Agents for preventing or improving neuropathy

Abstract

To provide an agent for preventing or ameliorating neuropathy caused by decreased nerve function due to nerve damage or diabetic neuropathy.SOLUTION: An agent for preventing or ameliorating neuropathy is obtained by combining one or more lactone compounds represented by formulae (1a) and (1b) and one or more substances from among hydroxybenzoic acid compounds represented by formula (2) and salts thereof. (In the formulas, R1 represents a hydrogen atom or a hydroxy group and R2 represents a hydrogen atom or a methyl group.)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 controlled by the damaged nerves are impaired. The number of stroke patients, a typical example of nerve damage, is extremely high in Japan, at approximately 1.2 million, resulting in a huge social loss.

[0003] When nerve damage occurs due to stroke or traffic accident, rehabilitation is recommended to recover nerve function. However, the recovery effect of the function by current rehabilitation is insufficient, and it has been reported that there are many cases where the disability remains even after rehabilitation or the patient cannot return to society. Thus, there is a limit to the effect of recovering nerve function by conventional rehabilitation, and there is a demand for a useful means that has the effect of promoting the rehabilitation effect.

[0004] Neuropathy is also a common complication of diabetes (diabetic neuropathy), and in this case, symptoms include repeated constipation and diarrhea, erectile dysfunction, dizziness, abnormal sweating, and other autonomic neuropathy, as well as sensory neuropathy, which presents numbness and abnormal sensations. These symptoms are thought to be the result of abnormalities in various parts of the body caused by the loss of peripheral nerve fibers and reduced nerve function. In many cases, symptoms begin with subjective symptoms such as numbness and pain in the feet, and gradually spread to the central nerves. If appropriate treatment is not given, the loss of sensory nerve fibers will cause the patient to be unable to feel pain or heat. As a result, foot ulcers will form, and if left untreated, this can lead to gangrene, and in the worst case, the patient will need to have their lower limbs amputated, significantly reducing the patient's quality of life (QOL).

[0005] The cause of diabetic neuropathy is said to be metabolic abnormalities in peripheral nerve tissue caused by persistent hyperglycemia, and reduced blood flow due to thickening and stenosis of small blood vessels. Risk factors involved in the onset and progression of diabetic neuropathy include poor glycemic control, duration of diabetes, hypertension, dyslipidemia, smoking, and alcohol consumption. Of these, the most important factor is poor glycemic control, and it is said that neuropathy occurs frequently in cases of poor glycemic control. However, even if poor glycemic control is a risk factor for onset and progression, it has not been necessarily established whether strict glycemic control can suppress onset and progression.

[0006] To date, there is no established cure for diabetic neuropathy, and the main treatments are symptomatic treatment to alleviate pain symptoms and treatment to slow the progression of neuropathy, such as with aldose reductase inhibitors (e.g., Epalrestat).

[0007] It has also been reported that decreased nerve function contributes to the decline in muscle function associated with aging (Non-Patent Document 1). In Japan, which is an ultra-aged society, it is important to develop technologies to improve decreased nerve function and to prevent the decline in nerve function.

[0008] When nerves are damaged, they are often perceived as pain (neuropathic pain). Pain can cause inconvenience and discomfort in daily life, a decline in motivation to work, and a decline in quality of life. Neuropathic pain occurs when damaged nerves remain excited and release excessive amounts of pain-transmitting substances from the damaged nerves. Therefore, even if the cause of the pain or the source of the disease is removed and the disease is cured, the pain may continue for a long time, be severe with slight stimulation, be painful with changes in weather or climate, or be painful even without moving. Neuropathic pain often manifests as symptoms such as electric shock-like pain or severe numbness.

[0009] Neuropathic pain is thought to be caused by calcium entering nerve cells through calcium channels, which causes the nerve cells to become excited and release excessive neurotransmitters, so calcium channel blockers are often used to treat and prevent it. Antidepressants and antiepileptic drugs may also be used. Furthermore, if these drugs do not relieve the pain and it interferes with daily activities, narcotic analgesics such as opioids are also used.

[0010] On the other hand, it is known that hydroxybenzoic acid compounds such as vanillic acid and protocatechuic acid have a neuroprotective effect and an improving effect against neuropathic pain when administered to animals such as mice and rats at a high dose (for example, 100 mg / kg body weight / day). For example, it has been reported that vanillic acid has a neuroprotective effect (Non-Patent Document 2), and protocatechuic acid also has a neuroprotective effect (Non-Patent Document 3) and an improving effect against neuropathic pain (Non-Patent Document 4).

[0011] However, it is not known at all that a hydroxybenzoic acid compound, when used in combination with a specific lactone compound, exhibits an excellent improving effect on nerve disorders. [Prior art documents] [Non-patent literature]

[0012] [Non-Patent Document 1] Nutrition 28: 495-503, 2012 [Non-Patent Document 2] Pharm Biol. May;53(5):630-6, 2015 [Non-Patent Document 3] Neuroscience. May 21;491:23-31, 2022 [Non-Patent Document 4] Bosn J Basic Med Sci. Apr 1;22(2):217-228, 2022 Summary of the Invention [Problem to be solved by the invention]

[0013] 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]

[0014] The present inventors have searched for materials that improve nerve function and have found that a combination of a specific lactone compound and a hydroxybenzoic acid compound is effective in improving decreased nerve function due to nerve damage or diabetic neuropathy.

[0015] That is, the present invention relates to the following 1) to 12). 1) An agent for preventing or improving nerve disorders comprising a combination of one or more lactone compounds represented by the following formulas (1a) and (1b) and one or more hydroxybenzoic acid compounds represented by the following formula (2) or salts thereof. 2) An agent for preventing or improving diabetic neuropathy comprising a combination of one or more lactone compounds represented by the following formulas (1a) and (1b) and one or more hydroxybenzoic acid compounds represented by the following formula (2) or salts thereof. 3) A nerve regeneration promoter comprising a combination of one or more lactone compounds represented by the following formulas (1a) and (1b) and one or more hydroxybenzoic acid compounds represented by the following formula (2) or salts thereof. 4) An agent for promoting recovery of motor function after nerve damage, comprising a combination of one or more lactone compounds represented by the following formulas (1a) and (1b) and one or more hydroxybenzoic acid compounds represented by the following formula (2) or salts thereof. 5) An agent for inhibiting muscle atrophy after nerve injury, comprising a combination of one or more lactone compounds represented by the following formulas (1a) and (1b) and one or more hydroxybenzoic acid compounds represented by the following formula (2) or salts thereof. 6) An agent for preventing or ameliorating neuropathic pain, comprising a combination of one or more lactone compounds represented by the following formulas (1a) and (1b) and one or more hydroxybenzoic acid compounds represented by the following formula (2) or salts thereof: 7) A food for preventing or improving nerve disorders, comprising a combination of one or more lactone compounds represented by the following formulas (1a) and (1b) and one or more hydroxybenzoic acid compounds represented by the following formula (2) or salts thereof. 8) A food for preventing or improving diabetic neuropathy comprising a combination of one or more lactone compounds represented by the following formulas (1a) and (1b) and one or more hydroxybenzoic acid compounds represented by the following formula (2) or salts thereof. 9) A food for promoting nerve regeneration comprising a combination of one or more lactone compounds represented by the following formulas (1a) and (1b) and one or more hydroxybenzoic acid compounds or salts thereof represented by the following formula (2): 10) A food for promoting recovery of motor function after nerve damage, comprising a combination of one or more lactone compounds represented by the following formulas (1a) and (1b) and one or more hydroxybenzoic acid compounds represented by the following formula (2) or salts thereof. 11) A food for inhibiting muscle atrophy after nerve damage, comprising a combination of one or more lactone compounds represented by the following formulas (1a) and (1b) and one or more hydroxybenzoic acid compounds or salts thereof represented by the following formula (2): 12) A food for preventing or improving neuropathic pain, comprising a combination of one or more lactone compounds represented by the following formulas (1a) and (1b) and one or more hydroxybenzoic acid compounds represented by the following formula (2) or salts thereof: 13) A composition for preventing or improving a nerve disorder, comprising one or more lactone compounds represented by the following formulas (1a) and (1b), and one or more hydroxybenzoic acid compounds represented by the following formula (2) or salts thereof: 14) A composition for preventing or ameliorating diabetic neuropathy, comprising one or more lactone compounds represented by the following formulas (1a) and (1b), and one or more hydroxybenzoic acid compounds represented by the following formula (2) or salts thereof: 15) A composition for promoting nerve regeneration comprising one or more lactone compounds represented by the following formulas (1a) and (1b), and one or more hydroxybenzoic acid compounds represented by the following formula (2) or salts thereof. 16) A composition for promoting recovery of motor function after nerve injury, comprising one or more lactone compounds represented by the following formulas (1a) and (1b), and one or more hydroxybenzoic acid compounds represented by the following formula (2) or salts thereof: 17) A composition for inhibiting muscle atrophy after nerve injury, comprising one or more lactone compounds represented by the following formulas (1a) and (1b), and one or more hydroxybenzoic acid compounds represented by the following formula (2) or salts thereof: 18) A composition for preventing or ameliorating neuropathic pain, comprising one or more lactone compounds represented by the following formulas (1a) and (1b), and one or more hydroxybenzoic acid compounds represented by the following formula (2) or salts thereof:

[0016] [ka] (In the formula, R 1 represents a hydrogen atom or a hydroxyl group, R 2 represents a hydrogen atom or a methyl group. Effect of the Invention

[0017] According to the present invention, it is possible to provide a medicine, a quasi-drug, a food or a supplement for preventing or improving nerve damage. According to the present invention, it is possible to promote recovery of nerve function and relieve pain associated with nerve damage by a food or supplement, and therefore it is possible to provide a new means for improving QOL for elderly people, patients receiving care at home due to nerve damage, and patients with disabilities due to diabetes. [Brief description of the drawings]

[0018] [Figure 1] Effect on motor function after spinal cord crush injury (1). * p<0.05 vs. Crush by Dunn test. [Diagram 2] Effect on motor function after spinal cord crush injury (2). * p<0.05 vs. Crush by Dunn test [Diagram 3]Effect on nerve regeneration after sciatic nerve crush injury (1). * p< 0.05, ** p< 0.01, *** p< 0.001 vs. Crush by Dunnett test [Figure 4] Effect on blood glucose level. ** p < 0.01 vs. B by Dunnett test [Diagram 5] Effect on diabetic neuropathy. ** p < 0.01 vs. B by Dunnett test [Figure 6] Effect on nerve regeneration after sciatic nerve crush injury (2). * p< 0.05, *** p< 0.001 vs. Crush by Dunn test [Figure 7] Effect of SNI treatment on neuropathic pain. * p< 0.05, ** p< 0.01 vs. control group by Mann-Whitney U test DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0019] In the present invention, the following formulae (1a) and (1b);

[0020] [ka] (In the formula, R 1 represents a hydrogen atom or a hydroxyl group.

[0021] Among the lactone compounds represented by formula (1a), the lactone compound represented by formula (1a) is D-ribonolactone (R 1 : hydroxy group) or 2-deoxy-D-ribono-1,4-lactone (R 1 : a hydrogen atom), and the lactone compound represented by formula (1b) is glucono-delta-lactone.

[0022] The lactone compound used in combination with the hydroxybenzoic acid compound represented by formula (2) or a salt thereof may be one or more of the compounds represented by formulas (1a) and (1b), and two or more of them may be used. Preferably, the lactone compound is any one of D-ribonolactone, 2-deoxy-D-ribono-1,4-lactone, and glucono delta-lactone.

[0023] In addition, the following formula (2):

[0024] [ka] (In the formula, R 2 represents a hydrogen atom or a methyl group.

[0025] The hydroxybenzoic acid compound represented by the formula: vanillic acid (R 2 : methyl group) or protocatechuic acid (R 2 : hydrogen atom).

[0026] Examples of the salt of the compound represented by the formula (2) include alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium and magnesium, and ammonium salts such as ammonium chloride, tetraethylammonium, and tetramethylammonium.

[0027] One or more of the hydroxybenzoic acid compounds represented by the formula (2) or salts thereof may be used. Either vanillic acid or a salt thereof, or protocatechuic acid or a salt thereof may be used, or both may be used in combination. Suitable combinations of the above-mentioned lactone compound and hydroxybenzoic acid compound or a salt thereof include, for example, a) a combination of 2-deoxy-D-ribono-1,4-lactone and protocatechuic acid and / or vanillic acid, b) a combination of D-ribonolactone and protocatechuic acid and / or vanillic acid, and c) a combination of glucono delta-lactone and protocatechuic acid and / or vanillic acid.

[0028] The lactone compound represented by the formula (1a) or (1b) and the hydroxybenzoic acid compound represented by the formula (2) or a salt thereof can be obtained by isolating them from natural products such as plants or by chemically synthesizing them according to known methods. Alternatively, it is also possible to use commercially available products as shown in the examples described later.

[0029] In the present invention, one or more lactone compounds represented by the formulae (1a) and (1b) and one or more hydroxybenzoic acid compounds represented by the formula (2) or salts thereof are used in combination (concomitant use), but the form is not limited thereto. That is, they may be a composition in which effective amounts of each compound are formulated in a single dosage form at an appropriate blending ratio as a combination drug, or a kit in which drugs containing effective amounts of each compound are formulated separately so that they can be used simultaneously or separately at intervals, but simultaneous use is preferred.

[0030] When one or more of the lactone compounds represented by the formulae (1a) and (1b) are combined with one or more of the hydroxybenzoic acid compounds or salts thereof represented by the formula (2) to prepare a formulation, the blending ratio can be appropriately selected depending on the raw material, application, or type of preparation, but is generally 1:0.0001-10, preferably 1:0.001-5, and more preferably 1:0.01-2, in terms of mass ratio of the lactone compound to the hydroxybenzoic acid compound (in terms of free form).

[0031] As shown in the examples below, the combined use of the lactone compound and the hydroxybenzoic acid compound exhibits a nerve regeneration promoting effect (inhibitory effect on the reduction of myelin area) in a nerve regeneration model (mouse) by sciatic nerve crush treatment at a dosage that does not show an effect when the lactone compound and the hydroxybenzoic acid compound are used alone. In addition, the combined use of the lactone compound and the hydroxybenzoic acid compound or a salt thereof improves motor disorders and promotes nerve regeneration in a central nerve regeneration model (zebrafish) by spinal cord crush treatment at a dosage that does not show an effect when the lactone compound and the hydroxybenzoic acid compound are used alone. Furthermore, the combined use of the lactone compound and the hydroxybenzoic acid compound improves the decrease in nerve conduction velocity in a diabetic neuropathy model without showing a blood sugar lowering effect.

[0032] Mice treated with sciatic nerve crush are known as a nerve regeneration model (Gaudet et al., Journal of Neuroinflammation 2011, 8:110, Nico L.et al., Arch Phys Med Rehabil, 78, 70-7(1997), Takemura et al., PLOS ONE 2012, 7: e44592), and the suppression of the decrease in myelin area in this model means that the regeneration of peripheral nerves is promoted. In addition, zebrafish treated with spinal nerve crush are known as a central nerve regeneration model (Mayssa H. et el., Science, 354, 630-634(2016)), and the promotion of recovery of motor function in this model means that the regeneration of central nerves is promoted.

[0033] Therefore, a combination of one or more lactone compounds represented by the formulas (1a) and (1b) and one or more hydroxybenzoic acid compounds represented by the formula (2) or their salts can be a preventive or ameliorating agent for neuropathy, a preventive or ameliorating agent for diabetic neuropathy, a nerve regeneration promoter, a motor function recovery promoter after nerve damage, a muscle atrophy inhibitor after nerve damage, or a preventive or ameliorating agent for pain associated with neuropathy (neuropathic pain) (referred to as a "preventive or ameliorating agent for neuropathy, etc."), and can be used to manufacture the preventive or ameliorating agent for neuropathy, etc. That is, a combination of one or more lactone compounds represented by the formulas (1a) and (1b) of the present invention and one or more hydroxybenzoic acid compounds represented by the formula (2) or their salts can be used for preventing or ameliorating neuropathy, preventing or ameliorating diabetic neuropathy, promoting nerve regeneration, promoting motor function recovery after nerve damage, promoting muscle atrophy inhibition after nerve damage, or preventing or ameliorating neuropathic pain. Here, the use may be therapeutic or non-therapeutic. "Non-therapeutic" refers to a concept that does not include medical procedures, i.e., a concept that does not include a method of surgery, therapy, or diagnosis of a human being, and more specifically, a concept that does not include a method of surgery, therapy, or diagnosis performed on a human being by a physician or a person under the instruction of a physician.

[0034] In the present invention, "neuropathy" refers to a pathological condition in which nerve functions are impaired due to damage to nerves, aging, or the like, resulting in impairment of Schwann cells and oligodendrocytes that form nerve cells and myelin sheaths. Specific symptoms include pain, loss of sensation (including anesthesia), a tingling or burning sensation in the limbs or extremities, paresthesia, muscle weakness, muscle mass loss, impaired motor function, impaired 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.

[0035] "Diabetic neuropathy" refers to neuropathy that appears after the onset of diabetes. "Diabetic neuropathy" is divided into distal symmetric polyneuropathy and focal mononeuropathy, and the diabetic neuropathy of the present invention includes both of them. Distal symmetric polyneuropathy is divided into sensory-motor neuropathy and autonomic neuropathy. In sensory-motor neuropathy, a decrease in nerve conduction velocity is observed in nerve conduction tests from the early stage of onset, and sensory abnormalities such as spontaneous pain, numbness, paresthesias, and hypoesthesia appear in the distal lower limbs, as well as motor abnormalities such as muscle weakness, muscle atrophy, and decreased balance function. As the symptoms ascend, symptoms also appear in the distal upper limbs. Eye and facial movements are also impaired. Autonomic neuropathy presents a variety of symptoms, including pupillary dysfunction, orthostatic hypotension, cardiac nerve disorders (sudden death, painless myocardial infarction), sweating disorders, gastrointestinal motility disorders (constipation, diarrhea), bladder dysfunction, erectile dysfunction, etc. Localized mononeuropathy includes cranial nerve disorders (especially external ophthalmoplegia), trunk and limb nerve disorders, and diabetic muscular atrophy (lumbosacral root plexus neuropathy).

[0036] "Improvement" of neuropathy (including diabetic 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.

[0037] "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 development, such as cell proliferation, differentiation, and maturation (tissue regeneration), and preferably, as a result, the phenomenon in which the original nerve function is completely or partially restored (functional regeneration).

[0038] "Promoting recovery of motor function after nerve damage" means recovering from motor dysfunction (eg, motor paralysis, muscle weakness) that occurs in the region innervated by the damaged nerve due to 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 causes such as trauma, compression by a cast, electric shock injury, herniated disc, and stroke is applicable.

[0039] "Suppression of muscle atrophy after nerve injury" means suppression of the decrease in muscle mass that occurs in the area innervated by the damaged nerve due to nerve injury.

[0040] "Neuropathic pain" refers to pain caused by a lesion or disease of the somatosensory nervous system. Symptoms include a burning or tingling sensation, 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). Symptoms are often accompanied by pain even when at rest (spontaneous pain).

[0041] For example, neuropathic pain can be diagnosed by answering the following seven questions on a five-point scale (0 points; a little (1 point); some (2 points); very much (3 points); and very much (4 points)), and then determining the total score (a score of 6 or more indicates neuropathic pain) (Rinseigaku Gait 47:565-574, 2012). 1) Pain as if being pricked by a needle 2) Electrical pain 3) Burning or stinging pain 4) I have severe pain and numbness 5) The pain is caused by the friction of clothing or exposure to cold air. 6) Decreased or hypersensitive sensation in the area of ​​pain 7) The skin at the site of pain becomes swollen or turns red or purple

[0042] 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 canal stenosis, multiple sclerosis, Guillain-Barré syndrome, sequelae of stroke, pain after herniorrhaphy, and postherpetic neuralgia.

[0043] "Amelioration" of neuropathic pain includes "prevention or treatment." "Prevention" of neuropathic pain means preventing or delaying the onset of neuropathic pain, and "treatment" means reducing neuropathic pain or preventing or delaying the progression (worsening) of neuropathic pain.

[0044] The agent for preventing or improving neuropathy of the present invention can itself be various compositions, such as a medicine, quasi-drug or food, that exhibits the effect of preventing or improving neuropathy, the effect of preventing or improving diabetic neuropathy, 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 a material or preparation for incorporation into these. In addition, the above-mentioned foods (also referred to as "foods for preventing or ameliorating neuropathy caused by nerve damage or aging," "foods for preventing or ameliorating diabetic neuropathy," "foods for promoting nerve regeneration," "foods for promoting motor function recovery after nerve damage," "foods for inhibiting muscle atrophy after nerve damage," and "foods for preventing or ameliorating 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 as necessary.

[0045] The above-mentioned 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 administering, 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, and injection, and administered in the form of a conventional pharmaceutical preparation.

[0046] Examples of such preparations include solid preparations such as tablets, granules, powders, and capsules, liquid preparations such as solutions, suspensions, and emulsions, and freeze-dried preparations. These preparations can be prepared by conventional means for preparations by appropriately adding conventional additives such as stabilizers, wetting agents, emulsifiers, binders, isotonicity agents, and excipients.

[0047] The food containing the active ingredient of the present invention may be in the form of soft drinks, tea drinks, coffee drinks, fruit juice drinks, carbonated drinks, jellies, wafers, biscuits, bread, noodles, sausages, and other foods and beverages, nutritional foods, and other 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). Among these, tablets are preferred. Foods of various forms 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.

[0048] The content of the lactone compound represented by formula (1a) or (1b) in the above composition (e.g., pharmaceuticals, quasi-drugs, foods) varies depending on the form of use, but is preferably 0.0000001 mass% or more, more preferably 0.000001 mass% or more, and preferably 0.01 mass% or less, more preferably 0.005 mass% or less, and is preferably 0.0000001 to 0.01 mass%, more preferably 0.000001 to 0.005 mass%.

[0049] The content of the hydroxybenzoic acid compound represented by the formula (2) or a salt thereof in the above composition (e.g., a pharmaceutical product, a quasi-drug product, a food product) varies depending on the form of use, but is preferably 0.00000002 mass% or more, more preferably 0.0000002 mass% or more, and preferably 0.001 mass% or less, more preferably 0.0005 mass% or less, and also preferably 0.00000002 to 0.001 mass%, more preferably 0.0000002 to 0.0005 mass%, calculated as the free hydroxybenzoic acid compound.

[0050] The dosage or intake of the above-mentioned medicines (including quasi-drugs) and foods 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 the lactone compound represented by formula (1a) or (1b) per adult (body weight 60 kg) per day is preferably 0.6 mg or more, more preferably 1 mg or more, and preferably 50 mg or less, more preferably 20 mg or less, and is preferably 0.6 to 50 mg, more preferably 2 to 20 mg. The amount of the hydroxybenzoic acid compound represented by formula (2) or a salt thereof, calculated as the free form of the hydroxybenzoic acid compound, per day is preferably 0.0002 mg or more, more preferably 0.002 mg or more, and preferably 5 mg or less, more preferably 4 mg or less, and is preferably 0.0002 to 5 mg, more preferably 0.002 to 4 mg.

[0051] Subjects to whom the present invention is to be ingested or administered for the prevention or amelioration of neuropathy include, for example, humans with reduced nerve function and various symptoms of neuropathy (sensory loss, paresthesia, muscle weakness, reduced neuromuscular reflexes, convulsions, neuromuscular paralysis, etc.), diabetic patients with sensory / motor neuropathy, autonomic neuropathy, or localized mononeuropathy, diabetic patients or humans with high blood sugar levels who wish to prevent, suppress, or delay the onset of such neuropathy, people who wish to maintain or improve nerve function, and humans 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, waist, etc., allodynia, hypersensitivity, etc.).

[0052] In relation to the above-described embodiment, the present invention further discloses the following aspects.

[0053] <1> An agent for preventing or improving nerve disorders comprising a combination of one or more lactone compounds represented by the following formulas (1a) and (1b) and one or more hydroxybenzoic acid compounds represented by the following formula (2) or salts thereof. <2> An agent for preventing or improving diabetic neuropathy comprising a combination of one or more lactone compounds represented by the following formulas (1a) and (1b) and one or more hydroxybenzoic acid compounds represented by the following formula (2) or salts thereof. <3> A nerve regeneration promoter comprising a combination of one or more lactone compounds represented by the following formulae (1a) and (1b) and one or more hydroxybenzoic acid compounds represented by the following formula (2) or salts thereof. <4> An agent for promoting recovery of motor function after nerve damage, comprising a combination of one or more lactone compounds represented by the following formulas (1a) and (1b) and one or more hydroxybenzoic acid compounds represented by the following formula (2) or salts thereof. <5> An agent for inhibiting muscle atrophy after nerve injury, comprising a combination of one or more lactone compounds represented by the following formulas (1a) and (1b) and one or more hydroxybenzoic acid compounds represented by the following formula (2) or salts thereof. <6> An agent for preventing or ameliorating neuropathic pain comprising a combination of one or more lactone compounds represented by the following formulas (1a) and (1b) and one or more hydroxybenzoic acid compounds represented by the following formula (2) or salts thereof. <7> A food for preventing or improving nerve disorders comprising a combination of one or more lactone compounds represented by the following formulas (1a) and (1b) and one or more hydroxybenzoic acid compounds or salts thereof represented by the following formula (2). <8> A food for preventing or improving diabetic neuropathy comprising a combination of one or more lactone compounds represented by the following formulas (1a) and (1b) and one or more hydroxybenzoic acid compounds or salts thereof represented by the following formula (2). <9> A food for promoting nerve regeneration comprising a combination of one or more lactone compounds represented by the following formulas (1a) and (1b) and one or more hydroxybenzoic acid compounds or salts thereof represented by the following formula (2). <10> A food for promoting recovery of motor function after nerve damage, comprising a combination of one or more lactone compounds represented by the following formulas (1a) and (1b) and one or more hydroxybenzoic acid compounds or salts thereof represented by the following formula (2). <11> A food for inhibiting muscle atrophy after nerve damage, comprising a combination of one or more lactone compounds represented by the following formulas (1a) and (1b) and one or more hydroxybenzoic acid compounds or salts thereof represented by the following formula (2). <12> A food for preventing or improving neuropathic pain, comprising a combination of one or more lactone compounds represented by the following formulas (1a) and (1b) and one or more hydroxybenzoic acid compounds or salts thereof represented by the following formula (2):

[0054] <13> Use of a combination of one or more lactone compounds represented by the following formulas (1a) and (1b) and one or more hydroxybenzoic acid compounds represented by the following formula (2) or salts thereof for the manufacture of an agent for preventing or improving nerve disorders. <14> Use of a combination of one or more lactone compounds represented by the following formulas (1a) and (1b) and one or more hydroxybenzoic acid compounds represented by the following formula (2) or salts thereof for the manufacture of an agent for preventing or improving diabetic neuropathy. <15> Use of a combination of one or more lactone compounds represented by the following formulas (1a) and (1b) and one or more hydroxybenzoic acid compounds or salts thereof represented by the following formula (2) for producing a nerve regeneration promoter. <16> Use of a combination of one or more lactone compounds represented by the following formulas (1a) and (1b) and one or more hydroxybenzoic acid compounds represented by the following formula (2) or salts thereof for producing an agent for promoting motor function recovery after nerve damage. <17> Use of a combination of one or more lactone compounds represented by the following formulas (1a) and (1b) and one or more hydroxybenzoic acid compounds represented by the following formula (2) or salts thereof for the manufacture of an agent for inhibiting muscle atrophy after nerve injury. <18> Use of a combination of one or more lactone compounds represented by the following formulae (1a) and (1b) and one or more hydroxybenzoic acid compounds represented by the following formula (2) or salts thereof for the manufacture of an agent for preventing or ameliorating neuropathic pain. <19> Use of a combination of one or more lactone compounds represented by the following formulas (1a) and (1b) and one or more hydroxybenzoic acid compounds represented by the following formula (2) or salts thereof for producing a food for preventing or improving nerve disorders. <20> Use of a combination of one or more lactone compounds represented by the following formulas (1a) and (1b) and one or more hydroxybenzoic acid compounds represented by the following formula (2) or salts thereof for producing a food for preventing or improving diabetic neuropathy. <21> Use of a combination of one or more lactone compounds represented by the following formulas (1a) and (1b) and one or more hydroxybenzoic acid compounds or salts thereof represented by the following formula (2) for producing a food for promoting nerve regeneration. <22> Use of a combination of one or more lactone compounds represented by the following formulas (1a) and (1b) and one or more hydroxybenzoic acid compounds represented by the following formula (2) or salts thereof for producing a food for promoting recovery of motor function after nerve damage. <23> Use of a combination of one or more lactone compounds represented by the following formulas (1a) and (1b) and one or more hydroxybenzoic acid compounds or salts thereof represented by the following formula (2) for producing a food for inhibiting muscle atrophy after nerve damage. <24> Use of a combination of one or more lactone compounds represented by the following formulas (1a) and (1b) and one or more hydroxybenzoic acid compounds represented by the following formula (2) or salts thereof for producing a food for preventing or improving neuropathic pain.

[0055] <25> A combination of one or more lactone compounds represented by the following formulas (1a) and (1b) and one or more hydroxybenzoic acid compounds represented by the following formula (2) or salts thereof for preventing or ameliorating nerve disorders. <26> A combination of one or more lactone compounds represented by the following formulas (1a) and (1b) and one or more hydroxybenzoic acid compounds represented by the following formula (2) or salts thereof for preventing or ameliorating diabetic neuropathy. <27> A combination of one or more lactone compounds represented by the following formulae (1a) and (1b) and one or more hydroxybenzoic acid compounds represented by the following formula (2) or salts thereof for promoting nerve regeneration. <28> A combination of one or more lactone compounds represented by the following formulae (1a) and (1b) and one or more hydroxybenzoic acid compounds represented by the following formula (2) or salts thereof for promoting recovery of motor function after nerve damage. <29> A combination of one or more lactone compounds represented by the following formulas (1a) and (1b) and one or more hydroxybenzoic acid compounds represented by the following formula (2) or salts thereof for suppressing muscle atrophy after nerve injury. <30> A combination of one or more lactone compounds represented by the following formulae (1a) and (1b) and one or more hydroxybenzoic acid compounds represented by the following formula (2) or salts thereof for preventing or ameliorating neuropathic pain.

[0056] <31> Non-therapeutic use of a combination of one or more lactone compounds represented by the following formulas (1a) and (1b) and one or more hydroxybenzoic acid compounds represented by the following formula (2) or salts thereof for preventing or ameliorating neurological disorders. <32> Non-therapeutic use of a combination of one or more lactone compounds represented by the following formulas (1a) and (1b) and one or more hydroxybenzoic acid compounds represented by the following formula (2) or salts thereof for preventing or ameliorating diabetic neuropathy. <33> Non-therapeutic use of a combination of one or more lactone compounds represented by the following formulas (1a) and (1b) and one or more hydroxybenzoic acid compounds represented by the following formula (2) or salts thereof for promoting nerve regeneration. <34> Non-therapeutic use of a combination of one or more lactone compounds represented by the following formulas (1a) and (1b) and one or more hydroxybenzoic acid compounds represented by the following formula (2) or salts thereof, for promoting recovery of motor function after nerve damage. <35> Non-therapeutic use of a combination of one or more lactone compounds represented by the following formulas (1a) and (1b) and one or more hydroxybenzoic acid compounds represented by the following formula (2) or salts thereof for suppressing muscle atrophy after nerve injury. <36> Non-therapeutic use of a combination of one or more lactone compounds represented by the following formulas (1a) and (1b) and one or more hydroxybenzoic acid compounds represented by the following formula (2) or salts thereof for preventing or ameliorating neuropathic pain.

[0057] <37> A method for preventing or improving nerve disorders, comprising ingesting or administering to a subject in need thereof one or more lactone compounds represented by the following formulas (1a) and (1b) in combination with one or more hydroxybenzoic acid compounds or salts thereof represented by the following formula (2). <38> A method for preventing or ameliorating diabetic neuropathy, comprising ingesting or administering to a subject in need thereof one or more lactone compounds represented by the following formulas (1a) and (1b) in combination with one or more hydroxybenzoic acid compounds or salts thereof represented by the following formula (2). <39> A method for promoting nerve regeneration, comprising ingesting or administering to a subject in need thereof one or more of the lactone compounds represented by the following formulas (1a) and (1b) in combination with one or more of the hydroxybenzoic acid compounds or salts thereof represented by the following formula (2). <40> A method for promoting recovery of motor function after nerve damage, comprising ingesting or administering to a subject in need thereof one or more lactone compounds represented by the following formulas (1a) and (1b) in combination with one or more hydroxybenzoic acid compounds or salts thereof represented by the following formula (2). <41> A method for inhibiting muscle atrophy after nerve injury, comprising ingesting or administering to a subject in need thereof one or more lactone compounds represented by the following formulas (1a) and (1b) in combination with one or more hydroxybenzoic acid compounds or salts thereof represented by the following formula (2). <42> A method for preventing or ameliorating neuropathic pain, comprising ingesting or administering to a subject in need thereof one or more lactone compounds represented by the following formulas (1a) and (1b) in combination with one or more hydroxybenzoic acid compounds or salts thereof represented by the following formula (2):

[0058] <43> A composition for preventing or improving nerve disorders, comprising one or more lactone compounds represented by the following formulas (1a) and (1b), and one or more hydroxybenzoic acid compounds represented by the following formula (2) or salts thereof. <44> A composition for preventing or improving diabetic neuropathy, comprising one or more lactone compounds represented by the following formulas (1a) and (1b), and one or more hydroxybenzoic acid compounds represented by the following formula (2) or salts thereof. <45> A composition for promoting nerve regeneration comprising one or more lactone compounds represented by the following formulas (1a) and (1b), and one or more hydroxybenzoic acid compounds or salts thereof represented by the following formula (2). <46> A composition for promoting recovery of motor function after nerve injury, comprising one or more lactone compounds represented by the following formulas (1a) and (1b), and one or more hydroxybenzoic acid compounds or salts thereof represented by the following formula (2): <47> A composition for inhibiting muscle atrophy after nerve injury, comprising one or more lactone compounds represented by the following formulas (1a) and (1b), and one or more hydroxybenzoic acid compounds or salts thereof represented by the following formula (2): <48> A composition for preventing or ameliorating neuropathic pain, comprising one or more lactone compounds represented by the following formulas (1a) and (1b), and one or more hydroxybenzoic acid compounds represented by the following formula (2) or salts thereof.

[0059] <49> <1> , <7> , <13> , <25> , <31> , <37> , <43> In the above, the neuropathy is preferably a decrease in nerve function caused by a physical injury to the central or peripheral nerves. <50> <1> ~ <24> , <43> ~ <48> In the agent, food or composition in the above, the content of the lactone compound represented by the following formula (1a) or (1b) is preferably 0.0000001 mass% or more, more preferably 0.000001 mass% or more, and preferably 0.01 mass% or less, more preferably 0.005 mass% or less, and also preferably 0.0000001 to 0.01 mass%, more preferably 0.000001 to 0.005 mass%. <51> <1> ~ <24> , <43> ~ <48> In the agent, food or composition in the above, the content of the hydroxybenzoic acid compound represented by the following formula (2) or a salt thereof, calculated as the free hydroxybenzoic acid compound, is preferably 0.00000002 mass% or more, more preferably 0.0000002 mass% or more, and preferably 0.001 mass% or less, more preferably 0.0005 mass% or less, and also preferably 0.00000002 to 0.001 mass%, more preferably 0.0000002 to 0.0005 mass%. <52> <1> ~ <42> In the above, the amount of the lactone compound represented by the following formula (1a) or (1b) and the hydroxybenzoic acid compound represented by the following formula (2) or a salt thereof, or the amount of a pharmaceutical product (including a quasi-drug) or food containing the same, administered or ingested orally, is preferably 0.5 mg or more, more preferably 1 mg or more, and preferably 60 mg or less, more preferably 20 mg or less, and is preferably 0.5 to 60 mg, more preferably 1 to 20 mg, per adult (body weight 60 kg) per day, in terms of the lactone compound represented by the following formula (1). <53> <1> ~ <42> In the above, the amount of the lactone compound represented by the following formula (1a) or (1b) and the hydroxybenzoic acid compound represented by the following formula (2) or a salt thereof, or a pharmaceutical (including quasi-drug) or food containing the same, administered or ingested orally, is preferably 0.00005 mg or more, more preferably 0.0005 mg or more, and preferably 5 mg or less, more preferably 4 mg or less, and also preferably 0.00005 to 5 mg, more preferably 0.0005 to 4 mg, per adult (body weight 60 kg) per day, calculated as the free form of the hydroxybenzoic acid compound, of the hydroxybenzoic acid compound represented by the following formula (2) or a salt thereof.

[0060] [ka] (In the formula, R 1 represents a hydrogen atom or a hydroxyl group, R 2 represents a hydrogen atom or a methyl group. EXAMPLES

[0061] Example 1: Improvement of nerve damage in a central nervous system regeneration model induced by spinal cord crush injury (1) Zebrafish (Danio rerio) aged 3-12 months were grouped (n=5-24) based on body weight and maximum swimming speed. 1.Sham group, control diet: (Sham) 2. Crush group, control diet: (Crush) 3. Crush group, 2-deoxy-D-ribono-1,4-lactone diet: (Crush+L) 4. Crush group, protocatechuic acid diet: (Crush+P) 5. Crush group, vanillic acid diet: (Crush+V) 6. Crush group, 2-deoxy-D-ribono-1,4-lactone + protocatechuic acid diet: (Crush + PL) 7. Crush group, 2-deoxy-D-ribono-1,4-lactone + vanillic acid diet: (Crush + VL)

[0062] The Sham and Spinal Nerve Crush groups were fed Otohime (Nisshin Marubeni Feed) as normal food, while the groups administered each ingredient were fed the same food with the active ingredient dissolved in 50% EtOH mixed in. The content ratio of each ingredient in the food is as shown in Table 1 below.

[0063] [Table 1]

[0064] The animals were then freeze-dried using a freeze dryer and coated with 20% lard. 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).

[0065] The following commercially available products (model numbers, manufacturers) were used for 2-deoxy-D-ribono-1,4-lactone, protocatechuic acid, and vanillic acid. 2-Deoxy-ribono-1,4-lactone (QB-2141, Fujifilm Wako Pure Chemical Industries, Ltd.) Protocatechuic acid (P6857, LKT Labs, Inc.) Vanillic acid (084-04462, Fujifilm Wako Pure Chemical Industries, Ltd.)

[0066] Spinal Cord Crush (SCC) was performed by making a 3 mm incision with a razor at the base of the fish's dorsal fin and applying pressure with tweezers for 1 second to crush the fish. In the Sham group, only the incision was performed. After surgery, the fish were kept in a methylene blue (Nichido, diluted approximately 6000 times) solution for 3 days to prevent infection from the wound. Food was administered one week before the SCC treatment and the fish were kept until 21 days after the treatment, and maximum swimming speed and body weight were measured as appropriate. Maximum swimming speed was measured using a flowing water exercise load device (Personal Tank PT-70S (Nishi Nippon Fluid Engineering Research Institute Co., Ltd.) modified for zebrafish testing). After acclimating 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 flow rate just before the stage at which 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.

[0067] The results are shown in Figure 1. Compared to the Crush group, no effect was observed in the groups administered either the lactone compound or the hydroxybenzoic acid compound alone (Crush+L group, Crush+P group, Crush+V group), whereas the groups administered the lactone compound and the hydroxybenzoic acid compound in combination (Crush+PL group, Crush+VL group) showed an accelerated recovery of maximum swimming speed (n=4-7 at the endpoint).

[0068] 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 into groups (n=6-16) with equal weight and maximum swimming speed. 1.Sham group, control diet: (Sham) 2. Crush group, control diet: (Crush) 3. Crush group, protocatechuic acid + vanillic acid + glucono delta-lactone diet: (Crush + PVGDL) 4. Crush group, protocatechuic acid + vanillic acid + D-ribonolactone diet: (Crush + PVDr)

[0069] The Sham and Spinal Nerve Crush groups were fed Otohime (Nisshin Marubeni Feed) as normal food, while the groups administered each ingredient were fed the same food with the active ingredient dissolved in 50% EtOH mixed in. The content ratio of each ingredient in the food is as shown in Table 2 below.

[0070] [Table 2]

[0071] The animals were then freeze-dried using a freeze dryer and coated with 20% lard. 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).

[0072] Glucono-delta-lactone, D-ribonolactone, protocatechuic acid, and vanillic acid were used as the following commercially available products (model number, manufacturer). Gluconodeltalactone (42009, Fuso Chemical Industries) D-ribonolactone (355-20541, Fujifilm Wako Pure Chemical Industries, Ltd.) Protocatechuic acid (P6857, LKT Labs, Inc.) Vanillic acid (084-04462, Fujifilm Wako Pure Chemical Industries, Ltd.)

[0073] Spinal Cord Crush (SCC) was performed by making a 3 mm incision with a razor at the base of the fish's dorsal fin and applying pressure with tweezers for 1 second to crush the fish. In the Sham group, only the incision was performed. After surgery, the fish were kept in a methylene blue (Nichido, diluted approximately 6000 times) solution for 3 days to prevent infection from the wound. Food was administered one week before the SCC treatment and the fish were kept until 21 days after the treatment, and maximum swimming speed and body weight were measured as appropriate. Maximum swimming speed was measured using a flowing water exercise load device (Personal Tank PT-70S (Nishi Nippon Fluid Engineering Research Institute Co., Ltd.) modified for zebrafish testing). After acclimating 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 flow rate just before the stage at which 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.

[0074] The results are shown in Figure 2. Compared with the Crush group, the groups administered the hydroxybenzoic acid compound in combination with the lactone compound (Crush+PVGDL group, Crush+PVDr group) showed accelerated recovery of maximum swimming speed (n=6-15 at the end point).

[0075] Example 3: Improvement of nerve damage in a nerve regeneration model induced by sciatic nerve crush treatment (1) Seven-week-old C57BL / 6J mice were pre-bred for one week and then divided into the following eight groups so that their body weights were equal (n=10 per group). 1.Sham group, control diet: (Sham) 2. Crush group, control diet: (Crush) 3. Crush group, lactone diet: (Crush+L) 4. Crush group, protocatechuic acid diet: (Crush+P) 5. Crush group, vanillic acid diet: (Crush+V) 6. Crush group, lactone + protocatechuic acid diet: (Crush + PL) 7. Crush group, lactone + vanillic acid diet: (Crush + VL) 8. Crush group, lactone + protocatechuic acid + vanillic acid diet: (Crush + PVL)

[0076] After feeding each diet ad libitum for 7 days, the right leg was subjected to sciatic nerve crush treatment. The hair on the thighs of the mice was shaved, an incision of about 1 cm was made, and the sciatic nerve was exposed. The sciatic nerve was crushed by compressing it with tweezers for 10 seconds, the incision was sutured, and the incision was disinfected with isodine. For the sham operation group, the hair on the thighs of the mice was shaved, an incision of about 1 cm was made, and the sciatic nerve was exposed, the incision was sutured, and the incision was disinfected with isodine. After the sciatic nerve crush, the mice were allowed to feed each diet ad libitum. The diet composition is shown in Table 3. The protocatechuic acid, vanillic acid, and lactone used were the commercially available products (model numbers, manufacturers) shown below.

[0077] Protocatechuic acid (P6857, LKT Labs, Inc.) Vanillic acid (084-04462, Fujifilm Wako Pure Chemical Industries, Ltd.) 2-Deoxy-ribono-1,4-lactone (QB-2141, Fujifilm Wako Pure Chemical Industries, Ltd.)

[0078] Mice were dissected 5 weeks after sciatic nerve crush. Peroneal nerves were isolated and pre-fixed in 2.5% glutaraldehyde (4℃, overnight) and post-fixed in 1% osmic acid (4℃, 2 hours). After embedding in Epon resin, semi-thin (1.5um) sections were prepared and stained with 0.5% toluidine blue. After imaging with an all-in-one fluorescence microscope (Keyence), the area of ​​the myelin sheath was quantified using a Hybrid Cell Count (Keyence). Quantification was performed for all myelinated axons in the peroneal nerve (n=5-8 per group). Statistics were performed using Dunnett's test with a significance level of P<0.05 (*p<0.05,**p<0.01,***p<0.001).

[0079] [Table 3]

[0080] The results are shown in Figure 3. The Crush+PL, Crush+VL, and Crush+PVL groups significantly suppressed the loss of myelin area due to sciatic nerve crush. In other words, the hydroxybenzoic acid compounds and lactone compounds did not show activity alone, but the combination of the hydroxybenzoic acid compounds (protocatechuic acid or vanillic acid, or both) with the lactone compound (2-deoxy-ribono-1,4-lactone) showed a nerve regeneration promoting effect (Figure 3).

[0081] Example 4: Neuropathy-ameliorating effect in diabetic neuropathy model by streptozotocin administration 1) Three-week-old C57BL / 6J mice were intraperitoneally administered streptozotocin (150 mg / kg, diluted with citrate buffer pH 4.0) or citrate buffer (pH 4.0), and 5 days after administration, blood samples were taken from the tail vein and blood glucose levels were measured. Those with blood glucose levels of 280 mg / dL or higher were selected. Those with blood glucose levels below 280 mg / dL were administered streptozotocin again, and those with blood glucose levels of 280 mg / dL or higher were selected 5 days after administration. Mice were divided into groups (solvent-administered control diet group, streptozotocin-administered 2-deoxy-ribono-1,4-lactone group, streptozotocin-administered vanillic acid group, streptozotocin-administered 2-deoxy-ribono-1,4-lactone + vanillic acid group; n=6-10 per group) to avoid significant differences in blood glucose levels, and were raised on each diet. The composition of the diet is shown in Table 4.

[0082] The following commercially available compounds (model numbers, manufacturers) were used. Vanillic acid (084-04462, Fujifilm Wako Pure Chemical Industries, Ltd.) 2-Deoxy-ribono-1,4-lactone (QB-2141, Fujifilm Wako Pure Chemical Industries, Ltd.)

[0083] [Table 4]

[0084] 2) After 8 weeks of feeding, blood was collected from the tail and blood glucose levels were measured at regular intervals.

[0085] 3) After 9 weeks of dietary loading, the sensory nerve conduction velocity (SNCV) of the sural nerve was measured under anesthesia using an electromyography-evoked potential tester (MEB-9402MB). Statistics were performed using the Dunnett test, with the significance level set at P<0.05.

[0086] 4) Results a) Blood glucose levels 8 weeks after dietary loading are shown in FIG. The administration of streptozotocin caused a marked increase in blood glucose levels, but no change in blood glucose levels was observed after the intake of each component diet. b) The results of nerve conduction tests 9 weeks after dietary loading are shown in Figure 5. Streptozotocin administration significantly reduced SNCV, while lactone + vanillic acid diet significantly improved the decrease in nerve conduction velocity caused by streptozotocin administration (Figure 5).

[0087] Example 5. Improvement of nerve damage in a nerve regeneration model induced by sciatic nerve crush treatment (2) Seven-week-old C57BL / 6J mice were pre-bred for one week and then divided into the following eight groups so that their body weights were equal (n=10 per group). 1.Sham group, control diet: (Sham) 2. Crush group, control diet: (Crush) 3. Crush group, lactone + vanillic acid (VL) diet: (Crush + VL) 4. Crush group, glucono-delta-lactone + vanillic acid (VG) diet: (Crush + VG) 5. Crush group, vanillic acid (V) diet: (Crush+V) 6.Crush group, GDL (G) food: (Crush+G)

[0088] After feeding each diet ad libitum for 7 days, the right leg was subjected to sciatic nerve crush treatment. The hair on the thighs of the mice was shaved, an incision of about 1 cm was made, and the sciatic nerve was exposed. The sciatic nerve was crushed by compressing it with tweezers for 10 seconds, the incision was sutured, and the incision was disinfected with isodine. For the sham operation group, the hair on the thighs of the mice was shaved, an incision of about 1 cm was made, and the sciatic nerve was exposed, the incision was sutured, and the incision was disinfected with isodine. After the sciatic nerve crush, the mice were allowed to feed each diet ad libitum. The diet composition is shown in Table 3. The vanillic acid, lactone, and glucono-delta-lactone used were the following commercially available products (model number, manufacturer).

[0089] Vanillic acid (084-04462, Fujifilm Wako Pure Chemical Industries, Ltd.) 2-Deoxy-ribono-1,4-lactone (QB-2141, Fujifilm Wako Pure Chemical Industries, Ltd.) Gluconodeltalactone (073-01572, Fujifilm Wako Pure Chemical Industries, Ltd.)

[0090] Mice were dissected 5 weeks after sciatic nerve crush. Peroneal nerves were isolated and pre-fixed with 2.5% glutaraldehyde (4°C, 2 hours) and post-fixed with 1% osmic acid (4°C, 1.5 hours). After embedding in Epon resin, semi-thin (1.5 um) sections were prepared and stained with 0.5% toluidine blue. After imaging with an all-in-one fluorescence microscope (Keyence), the area of ​​the myelin sheath was quantified using a Hybrid Cell Count (Keyence). Quantification was performed for all myelinated axons in the peroneal nerve (n=7-9 per group). Statistics were performed using the Dunn test with a significance level of P<0.05 (*p<0.05,***p<0.001).

[0091] [Table 5]

[0092] The results are shown in Figure 6. The Crush+VL group and Crush+VG group significantly suppressed the decrease in myelin area caused by sciatic nerve crush. In other words, the hydroxybenzoic acid compound (vanillic acid) and glucono delta lactone did not show activity on their own, but the combination of the hydroxybenzoic acid compound (vanillic acid) and the lactone compound (glucono delta lactone) showed a nerve regeneration promoting effect (Figure 6).

[0093] Example 6 Effect of combined use of 2-deoxy-ribonucleo-1,4-lactone and vanillic acid on a neuropathic pain model induced by spared nerve injury 1) Spared Nerve Injury (SNI) was performed on male C57BL / 6J mice aged 51-54 weeks. Specifically, the hair on the left thigh of the mouse was shaved and disinfected with alcohol and isodine. The thigh was incised about 1 cm, and the tibial and peroneal nerves of the left leg were ligated with 8-0 silk thread. The tibial and peroneal nerves distal to the ligation site were excised 2-4 mm with scissors, and the incision was sutured with 6-0 silk thread. The mice were raised on each diet (control diet, 2-DL+VA diet) (n=12-16 per group) one week before SNI treatment. The diet was solid, and each diet was made with Oriental Yeast. The diet composition is shown in Table 6. "2-DL" refers to 2-deoxy-ribono-1,4-lactone and "VA" refers to vanillic acid. The following commercially available compounds (model numbers, manufacturers) were used. 2-DL: QB-2141, Fujifilm Wako Pure Chemical ·VA:084-04462, Fujifilm Wako Pure Chemical

[0094] [Table 6]

[0095] 2) Pain was evaluated using the Von Frey test 1 and 2 weeks after SNI treatment. Starting 2 days before the Von Frey test, the mice were placed on a wire mesh and allowed to acclimate in the animal chamber for 60 minutes every day. On the day of the test, the mice were also allowed to acclimate in the chamber for 40 minutes or more, and it was confirmed that spontaneous movement had disappeared. A Semmes-Weinstein monofilament (0.16g) was pressed vertically against the little toe, which is the area controlled by the sural nerve, for 3 seconds, and the escape reaction was observed. A 3-minute interval was allowed between each stimulation, and the results were shown as the response rate for 5 stimulations. Pain assessment was treated as count data and the Mann-Whitney U test was used with a significance level of p<0.05.

[0096] 3) Results a) The results of the Von Frey test 1 and 2 weeks after SNI treatment are shown in FIG. To investigate the combined effect of 2-DL and VA on neuropathic pain induced by SNI treatment, pain was evaluated using the Von Frey test. Compared to the control group, the combined 2-DL and VA (2-DL+VA) group showed a significant decrease in the response rate of the Von Frey test 1 and 2 weeks after SNI treatment. In other words, it was shown that the combined intake of 2-DL and VA significantly suppressed neuropathic pain.

Claims

1. An agent for preventing or improving nerve disorders comprising a combination of a lactone compound represented by the following formula (1a) and one or more hydroxybenzoic acid compounds represented by the following formula (2) or salts thereof. 【Chemistry 1】 (In the formula, R １ represents a hydroxy group, R ２ represents a hydrogen atom or a methyl group.)

2. A nerve regeneration promoter comprising a combination of a lactone compound represented by the following formula (1a) and one or more hydroxybenzoic acid compounds represented by the following formula (2) or salts thereof. 【Chemistry 2】 (In the formula, R １ represents a hydroxy group, R ２ represents a hydrogen atom or a methyl group.)

3. An agent for promoting recovery of motor function after nerve injury, comprising a combination of a lactone compound represented by the following formula (1a) and one or more hydroxybenzoic acid compounds represented by the following formula (2) or salts thereof: 【Chemistry 3】 (In the formula, R １ represents a hydroxy group, R ２ represents a hydrogen atom or a methyl group.)

4. A food for preventing or improving nerve disorders, comprising a combination of a lactone compound represented by the following formula (1a) and one or more hydroxybenzoic acid compounds represented by the following formula (2) or salts thereof: 【Chemistry 4】 (In the formula, R １ represents a hydroxy group, R ２ represents a hydrogen atom or a methyl group.)

5. A food for promoting nerve regeneration comprising a combination of a lactone compound represented by the following formula (1a) and one or more hydroxybenzoic acid compounds represented by the following formula (2) or salts thereof. 【Chemistry 5】 (In the formula, R １ represents a hydroxy group, R ２ represents a hydrogen atom or a methyl group.)

6. A food for promoting recovery of motor function after nerve damage, comprising a combination of a lactone compound represented by the following formula (1a) and one or more hydroxybenzoic acid compounds represented by the following formula (2) or salts thereof. 【Chemistry 6】 (In the formula, R １ represents a hydroxy group, R ２ represents a hydrogen atom or a methyl group.)

7. The agent according to claim 1 or the food according to claim 4, wherein the nerve disorder is a decrease in nerve function caused by physical damage to the central or peripheral nerves.

8. A composition for preventing or improving a nerve disorder, comprising a lactone compound represented by the following formula (1a) and one or more hydroxybenzoic acid compounds represented by the following formula (2) or salts thereof: 【Chemistry 8】 (In the formula, R １ represents a hydroxy group, R ２ represents a hydrogen atom or a methyl group.)

9. A composition for promoting nerve regeneration comprising a lactone compound represented by the following formula (1a) and one or more hydroxybenzoic acid compounds represented by the following formula (2) or salts thereof: 【Chemistry 9】 (In the formula, R １ represents a hydroxy group, R ２ represents a hydrogen atom or a methyl group.)

10. (Original claim 17) A composition for promoting recovery of motor function after nerve injury, comprising a lactone compound represented by the following formula (1a) and one or more hydroxybenzoic acid compounds represented by the following formula (2) or salts thereof: 【Chemistry 10】 (In the formula, R １ represents a hydroxy group, R ２ represents a hydrogen atom or a methyl group.)

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