvents such as fats, oils, waxes, and other oils; and mixtures thereof. Suitable solvents include water, alcohols, and alcohol-water mixtures, with ethanol being preferred as the alcohol. Alcohol-water mixtures can be used in any ratio, but a mixture containing 0 to 50% alcohol (v / v % at 20°C) is preferred. The plum extract is preferably an extract using a 20 to 70 v / v % aqueous ethanol solution. The coffee bean extract is preferably an extract that contains a large amount of coffee polyphenols (for example, nine types of chlorogenic acids including monocaffeoylquinic acids such as neochlorogenic acid, cryptochlorogenic acid, and chlorogenic acid, monoferuloylquinic acids such as 3-feruloylquinic acid (3-FQA), 4-feruloylquinic acid (4-FQA), and 5-feruloylquinic acid (5-FQA), and dicaffeoylquinic acids such as 3,4-dicaffeoylquinic acid (3,4-diCQA), 3,5-dicaffeoylquinic acid (3,5-diCQA), and 4,5-dicaffeoylquinic acid (4,5-diCQA)), and is preferably an extract using a 5 to 95 v / v% aqueous ethanol solution, an aqueous ascorbic acid solution, an aqueous citric acid solution, or hot water.

[0023] The amount of extraction solvent used is not particularly limited as long as sufficient extraction efficiency is obtained, but for example, it is preferably 2 to 60 times by mass, more preferably 3 to 30 times by mass, and most preferably 5 to 15 times by mass relative to the amount of dried plums or coffee beans. The extraction conditions are not particularly limited as long as they are conditions that provide sufficient extraction efficiency. The extraction temperature is preferably 0°C or higher and lower than the boiling point of the solvent used, more preferably room temperature, but the higher the extraction temperature, the shorter the extraction time. The extraction period (time) is preferably 10 minutes to 1 day when extraction is performed by heating to 40°C or higher, and examples include 12 to 24 hours at 40 to 50°C, 2 to 12 hours at 50 to 60°C, 10 minutes to 10 hours at 60 to 70°C, and 10 minutes to 6 hours at 70 to 100°C. When extraction is performed at 40°C or below, the extraction period is preferably 1 to 30 days, more preferably 3 to 21 days. For example, the extraction period includes 1 to 7 days at 40 to 30°C, 3 to 21 days at 30 to 20°C, and 21 to 30 days at 20 to 10°C. At room temperature, the extraction period is even more preferably 3 to 14 days.

[0024] The extraction means is not particularly limited, but for example, conventional means such as solid-liquid extraction, liquid-liquid extraction, maceration, decoction, percolation, reflux extraction, pressurized heating extraction, and supercritical extraction can be used.

[0025] It is also possible to prepare a coffee bean extract from which caffeine has been removed. Note that the coffee bean extract may also be a commercially available preparation containing chlorogenic acids, such as Green Coffee Bean Extract WSP (manufactured by Oryza Oil & Fat Chemical Co., Ltd.) or Lunaphenon C-200 (manufactured by Kao Corporation).

[0026] The plum extract and coffee bean extract of the present invention may be a crude product, as long as they meet, for example, food and pharmaceutical acceptable standards and exhibit the effects of the present invention. Furthermore, if necessary, they may be subjected to treatments such as removal of inactive contaminants, deodorization, and decolorization using known techniques such as liquid-liquid partitioning, solid-liquid partitioning, activated carbon treatment, and ion exchange resin treatment. Furthermore, the concentration or proportion of a specific component (fraction) may be increased by appropriately combining known separation and purification methods. Purification methods include organic solvent precipitation, centrifugation, ultrafiltration membrane separation, high performance liquid chromatography, and column chromatography.

[0027] In the present invention, the above extract can be used as is, or it can be diluted, concentrated, or freeze-dried to prepare a powder or paste. It can also be freeze-dried and then dissolved or diluted with a solvent commonly used in extraction, such as water, ethanol, propylene glycol, a water-ethanol mixture, a water-propylene glycol mixture, or a water-1,3-butylene glycol mixture, before use. It can also be encapsulated in vesicles such as liposomes or microcapsules.

[0028] In the present invention, monocaffeoylquinic acid or a salt thereof, plum or coffee bean, or an extract thereof, and glucono-delta-lactone are used in combination (concomitant use), but the form is not limited thereto. That is, the combination may be a composition in which effective amounts of each ingredient are formulated in an appropriate ratio into a single dosage form, or a kit in which drugs containing effective amounts of each ingredient are formulated individually and can be used simultaneously or separately at intervals, but simultaneous use is preferred. Note that the combined use of gluconoylquinic acid and monocaffeoylquinic acid or a salt thereof has not been reported to date, and a composition containing glucono-delta-lactone and monocaffeoylquinic acid or a salt thereof is a novel composition.

[0029] When monocaffeoylquinic acid or a salt thereof is combined with glucono delta lactone to form a formulation, the blending ratio can be selected appropriately depending on the material, application, or type of formulation, but is generally a mass ratio of monocaffeoylquinic acid (in free form) to glucono delta lactone of 1:1 to 100, preferably 1:1 to 10. Furthermore, when combining plums or coffee beans, or an extract thereof, with glucono delta lactone to form a formulation, the blending ratio can be selected appropriately depending on the material, application, or type of formulation, but is generally a mass ratio of plums or coffee beans, or an extract thereof (in dry matter terms) to glucono delta lactone of 1:0.01-100, preferably 1:0.01-1.

[0030] As shown in the Examples below, the combination of neochlorogenic acid and glucono delta lactone, and the combination of plum extract or coffee bean extract and glucono delta lactone improve motor impairment and promote nerve regeneration in a central nervous system regeneration model (zebrafish) following spinal cord crush injury.

[0031] Zebrafish treated with spinal nerve crush injury are known as a model of central nervous system regeneration (Mayssa H. et al., Science, 354, 630-634 (2016)), and the promotion of recovery of motor function in this model indicates the promotion of central nervous system regeneration.

[0032] Therefore, the combination of monocaffeoylquinic acid or a salt thereof with glucono delta lactone, and the combination of plum or coffee beans, or an extract thereof, with glucono delta lactone (hereinafter also referred to as the "active ingredients of the present invention") can serve as an agent for preventing or ameliorating neuropathy, an agent for promoting nerve regeneration, an agent for promoting motor function recovery after nerve injury, an agent for inhibiting muscle atrophy after nerve injury, or an agent for preventing or ameliorating pain associated with nerve injury (neuropathic pain) (hereinafter referred to as an "agent for preventing or ameliorating neuropathy, etc."), and can be used to manufacture such an agent for preventing or ameliorating neuropathy, etc. That is, the combination of monocaffeoylquinic acid or a salt thereof with glucono delta lactone, and the combination of plum or coffee beans, or an extract thereof, with glucono delta lactone of the present invention can be used for preventing or ameliorating neuropathy, promoting nerve regeneration, promoting motor function recovery after nerve injury, promoting the inhibition of muscle atrophy after nerve injury, or preventing or ameliorating neuropathic pain. Here, the use may be therapeutic or non-therapeutic. "Non-therapeutic" is a concept that does not include medical procedures, i.e., a concept that does not include methods of surgery, therapy, or diagnosis on humans, and more specifically, a concept that does not include methods of surgery, therapy, or diagnosis on humans by a physician or a person under the direction of a physician.

[0033] In the present invention, "neuropathy" refers to a pathological condition in which nerve function is impaired due to damage to nerve cells and Schwann cells and oligodendrocytes that form myelin sheaths, caused by nerve damage, aging, etc., and specific symptoms include pain, loss of sensation (including numbness), tingling or burning sensation in the limbs or extremities, paresthesia, muscle weakness, muscle mass loss, motor function decline, decreased neuromuscular reflexes, convulsions, neuromuscular paralysis, and sexual dysfunction. Here, "nerve damage" mainly includes physical damage, hemorrhagic or ischemic damage to central nerves such as the trigeminal nerve, spinal cord, and nerve roots, or peripheral nerves such as the sciatic nerve and median nerve, caused by trauma, contusion, compression, etc., and is preferably physical damage. Age-related neurological dysfunction includes changes in the central nervous system, such as a decrease in motor cortex excitability and changes in cortical plasticity, and changes in the peripheral nervous system, such as a decrease in the number of axons, thinning of the myelin sheath, and fragmentation of acetylcholine receptors.

[0034] "Improvement" of neuropathy includes "prevention or treatment." "Prevention" of neuropathy means preventing or delaying the onset of neuropathy, and "treatment" means alleviating the symptoms of neuropathy or preventing or delaying the progression (worsening) of the symptoms.

[0035] "Nerve regeneration" means at least a partial reproduction of the normal developmental process in nerves, i.e., reproduction of at least one of the phenomena occurring during nerve repair or nerve development, such as cell proliferation, differentiation, and maturation (tissue regeneration), and preferably, as a result, the phenomenon of complete or partial recovery of the original nerve function (functional regeneration).

[0036] "Promoting recovery of motor function after nerve damage" means recovering from motor dysfunction (for example, motor paralysis, muscle weakness) that occurs in the region innervated by the damaged nerve following nerve damage. The nerve damage may be either peripheral nerve damage or central nerve damage, but is preferably peripheral nerve damage. The cause of the nerve damage is not particularly limited, and nerve damage caused by various factors such as trauma, compression by a cast, electrical injury, herniated disc, and stroke is applicable.

[0037] "Suppression of muscle atrophy after nerve damage" means suppression of muscle loss that occurs in the area innervated by the damaged nerve following nerve damage.

[0038] "Neuropathic pain" refers to pain caused by lesions or diseases of the somatosensory nervous system. Symptoms include burning or tingling sensations, and hypersensitivity to touch and cold. The sense of touch can also become so sensitive that even a light touch can cause pain (allodynia, hyperesthesia). Furthermore, symptoms often include pain even when at rest (spontaneous pain).

[0039] For example, neuropathic pain can be diagnosed by answering the following seven questions on a five-point scale (no symptoms (0 points), slight symptoms (1 point), symptoms (2 points), severe symptoms (3 points), and very severe symptoms (4 points)), and then determining the total score (6 points or more indicates neuropathic pain) (Rinsei Gai 47:565-574, 2012). 1) Pain like being stabbed with needles 2) Electric shock-like pain 3) Burning or stinging pain 4) There is severe pain with numbness 5) Pain occurs even when clothing rubs against the skin or when exposed to cold air 6) Decreased or hypersensitive sensation in the area of ​​pain 7) Swelling or red or reddish-purple discoloration of the skin in the area of ​​pain

[0040] Major diseases that cause neuropathic pain include the above-mentioned nerve disorders or diseases that can cause nerve disorders, such as, but not limited to, herniated disc, low back pain, entrapment neuropathy, sciatica, trigeminal neuralgia, carpal tunnel syndrome, lumbar spondylolisthesis, spinal stenosis, multiple sclerosis, Guillain-Barré syndrome, sequelae of stroke, pain after herniorrhaphy, and postherpetic neuralgia.

[0041] "Amelioration" of neuropathic pain includes "prevention or treatment." "Prevention" of neuropathic pain means preventing or delaying the onset of neuropathic pain, and "treatment" means alleviating neuropathic pain or preventing or delaying the progression (worsening) of neuropathic pain.

[0042] The agent for preventing or improving nerve damage of the present invention can itself be used as various compositions, such as pharmaceuticals, quasi-drugs, or foods, that exhibit the effect of preventing or improving nerve damage, the effect of promoting nerve regeneration, the effect of promoting recovery of motor function after nerve damage, the effect of inhibiting muscle atrophy after nerve damage, or the effect of preventing or improving neuropathic pain, or can be used as a material or preparation (pharmaceutical composition, food composition, etc.) to be incorporated into these. The above foods (also referred to as "foods for preventing or improving nerve disorders caused by nerve damage or aging," "foods for promoting nerve regeneration," "foods for promoting recovery of motor function after nerve damage," "foods for inhibiting muscle atrophy after nerve damage," and "foods for preventing or improving neuropathic pain") include not only general foods and beverages, but also foods, functional foods, foods for the sick, foods for specified health uses, foods with functional claims, and supplements that are labeled as such if necessary, for example, to improve the various symptoms of the above-mentioned nerve disorders, or to improve discomfort such as stiff shoulders and lower back pain caused by nerve disorders.

[0043] The pharmaceuticals (including quasi-drugs) containing the active ingredient of the present invention can be administered in any dosage form, but oral administration is preferred. When administered, the active ingredient can be mixed with a solid or liquid pharmaceutical non-toxic carrier suitable for administration methods such as oral administration, rectal administration, or injection, and administered in the form of a conventional pharmaceutical formulation.

[0044] Examples of such formulations include solid formulations such as tablets, granules, powders, and capsules, liquid formulations such as solutions, suspensions, and emulsions, and freeze-dried formulations. These formulations can be prepared by conventional pharmaceutical means by appropriately adding conventional additives such as stabilizers, wetting agents, emulsifiers, binders, isotonicity agents, and excipients.

[0045] The food containing the active ingredient of the present invention may take the form of various foods and beverages, such as soft drinks, tea drinks, coffee drinks, fruit juice drinks, carbonated drinks, jellies, wafers, biscuits, uncooked cereals, cooked cereals, bread, noodles, sausages, and nutritional foods, as well as nutritional supplement compositions in the same form as the oral preparations described above (solid preparations such as tablets, capsules, and lozenges). Of these, heat-processed cereals and tablets are preferred. Various forms of food products can be prepared using the active ingredient of the present invention alone or in appropriate combination with other food ingredients, solvents, softeners, oils, emulsifiers, preservatives, flavorings, stabilizers, colorants, antioxidants, moisturizers, thickeners, etc.

[0046] The content of monocaffeoylquinic acid or a salt thereof in the above-mentioned composition (e.g., pharmaceutical, quasi-drug, food) containing the active ingredient of the present invention varies depending on the form of use, but is preferably 0.1% by mass or more, more preferably 2% by mass or more, and preferably 50% by mass or less, more preferably 30% by mass or less, and also preferably 0.1 to 50% by mass, more preferably 2 to 30% by mass, calculated as the free monocaffeoylquinic acid. Furthermore, the content of plum or coffee beans, or an extract thereof, in the above-mentioned composition (e.g., pharmaceutical, quasi-drug, food) containing the active ingredient of the present invention varies depending on the form of use, but is preferably 1% by mass or more, more preferably 10% by mass or more, and preferably 99% by mass or less, more preferably 90% by mass or less, and also preferably 1 to 99% by mass, more preferably 10 to 90% by mass, calculated as a dried substance (e.g., a dried substance dried in the sun for 1 to 1.5 weeks).

[0047] The content of glucono-delta-lactone in the above-mentioned compositions (e.g., pharmaceuticals, quasi-drugs, foods) containing the active ingredient of the present invention can be adjusted appropriately depending on the form of use. For example, in liquid compositions (e.g., beverages, syrups), the content is preferably 0.01% by mass or more, more preferably 0.05% by mass or more, and preferably 10% by mass or less, more preferably 1% by mass or less, and also preferably 0.01 to 10% by mass, more preferably 0.1 to 1% by mass. In solid compositions (e.g., tablets, capsules, granule powders, candies), the content is preferably 1% by mass or more, more preferably 5% by mass or more, and preferably 50% by mass or less, more preferably 30% by mass or less, and also preferably 1 to 50% by mass, more preferably 5 to 30% by mass.

[0048] The dosage or intake of the active ingredient of the present invention may vary depending on the condition, body weight, sex, age, or other factors of the subject. In the case of oral administration or intake, the amount of monocaffeoylquinic acid or a salt thereof per adult (body weight 60 kg) per day is preferably 1 mg or more, more preferably 5 mg or more, and preferably 200 mg or less, more preferably 120 mg or less, and also preferably 1 to 200 mg, more preferably 5 to 120 mg, calculated as free monocaffeoylquinic acid. Furthermore, the daily intake of coffee beans or an extract thereof, calculated on a dry matter basis, is preferably 10 mg or more, more preferably 20 mg or more, and preferably 2 g or less, more preferably 700 mg or less, and also preferably 10 mg to 2 g, more preferably 20 mg to 700 mg. Furthermore, the daily intake of plum or an extract thereof is preferably 1 g or more, more preferably 3 g or more, and preferably 50 g or less, more preferably 10 g or less, and is also preferably 1 to 50 g, more preferably 3 to 10 g, in terms of dry matter. The daily amount of glucono-delta-lactone is preferably 5 mg or more, more preferably 50 mg or more, and preferably 2000 mg or less, more preferably 200 mg or less, and also preferably 5 to 2000 mg, more preferably 50 to 200 mg.

[0049] Subjects to whom the preventive or ameliorative agent of the present invention for nerve damage may be ingested or administered include, for example, people who have developed reduced nerve function and various symptoms of nerve damage (sensation loss, paresthesia, muscle weakness, decreased neuromuscular reflexes, convulsions, neuromuscular paralysis, etc.), or symptoms such as discomfort caused by such nerve damage, such as stiff shoulders and lower back, people who wish to maintain or improve nerve function, and people who have developed or are at risk of developing various symptoms of neuropathic pain (burning pain or tingling sensation in the buttocks, thighs, shins, calves, knees, ankles, toes, elbows, fingers, shoulders, back, lower back, etc., allodynia, hyperesthesia, etc.).

[0050] In relation to the above-described embodiment, the present invention further discloses the following aspects. <1> An agent for preventing or improving nerve disorders comprising a combination of glucono-delta-lactone and monocaffeoylquinic acid or a salt thereof. <2> A nerve regeneration promoter comprising a combination of glucono-delta-lactone and monocaffeoylquinic acid or a salt thereof. <3> A promoter for recovery of motor function after nerve damage, comprising a combination of glucono-delta-lactone and monocaffeoylquinic acid or a salt thereof. <4> An agent for inhibiting muscle atrophy after nerve injury, comprising a combination of glucono-delta-lactone and monocaffeoylquinic acid or a salt thereof. <5> An agent for preventing or ameliorating neuropathic pain comprising a combination of glucono-delta-lactone and monocaffeoylquinic acid or a salt thereof. <6> An agent for preventing or improving nerve disorders comprising a combination of glucono-delta-lactone and plum or coffee beans or extracts thereof. <7> A nerve regeneration promoter comprising a combination of glucono-delta-lactone and plum or coffee beans or extracts thereof. <8> A promoter for recovery of motor function after nerve damage, comprising a combination of glucono-delta-lactone and plum or coffee beans or extracts thereof. <9> An agent for inhibiting muscle atrophy after nerve injury, comprising a combination of glucono-delta-lactone and plum or coffee beans, or extracts thereof. <10> An agent for preventing or ameliorating neuropathic pain comprising a combination of glucono-delta-lactone and plum or coffee beans or extracts thereof. <11> A food for preventing or improving nerve disorders, comprising a combination of glucono-delta-lactone and monocaffeoylquinic acid or a salt thereof. <12> A nerve regeneration promoting food comprising a combination of glucono-delta-lactone and monocaffeoylquinic acid or a salt thereof. <13> A food for promoting recovery of motor function after nerve damage, comprising a combination of glucono-delta-lactone and monocaffeoylquinic acid or a salt thereof. <14> A food for inhibiting muscle atrophy after nerve damage, comprising a combination of glucono-delta-lactone and monocaffeoylquinic acid or a salt thereof. <15> A food for preventing or ameliorating neuropathic pain, comprising a combination of glucono-delta-lactone and monocaffeoylquinic acid or a salt thereof. <16> The food for preventing or improving nerve disorders comprises a combination of glucono-delta-lactone and a plum extract or a coffee bean extract. <17> A nerve regeneration promoting food comprising a combination of glucono-delta-lactone and a plum extract or a coffee bean extract. <18> A food for promoting recovery of motor function after nerve damage, comprising a combination of glucono-delta-lactone and a plum extract or a coffee bean extract. <19> A food for inhibiting muscle atrophy after nerve damage, comprising a combination of glucono-delta-lactone and a plum extract or a coffee bean extract. <20> A food for preventing or improving neuropathic pain, comprising a combination of glucono-delta-lactone and a plum extract or a coffee bean extract. <21> Neuropathy is a decline in nerve function due to physical damage to the central or peripheral nerves. <1> or <6> or <11> or <16> The food product described in <22> Monocaffeoylquinic acid contains neochlorogenic acid, <1> ~ <5> or <11> ~ <15> 1. A food product according to any one of the preceding items. <23> A pharmaceutical or food composition comprising glucono-delta-lactone and monocaffeoylquinic acid or a salt thereof.

[0051] <24> Use of a combination of glucono-delta-lactone and monocaffeoylquinic acid or a salt thereof for the manufacture of an agent for preventing or ameliorating nerve disorders. <25> Use of a combination of glucono-delta-lactone and monocaffeoylquinic acid or a salt thereof for producing a nerve regeneration promoter. <26> Use of a combination of glucono-delta-lactone and monocaffeoylquinic acid or a salt thereof for producing an agent for promoting recovery of motor function after nerve injury. <27> Use of a combination of glucono-delta-lactone and monocaffeoylquinic acid or a salt thereof for producing an agent for inhibiting muscle atrophy after nerve injury. <28> Use of a combination of glucono-delta-lactone and monocaffeoylquinic acid or a salt thereof for the manufacture of an agent for preventing or ameliorating neuropathic pain. <29> Use of a combination of glucono-delta-lactone and a plum extract or a coffee bean extract for the manufacture of an agent for preventing or improving nerve disorders. <30> Use of a combination of glucono-delta-lactone and a plum extract or a coffee bean extract for producing a nerve regeneration promoter. <31> 1. Use of a combination of glucono-delta-lactone and a plum extract or a coffee bean extract for producing an agent for promoting recovery of motor function after nerve injury. <32> Use of a combination of glucono-delta-lactone and a plum extract or a coffee bean extract for the manufacture of an agent for inhibiting muscle atrophy after nerve injury. <33> 1. Use of a combination of glucono-delta-lactone and a plum extract or a coffee bean extract for the manufacture of an agent for preventing or ameliorating neuropathic pain.

[0052] <34> Use of a combination of glucono-delta-lactone and monocaffeoylquinic acid or a salt thereof for producing a food for preventing or improving neurological disorders. <35> Use of a combination of glucono-delta-lactone and monocaffeoylquinic acid or a salt thereof for producing a food for promoting nerve regeneration. <36> Use of a combination of glucono-delta-lactone and monocaffeoylquinic acid or a salt thereof for producing a food for promoting recovery of motor function after nerve injury. <37> Use of a combination of glucono-delta-lactone and monocaffeoylquinic acid or a salt thereof for producing a food for inhibiting muscle atrophy after nerve injury. <38> Use of a combination of glucono-delta-lactone and monocaffeoylquinic acid or a salt thereof for producing a food for preventing or ameliorating neuropathic pain. <39> Use of a combination of glucono-delta-lactone and a plum extract or a coffee bean extract for producing a food for preventing or improving neurological disorders. <40> Use of a combination of glucono-delta-lactone and plum extract or coffee bean extract for producing a food for promoting nerve regeneration. <41> Use of a combination of glucono-delta-lactone and a plum extract or a coffee bean extract for producing a food for promoting recovery of motor function after nerve injury. <42> Use of a combination of glucono-delta-lactone and plum extract or coffee bean extract for producing a food for inhibiting muscle atrophy after nerve injury. <43> Use of a combination of glucono-delta-lactone and plum extract or coffee bean extract for producing a food for preventing or ameliorating neuropathic pain. <44> Neuropathy is a decline in nerve function due to physical damage to the central or peripheral nerves. <24> or <29> Use as described in <34> or <39> Use as described in. <45> Monocaffeoylquinic acid contains neochlorogenic acid, <24> ~ <28> Use according to any one of the preceding claims or <34> ~ <38> The use according to any one of the preceding claims.

[0053] <46> A combination of glucono-delta-lactone and monocaffeoylquinic acid or a salt thereof for preventing or ameliorating neurological disorders. <47> A combination of glucono-delta-lactone and monocaffeoylquinic acid or a salt thereof for promoting nerve regeneration. <48> A combination of glucono-delta-lactone and monocaffeoylquinic acid or a salt thereof for promoting motor function recovery after nerve injury. <49> A combination of glucono-delta-lactone and monocaffeoylquinic acid or a salt thereof for inhibiting muscle atrophy after nerve injury. <50> A combination of glucono-delta-lactone and monocaffeoylquinic acid or a salt thereof for preventing or ameliorating neuropathic pain. <51> A combination of glucono-delta-lactone and plum extract or coffee bean extract for preventing or ameliorating neurological disorders. <52> A combination of glucono-delta-lactone and plum extract or coffee bean extract for promoting nerve regeneration. <53> A combination of glucono-delta-lactone and plum extract or coffee bean extract for promoting motor function recovery after nerve injury. <54> A combination of glucono-delta-lactone and plum extract or coffee bean extract for inhibiting muscle atrophy after nerve injury. <55> A combination of glucono-delta-lactone and plum extract or coffee bean extract for preventing or ameliorating neuropathic pain. <56> Neuropathy is a decline in nerve function due to physical damage to the central or peripheral nerves. <46> or <51> The combination described in <57> Monocaffeoylquinic acid contains neochlorogenic acid, <46> ~ <50> The combination according to any one of the preceding claims.

[0054] <58> 1. Non-therapeutic use of a combination of glucono-delta-lactone and monocaffeoylquinic acid or a salt thereof for preventing or ameliorating neurological disorders. <59> 1. Non-therapeutic use of a combination of glucono-delta-lactone and monocaffeoylquinic acid or a salt thereof to promote nerve regeneration. <60> 1. Non-therapeutic use of a combination of glucono-delta-lactone and monocaffeoylquinic acid or a salt thereof to promote recovery of motor function after nerve injury. <61> 1. Non-therapeutic use of a combination of glucono-delta-lactone and monocaffeoylquinic acid or a salt thereof to inhibit muscle atrophy following nerve injury. <62> 1. Non-therapeutic use of a combination of glucono-delta-lactone and monocaffeoylquinic acid or a salt thereof for preventing or ameliorating neuropathic pain. <63> 1. Non-therapeutic use of a combination of glucono-delta-lactone and a plum extract or a coffee bean extract to prevent or ameliorate neurological disorders. <64> 1. Non-therapeutic use of a combination of glucono-delta-lactone and plum extract or coffee bean extract to promote nerve regeneration. <65> 1. Non-therapeutic use of a combination of glucono-delta-lactone and a plum extract or a coffee bean extract to promote recovery of motor function after nerve injury. <66> 1. Non-therapeutic use of a combination of glucono-delta-lactone and a plum extract or a coffee bean extract to inhibit muscle atrophy following nerve injury. <67> 1. Non-therapeutic use of a combination of glucono-delta-lactone and a plum extract or a coffee bean extract for preventing or ameliorating neuropathic pain. <68> Neuropathy is a decline in nerve function due to physical damage to the central or peripheral nerves. <58> or <63> Use as described in. <69> Monocaffeoylquinic acid contains neochlorogenic acid, <58> ~ <62> The use according to any one of the preceding claims.

[0055] <70> A method for preventing or improving nerve disorders, which comprises ingesting or administering a combination of glucono-delta-lactone and monocaffeoylquinic acid or a salt thereof to a subject in need thereof. <71> A method for promoting nerve regeneration, comprising ingesting or administering a combination of glucono-delta-lactone and monocaffeoylquinic acid or a salt thereof to a subject in need thereof. <72> A method for promoting recovery of motor function after nerve damage, comprising ingesting or administering a combination of glucono-delta-lactone and monocaffeoylquinic acid or a salt thereof to a subject in need thereof. <73> A method for inhibiting muscle atrophy after nerve injury, comprising ingesting or administering a combination of glucono-delta-lactone and monocaffeoylquinic acid or a salt thereof to a subject in need thereof. <74> A method for preventing or ameliorating neuropathic pain, which comprises ingesting or administering a combination of glucono-delta-lactone and monocaffeoylquinic acid or a salt thereof to a subject in need thereof. <75> A method for preventing or improving nerve damage, comprising ingesting or administering to a subject in need thereof a combination of glucono-delta-lactone and a plum extract or a coffee bean extract. <76> A method for promoting nerve regeneration, comprising ingesting or administering a combination of glucono-delta-lactone and a plum extract or a coffee bean extract to a subject in need thereof. <77> A method for promoting recovery of motor function after nerve damage, comprising ingesting or administering to a subject in need thereof a combination of glucono-delta-lactone and a plum extract or a coffee bean extract. <78> A method for inhibiting muscle atrophy after nerve injury, comprising ingesting or administering to a subject in need thereof a combination of glucono-delta-lactone and a plum extract or a coffee bean extract. <79> A method for preventing or ameliorating neuropathic pain, comprising ingesting or administering to a subject in need thereof a combination of glucono-delta-lactone and a plum extract or a coffee bean extract. <80> Neuropathy is a decline in nerve function due to physical damage to the central or peripheral nerves. <70> or <75> The combination described in <81> Monocaffeoylquinic acid contains neochlorogenic acid, <70> ~ <74> The combination according to any one of the preceding claims.

[0056] <82> <1> ~ <45> In the agent, food or composition, the content of glucono-delta-lactone is preferably 0.01% by mass or more, more preferably 0.05% by mass or more, and preferably 10% by mass or less, more preferably 1% by mass or less, and also preferably 0.01 to 10% by mass, more preferably 0.1 to 1% by mass, in the case of a liquid composition; and preferably 1% by mass or more, more preferably 5% by mass or more, and preferably 50% by mass or less, more preferably 30% by mass or less, and also preferably 1 to 50% by mass, more preferably 5 to 30% by mass, in the case of a solid composition. <83> <1> ~ <5> , <11> ~ <15> , <24> ~ <28> , <34> ~ <38> In the agent or food, the content of monocaffeoylquinic acid or a salt thereof, calculated as the free form of monocaffeoylquinic acid, is preferably 0.1% by mass or more, more preferably 2% by mass or more, and preferably 50% by mass or less, more preferably 30% by mass or less, and is also preferably 0.1 to 50% by mass, more preferably 2 to 30% by mass. <84> <6> ~ <10> , <16> ~ <20> , <29> ~ <33> , <39> ~ <43> The content of plum or coffee beans, or an extract thereof, in the agent or food varies depending on the form of use, but is preferably 1% by mass or more, more preferably 10% by mass or more, and preferably 99% by mass or less, more preferably 90% by mass or less, and also preferably 1 to 99% by mass, more preferably 10 to 90% by mass, calculated as a dried substance (for example, a dried substance dried in the sun for 1 to 1.5 weeks).

[0057] <85> <1> ~ <81> In the case of oral administration or ingestion, the amount of glucono-delta-lactone administered or ingested is preferably 5 mg or more, more preferably 50 mg or more, and preferably 2000 mg or less, more preferably 200 mg or less, and also preferably 5 to 2000 mg, more preferably 50 to 200 mg, per adult (body weight 60 kg) per day. <86> <1> ~ <5> , <11> ~ <15> , <24> ~ <28> , <34> ~ <38> , <46> ~ <50> , <58> ~ <62> , <70> ~ <74> In the case of oral administration or ingestion, the amount of monocaffeoylquinic acid or a salt thereof administered or ingested is preferably 1 mg or more, more preferably 5 mg or more, and preferably 200 mg or less, more preferably 120 mg or less, and also preferably 1 to 200 mg, more preferably 5 to 120 mg, per day per adult (body weight 60 kg) in terms of free monocaffeoylquinic acid. <87> <6> ~ <10> , <16> ~ <20> , <29> ~ <33> , <39> ~ <43> , <51> ~ <55> , <63> ~ <67> , <75> ~ <79> In the above, the amount of coffee beans or an extract thereof administered or ingested orally is, in dry matter terms, preferably 10 mg or more, more preferably 20 mg or more, and preferably 2 g or less, more preferably 700 mg or less, and also preferably 10 mg to 2 g, more preferably 20 mg to 700 mg, per adult (body weight 60 kg) per day. <88> <6> ~ <10> , <16> ~ <20> , <29> ~ <33> , <39> ~ <43> , <51> ~ <55> , <63> ~ <67> , <75> ~ <79> In the above, the amount of plum or its extract administered or ingested orally is, in dry matter terms, preferably 1 g or more, more preferably 3 g or more, and preferably 50 g or less, more preferably 10 g or less, and preferably 1 to 50 g, more preferably 3 to 10 g, per adult (body weight 60 kg) per day. [Example]

[0058] 1. Test Substance (1) Plum extract 50.19 g of dried prune fruit (product name: Sun Sweet Dry, produced in the USA, Pokka Sapporo) was taken and 500 mL of 50 v / v% aqueous ethanol solution was added. After extracting at room temperature for 4 days under static conditions, the extract was obtained by cotton plug filtration. This was concentrated under reduced pressure to obtain 26.87 g of plum extract. The prepared plum extract was a syrupy liquid containing 0.146 mass% neochlorogenic acid. (2) Coffee bean extract Green coffee bean extract-WSP (Oryza Oil & Fat Chemical, lot number Z-331) was used. Green Coffee Bean Extract-WSP is a powder obtained by extracting the seeds of the coffee plant, Coffea robusta, with hydrous ethanol, and contains over 40.0% of chlorogenic acids (9 types). It also contains 5.3% neochlorogenic acid, 6.9% cryptochlorogenic acid, 26.8% chlorogenic acid, and a total of 39.1% monocaffeoylquinic acid. (3) Monocaffeoylquinic acid Neochlorogenic acid (N1155, Tokyo Chemical Industry Co., Ltd.) was used. (4) Glucono-delta-lactone (GDL) Glucono-delta-lactone (42009, Fuso Chemical Industries) was used.

[0059] Example 1: Improvement of nerve damage in a central nervous system regeneration model induced by spinal cord crush injury (1) Six-month-old zebrafish (Danio rerio) were grouped (n=16) based on equal maximum swimming speed. 1. Sham group, control diet: (Sham) 2. Crush group, control diet: (Crush) 3. Crush group, Neochlorogenic acid: (Crush, Neochlorogenic acid) 4. Crush group, neochlorogenic acid + GDL diet: (Crush, neochlorogenic acid + GDL) 5. Crush group, coffee bean extract diet: (Crush, coffee bean extract) 6. Crush group, coffee bean extract + GDL diet: (Crush, coffee bean extract + GDL)

[0060] The sham and spinal nerve crush (Crush) groups were fed regular food, Otohime (Nisshin Marubeni Feed), while the intervention group was fed neochlorogenic acid, coffee bean extract, and GDL. The wet weight of each ingredient in the mixed food is shown in Table 1.

[0061] [Table 1]

[0062] The animals were then freeze-dried in a freeze dryer and coated with lard at a ratio of 20% of the diet. Each animal was given 10 mg of the diet per day (5 mg twice a day, at 9:00 in the morning and 16:00 in the evening).

[0063] Spinal cord crush (SCC) was performed by making a 3mm incision with a razor at the base of the fish's dorsal fin and applying pressure with tweezers for 1 second. In the sham group, only the incision was performed. After surgery, the fish were kept in a methylene blue (Nichido, approximately 6000 times diluted) solution for 3 days to prevent infection from the wound. Food was administered one week before SCC, and the fish were kept until 16 days after treatment, with maximum swimming speed measured accordingly. Maximum swimming speed was measured using a flow-water exercise device (a Personal Tank PT-70S (Nishi-Nihon Fluid Engineering Research Co., Ltd.) modified for zebrafish testing). After acclimatizing the fish at a speed of 1 Hz for 10 minutes, the flow rate was accelerated by 1 Hz every minute. The maximum swimming speed was defined as the speed just before the fish could no longer swim (1 Hz = 4.5 cm / sec). "No longer able to swim" refers to the state in which the fish could no longer resist the water flow and was stuck to the net downstream of the tank. Statistics were performed using the Dunn test, with a significance level of P<0.05.

[0064] The results are shown in Figures 1 and 2. Compared to the Crush group, the group administered neochlorogenic acid and GDL in combination demonstrated an accelerated recovery of maximum swimming speed, whereas neochlorogenic acid alone did not demonstrate such an enhancement (Figure 1, n = 12-16 at the endpoint). Furthermore, compared to the Crush group, the group administered coffee bean extract and GDL in combination demonstrated an accelerated recovery of maximum swimming speed, whereas coffee bean extract alone did not demonstrate such an enhancement (Figure 1, n = 11-16 at endpoint).

[0065] Example 2: Improvement of nerve damage in a central nervous system regeneration model induced by spinal cord crush injury (2) Six-month-old zebrafish (Danio rerio) were grouped (n=8-16) to match their maximum swimming speed. 1. Sham group, control diet: (Sham) 2. Crush group, control diet: (Crush) 3. Crush group, plum extract + GDL diet: (Crush, plum + GDL)

[0066] The sham and spinal nerve crush (Crush) groups were fed regular food, Otohime (Nisshin Marubeni Feed), while the intervention group was fed food containing plum extract and glucono-delta-lactone (GDL). The wet weight of each ingredient in the mixed food is shown in Table 1.

[0067] [Table 2]

[0068] The animals were then freeze-dried in a freeze dryer and coated with lard at a ratio of 20% of the diet. Each animal was given 10 mg of the diet per day (5 mg twice a day, at 9:00 in the morning and 16:00 in the evening).

[0069] Spinal cord crush (SCC) was performed by making a 3mm incision with a razor at the base of the fish's dorsal fin and applying pressure with tweezers for 1 second. In the sham group, only the incision was performed. After surgery, the fish were kept in a methylene blue (Nichido, approximately 6000 times diluted) solution for 3 days to prevent infection from the wound. Food was administered one week before SCC, and the fish were kept until 16 days after treatment, with maximum swimming speed measured accordingly. Maximum swimming speed was measured using a flow-water exercise device (a Personal Tank PT-70S (Nishi-Nihon Fluid Engineering Research Co., Ltd.) modified for zebrafish testing). After acclimatizing the fish at a speed of 1 Hz for 10 minutes, the flow rate was accelerated by 1 Hz every minute, and the maximum swimming speed was defined as the speed just before the fish could no longer swim (1 Hz = 4.5 cm / sec). "No longer able to swim" refers to the state in which the fish could no longer resist the water flow and was stuck to the net downstream of the tank. Statistics were performed using t-tests, with a significance level of P<0.05. The results are shown in Figure 3. Compared to the Crush group, the group administered the plum extract and GDL showed a tendency toward an accelerated recovery of maximum swimming speed (Figure 3, n = 8-16 at the endpoint).

[0070] Example 3: Improvement of nerve damage in an animal model of sciatic nerve crush injury 1) Ten-week-old male C57BL / 6J mice were fed ad libitum a control diet or a control diet supplemented with GDL, neochlorogenic acid, or coffee bean extract for one week (groups A to E). Under isoflurane inhalation anesthesia, they underwent sciatic nerve crush surgery. Specifically, the right thigh of the mice was shaved and disinfected with alcohol and isodine. A 1-cm incision was made in the thigh to expose the sciatic nerve. The nerve was injured by firmly compressing it with forceps for 10 seconds, and the incision was sutured with 5-0 nylon. In the sham group, the nerve was exposed without nerve injury and then sutured. A heating pad was placed under the mouse during surgery to maintain body temperature. After nerve injury, the mice continued to be fed the respective diets and dissected 4 weeks after the procedure. The control diet and test diet were powdered feeds, and the compositions of the control diet and each diet are shown in Table 3.

[0071] A. Sham operation - control diet: Sham group B. Nerve crush injury - control diet: Cont group C. Nerve crush injury - neochlorogenic acid + GDL diet: neochlorogenic acid + GDL group D. Nerve crush - neochlorogenic acid (10x) + GDL diet: neochlorogenic acid (10x) + GDL group E. Nerve crush injury - Coffee bean extract + GDL diet: Coffee bean extract + GDL group The GDL used was #073-01572 manufactured by Fujifilm Wako Pure Chemical Industries.

[0072] [Table 3]

[0073] 2) Neurohistological examination Peroneal nerves were isolated from anesthetized mice and pre-fixed in 2.5% glutaraldehyde (4°C, 2 hours), followed by post-fixation in 1% osmic acid (4°C, 1.5 hours). After embedding in Epon resin, semi-thin (1.5 μm) sections were prepared and stained with 0.5% toluidine blue. Images were taken using an all-in-one fluorescence microscope (Keyence), and the g-ratio was calculated to assess the thickness of the myelin sheath. The g-ratio was calculated by dividing the diameter of the nerve axon by the diameter of the nerve fiber, including the thickness of the myelin sheath. More than 100 nerves were measured per animal.

[0074] 3) Results The results of g-ratio 4 weeks after sciatic nerve crush (n=5-8 per group, mean value±standard error) are shown in FIG. Histological examination of the nerves was performed to examine the effects of neochlorogenic acid and GDL combinations, and coffee bean extract and GDL combinations, on neuropathy caused by sciatic nerve crush. Compared with the sham group, the control group showed a significant increase in g-ratio, i.e., thinning of the myelin sheath. On the other hand, the neochlorogenic acid + GDL group, neochlorogenic acid (10x) + GDL group, and coffee bean extract + GDL group showed a significant decrease in g-ratio compared with the control group. This indicates that the combination of neochlorogenic acid and GDL, and the combination of coffee bean extract and GDL suppressed myelin thinning caused by neuropathy. Furthermore, to examine the effects of neochlorogenic acid and GDL combinations, and coffee bean extract and GDL combinations on muscle weight loss due to sciatic nerve crush injury, we measured the weight of the extensor digitorum longus muscle (Figure 5; n = 10 per group, mean ± standard error). A significant decrease in extensor digitorum longus muscle weight was observed in the control group compared to the sham group. Meanwhile, a significant decrease in g-ratio was observed in the neochlorogenic acid (10x) + GDL group and the coffee bean extract + GDL group compared to the control group. These results demonstrate that the combination of neochlorogenic acid and GDL, and the combination of coffee bean extract and GDL, suppresses muscle atrophy due to neuropathy.

Claims

1. An agent for preventing or improving nerve disorders comprising a combination of glucono-delta-lactone and monocaffeoylquinic acid or a salt thereof.

2. A nerve regeneration promoter comprising a combination of glucono-delta-lactone and monocaffeoylquinic acid or a salt thereof.

3. A promoter for recovery of motor function after nerve damage, comprising a combination of glucono-delta-lactone and monocaffeoylquinic acid or a salt thereof.

4. An agent for inhibiting muscle atrophy after nerve injury, comprising a combination of glucono-delta-lactone and monocaffeoylquinic acid or a salt thereof.

5. An agent for preventing or ameliorating neuropathic pain comprising a combination of glucono-delta-lactone and monocaffeoylquinic acid or a salt thereof.

6. An agent for preventing or improving nerve disorders comprising a combination of glucono-delta-lactone and plum or coffee beans or extracts thereof.

7. A nerve regeneration promoter comprising a combination of glucono-delta-lactone and plum or coffee beans or extracts thereof.

8. A promoter for recovery of motor function after nerve damage, comprising a combination of glucono-delta-lactone and plum or coffee beans or extracts thereof.

9. An agent for inhibiting muscle atrophy after nerve injury, comprising a combination of glucono-delta-lactone and plum or coffee beans, or extracts thereof.

10. An agent for preventing or ameliorating neuropathic pain comprising a combination of glucono-delta-lactone and plum or coffee beans or extracts thereof.

11. A food for preventing or improving nerve disorders, comprising a combination of glucono-delta-lactone and monocaffeoylquinic acid or a salt thereof.

12. A nerve regeneration promoting food comprising a combination of glucono-delta-lactone and monocaffeoylquinic acid or a salt thereof.

13. A food for promoting recovery of motor function after nerve damage, comprising a combination of glucono-delta-lactone and monocaffeoylquinic acid or a salt thereof.

14. A food for inhibiting muscle atrophy after nerve damage, comprising a combination of glucono-delta-lactone and monocaffeoylquinic acid or a salt thereof.

15. A food for preventing or ameliorating neuropathic pain, comprising a combination of glucono-delta-lactone and monocaffeoylquinic acid or a salt thereof.

16. The food for preventing or improving nerve disorders comprises a combination of glucono-delta-lactone and a plum extract or a coffee bean extract.

17. A nerve regeneration promoting food comprising a combination of glucono-delta-lactone and a plum extract or a coffee bean extract.

18. A food for promoting recovery of motor function after nerve damage, comprising a combination of glucono-delta-lactone and a plum extract or a coffee bean extract.

19. A food for inhibiting muscle atrophy after nerve damage, comprising a combination of glucono-delta-lactone and a plum extract or a coffee bean extract.

20. A food for preventing or improving neuropathic pain, comprising a combination of glucono-delta-lactone and a plum extract or a coffee bean extract.

21. The agent according to claim 1 or 6 or the food according to claim 11 or 16, wherein the nerve disorder is a decrease in nerve function due to physical damage to the central or peripheral nerves.

22. The agent according to any one of claims 1 to 5 or the food according to any one of claims 11 to 15, wherein the monocaffeoylquinic acid comprises neochlorogenic acid.

23. A pharmaceutical or food composition comprising glucono-delta-lactone and monocaffeoylquinic acid or a salt thereof.

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