JP2007246507A - Prophylactic or curative composition for fatigue and method for preventing or treating fatigue - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a pharmaceutical composition and food/drink containing an NMDA(N-methyl-D-aspartic acid) receptor antagonist as active ingredient for the purpose of preventing or treating various fatigues. <P>SOLUTION: The pharmaceutical composition and food/drink containing an NMDA(N-methyl-D-aspartic acid) receptor antagonist is provided based on the findings that such a mechanism that quinolinic acid as a metabolite of tryptophan in kynurenine path damages cerebral neurocytes by causing the excessive activation of an NMDA receptor, leading to cause various fatigues, has been confirmed, and the NMDA receptor antagonist has the effect of mitigating fatigue. That is, the pharmaceutical composition and food/drink containing an NMDA receptor antagonist are effective for preventing or treating fatigues including physical fatigue, mental fatigue, chronic fatigue syndrome and feeling of fatigue associated with various diseases. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to physical fatigue, mental fatigue, chronic fatigue syndrome, and bacterial infection, viral infection, inflammation, allergy, diabetes, containing N-methyl-D-aspartate (NMDA) receptor antagonist as an active ingredient, The present invention relates to a preventive / therapeutic composition and a preventive / therapeutic method for various fatigue such as fatigue associated with various diseases such as anemia, hypothyroidism, rheumatism, cancer and AIDS.

  Fatigue is generally defined as "a diminished state of physical or mental function with specific pathological discomfort caused by excessive physical or mental activity and a desire for rest".

  First, physical fatigue is a typical example of fatigue. Physical fatigue is thought to occur as a result of accumulation of lactic acid, a fatigue substance, in the body due to a decrease in the metabolic function of the body due to prolonged or excessive exercise. Usually, physical fatigue can be reduced or eliminated by resting or massage.

  Next is mental fatigue. Mental fatigue is thought to be caused by rapid changes in lifestyle, diversification of social systems, or complex human relationships, but the details are unknown. In recent years, there has been a rapid increase in the number of people who are aware of mental fatigue. For mental fatigue, in addition to elucidating the cause based on scientific evidence, the development of methods for preventing and treating it is required.

  Next, chronic fatigue syndrome is mentioned. Chronic fatigue syndrome is triggered by a common person who has lived well, and since then, symptoms such as intense fatigue, slight fever, headache, muscle pain, weakness, poor thinking / concentration, depression, etc. It is a disease that appeals over a period of time and prevents a healthy social life. In patients with chronic fatigue syndrome, reactivation of various infected viruses, abnormal production of various cytokines, decreased blood dehydroepiandrosterone sulfate (DHEA-S), abnormal acetylcarnitine metabolism, natural killer (NK) It has been confirmed that various abnormalities such as a decrease in activity have occurred, but none of them has been able to elucidate the causal relationship with the cause of the onset.

  Other fatigues include fatigue associated with various diseases such as bacterial infection, viral infection, inflammation, allergy, diabetes, anemia, hypothyroidism, rheumatism, cancer and AIDS.

  As a medical treatment of these various types of fatigue, for physical fatigue, vitamins such as vitamins such as vitamins B1, B2, and biotin, including saccharides such as glucose and fructose, various amino acids such as valine, leucine, and isoleucine. Vitamins represented by Group B, herbal medicines such as Ezogigi, carrots, and garlic, and Chinese medicines such as Hochuekkito, Juzen Daiyuto, and Ginseng Yoeito are used.

  In addition to these, recently, for the purpose of promoting production of adenosine-3-phosphate (ATP), which is a high-energy substance such as coenzyme Q10 (CoQ10), L-carnitine, α-lipoic acid, and lactic acid metabolism. The substance etc. which were made are used (patent document 1, patent document 2).

  However, these substances have a certain effect on physical fatigue, but in reality, sufficient effects are not obtained for mental fatigue and chronic fatigue syndrome caused by stress.

  Therefore, the present inventor has sought a substance having preventive and therapeutic effects on various fatigue such as mental fatigue and chronic fatigue syndrome as well as physical fatigue, and a new action mechanism different from conventional anti-fatigue substances. As a result, we focused on the metabolic pathway of tryptophan, one of the essential amino acids.

  Tryptophan is metabolized by the serotonin pathway and kynurenine pathway in the living body, and is metabolized as a precursor of serotonin involved in regulation of mind and emotion and melatonin involved in regulation of sleep and biological rhythm in the serotonin pathway. On the other hand, in the case of humans in the kynurenine pathway, about 95% of ingested tryptophan is metabolized by this pathway, and tryptophan is finally metabolized to nicotinamide while producing metabolites such as kynurenine and quinolinic acid. In recent years, it has been noted that metabolites in this kynurenine pathway are involved in various diseases.

  Infectious diseases and inflammatory diseases, inflammatory cytokines such as interferon (IFN), tumor necrosis factor (TNF) -α, and interleukin (IL) -6 are produced. Among these cytokines, IFN and TNF-α are known to induce the synthesis of indoleamine 2,3 dioxygenase (IDO), which is a starting enzyme of tryptophan metabolism in the kynurenine pathway (Non-patent Document 1). There is also a report that this IDO is dramatically induced locally or systemically in infectious diseases and inflammatory diseases (Non-patent Document 2). On the other hand, it is known that the above-mentioned IFN used for the treatment of cancer and hepatitis C exhibits fatigue (general malaise) as a side effect. Based on these facts, the present inventor speculated that an increase in tryptophan metabolism in the kynurenine pathway may be involved in the feeling of fatigue that appears in infectious diseases, inflammatory diseases, or IFN treatment.

  Quinolic acid, a metabolite of tryptophan in the kynurenine pathway, causes oxidative stress and increases in the body during uremia, and acts as an NMDA receptor activator in the brain, like glutamate and aspartate, in nerve cells. It is known that it shows a strong toxicity with respect to non-patent documents 3 and 4.

  The NMDA receptor is one of glutamate receptors that are excitatory amino acids and is present on the surface of nerve cells. This glutamate receptor is roughly classified into an ion channel type and a metabotropic type, and the ion channel type is further NMDA receptor, AMPA (2-amino-3- (3-hydroxy-5-methylisoxazol-4-yl). Propanic acid) receptors and kainate receptors are classified into three types.

  Among these, when the NMDA receptor is activated by excitatory amino acids such as glutamic acid and aspartic acid, a large amount of calcium ion flows into the nerve cell, and then various calcium ion-dependent enzymes are activated to enter the intracellular region. A chained change occurs. If NMDA receptor activation is normal, it plays an important role in various physiological functions such as brain plasticity, learning and memory, and neurotransmission in the sensory system. Damages and eventually leads to cell death.

  From these facts, in the treatment of infection, inflammatory disease or IFN, the present inventors have increased tryptophan metabolism in the kynurenine pathway and rapidly increased quinolinic acid. This rapidly increased quinolinic acid causes excessive activity of NMDA receptor in the brain. As a result, it was thought that nerve cells were injured, and that the damage of nerve cells caused fatigue.

In mouse experiments, it has been recognized that the blood concentration of TNF-α, a cytokine that induces IDO, is increased by various stresses such as fasting / fast water stress, sleeplessness stress and restraint stress (non-patented). Reference 5). Therefore, the present inventor has also found that the neuronal injury caused by the above-described kynurenine pathway, such as increased tryptophan metabolism, increased quinolinic acid, and excessive activation of the NMDA receptor accompanying the cause of mental fatigue due to stress or the like. Thought it was involved.

  On the other hand, when exercise load is given to mice, it has been confirmed that inflammatory cytokines such as TNF-α, IL-1β, and IL-6 increase in muscle and blood (Non-Patent Document 6). In rats, there is a report that after exercise, kynurenine, which is one of the metabolites of tryptophan in the kynurenine pathway, is increased (Patent Document 3) and IDO activity of peritoneal macrophages is further increased (Non-Patent Document 7). From these facts, the present inventor has also found that the cause of physical fatigue due to exercise is the increase in tryptophan metabolism accompanying the induction of IDO, the increase in quinolinic acid, and the concomitant activation of the NMDA receptor resulting in the damage of the brain neurons. I thought it was involved.

  By the way, quinolinic acid is produced in the periphery such as the liver and normally cannot pass through the blood-brain barrier (BBB), so quinolinic acid does not flow into the brain. However, since young BBB rats are vulnerable to BBB, it has been recognized that quinolinic acid migrates into the brain (Non-patent Document 8). Moreover, in higher animals such as humans, it has been reported that stress changes the permeability of the BBB, and when subjected to stress, corticotropin releasing factor (CRF) is secreted from the hypothalamic paraventricular nucleus of the brain, It has been confirmed that this CRF enhances the permeability of BBB (Non-patent Document 9). From this, it is considered that in the stress state, the permeability of the BBB is enhanced, and peripheral quinolinic acid is easily transferred into the brain.

  From the above, the present inventor can prevent the activation of NMDA receptor by quinolinic acid by using a substance having an NMDA receptor antagonistic action, and as a result, prevents injury of brain neurons, and the body. Various fatigue such as mental fatigue, mental fatigue, chronic fatigue syndrome, and bacterial infections, viral infections, inflammation, allergies, diabetes, anemia, hypothyroidism, rheumatism, cancer, fatigue caused by various diseases such as AIDS It was speculated that it could be expected to exert a preventive or therapeutic effect.

JP-A-6-305963 JP-A-2005-97161 JP 2004-198325 A “Brain, Behavior, Immunity” 2002, 16, p. 596-601 “Nature Reviews Immunology” 2004, 4, 10, p. 762-774 “Journal Fur Hirnforschung” 1990, 31, (5), p. 635-643 "From receptor knowledge of cell membranes to the latest information", Nanzan-do “European Cytokine Network” 1992, 3, p. 391-398 “International Journal of Sports Medicine” 2001, 22, p. 261-267 “Advanceds in Experiential Medicine and Biology” 2003, 527, p. 531-535 “Neuropharmacology” 2000, 39, p. 507-514 “Journal of Physiology and Pharmacology” 2002, 53, (1) p. 85-94

  The present invention includes physical fatigue due to excessive exercise, mental fatigue due to stress and sleep disorder, chronic fatigue syndrome, and bacterial infection and viral infection, inflammation, allergy, diabetes, anemia, hypothyroidism, rheumatism, cancer, In order to prevent or treat various fatigue such as fatigue caused by various diseases such as AIDS, a pharmaceutical composition and a food or drink containing an NMDA receptor antagonist as an active ingredient are provided.

  The present inventor has found that quinolinic acid, a metabolite of tryptophan in the kynurenine pathway, causes excessive activation of the NMDA receptor and damages brain neurons, causing various fatigues. The inventors have found that various fatigues can be prevented and reduced by administering an NMDA receptor antagonist, and the present invention has been completed.

  That is, the composition for preventing and treating fatigue according to the present invention is characterized by containing an N-methyl-D-aspartic acid (NMDA) receptor antagonist as an active ingredient. This NMDA receptor antagonist includes memantine, dizocilpine (MK801), phencyclidine (PCP), dextromethorphan, amantadine, ifenprodil, 3- (2-carboxypiperazin-4-yl) propyl having NMDA receptor antagonistic activity. -1-phosphate (CPP), ketamine, thiretamine, budipine, flupirtine, N- [1- (2-thienyl) cyclohexyl] piperidine (TCP), D (-)-2-amino-5-phosphonovaleric acid (D- AP5), D (-)-2-amino-7-phosphonoheptanoic acid (D-AP7), kynurenic acid, 6-hydroxykynurenic acid, 7-chlorokynurenic acid, theanine (L-glutamic acid-γ-ethylamide), etc. Or one or more selected from the group consisting of derivatives of said compounds Alternatively, one or more are selected from the group consisting of extracts from ginkgo biloba leaves, green tea, black tea and the like having NMDA receptor antagonistic action.

The fatigue prevention / treatment method of the present invention is characterized by using the fatigue prevention / treatment composition of the present invention.

  According to the present invention, physical fatigue, mental fatigue, chronic fatigue syndrome, and bacterial infection and viral infection, inflammation, allergy, diabetes, anemia, hypothyroidism, rheumatism, cancer, containing NMDA receptor antagonist as an active ingredient A pharmaceutical composition and food and drink having a preventive or therapeutic action against various fatigue such as fatigue caused by various diseases such as AIDS can be provided.

Hereinafter, the present invention will be described in detail. The NMDA receptor antagonist used in the present invention includes memantine, dizocilpine (MK801), phencyclidine (PCP), dextromethorphan, amantadine, ifenprodil, 3- (2-carboxypiperazin-4-yl) propyl-1 -Phosphate (CPP), ketamine, thiretamine, budipine, flupirtine, N- [1- (2-thienyl) cyclohexyl] piperidine (TCP), D (-)-2-amino-5-phosphonovaleric acid (D-AP5) , D (−)-2-amino-7-phosphonoheptanoic acid (D-AP7), kynurenic acid, 6-hydroxykynurenic acid, 7-chlorokynurenic acid, theanine (L-glutamic acid-γ-ethylamide), etc. Or natural products such as ginkgo biloba leaves, green tea, black tea or extracts thereof, preferably memantine hydrochloride It is. As a specific amount of use, 1 to 50 mg / kg (body weight) per day should be taken within the range of appropriate daily intake for humans and within the range where bitterness is not too strong for foods. Is preferred. In the case of a natural product or an extract thereof, it is preferably taken at 1 to 500 mg / kg (body weight).

  The present inventor has revealed that fatigue is associated with an increase in quinolinic acid in the brain, and that fatigue is reduced by administering an NMDA receptor antagonist, using a mouse fatigue model.

  First, in order to demonstrate that “fatigue symptoms occur due to an increase in quinolinic acid in the brain”, quinolinic acid was administered directly into the mouse brain to test whether fatigue symptoms were induced.

(Test 1) Fatigue degree due to intracerebral administration of quinolinic acid [Test method]
0.01-12 mL of quinolinic acid (dissolved in physiological saline) at a concentration of 4 μmol / mL was administered into 9 to 12 ddY male mice (6 weeks old) per group (condition A). On the other hand, the same amount of physiological saline was administered in the brain to the control group (Condition B). Thirty minutes after administration, the mouse was placed in a rotating cage equipped with a rotation counter, and the number of rotations in a total of 15 hours including 12 hours in the dark period and 3 hours in the light period was measured in the light-dark cycle breeding room, and used as an index of spontaneous exercise. . A home cage that can freely feed and drink is attached to the side of the rotating cage, so that the mouse can freely move between the home cage and the rotating cage. The results are expressed as mean values ± standard error. Significant difference between Condition A group (quinolinic acid administration) and Condition B group (physiological saline administration) was performed by Student's t-test, and the risk rate was less than 5% (P < 0.05) was considered significant.

[Test results]
The results are shown in Table 1. From this result, it can be said that “when quinolinic acid increases in the brain, the spontaneous momentum is clearly reduced and a fatigue state occurs”.

  Next, “involvement of quinolinic acid in a mental fatigue model and whether the fatigue level is reduced by administering an NMDA receptor antagonist” were examined.

(Test 2) Fatigue degree by peripheral administration of quinolinic acid under restraint stress [Test method]
5 to 8 ddY male mice (6 weeks old) per group were housed in a 50 mL polypropylene tube with a hole for ventilation and subjected to restraint stress. One hour after restraint, quinolinic acid (dissolved in physiological saline) was intraperitoneally administered at a dose of 100 mg / kg (in terms of mouse body weight), and restraint stress was further applied for 1 hour (Condition C). On the other hand, as control groups, physiological saline was administered intraperitoneally instead of quinolinic acid (Condition D), quinolinic acid was administered intraperitoneally without applying restraint stress (Condition E), and physiological saline was administered intraperitoneally. It was set as what was administered (condition F). Then, immediately after the release, it was placed in the same rotating cage as that used in Test 1, and the number of rotations in a total of 15 hours including a dark period of 12 hours and a light period of 3 hours was measured in a light-dark cycle breeding room. Results are expressed as mean ± standard error. Significant difference test between Condition C group (restraint stress + quinolinic acid) and each group is performed by Student's t-test, and the risk rate is less than 5% (P <0.05). Significant.

[Test results]
The results are shown in Table 2. From this result, it was confirmed that “intraperitoneal administration of quinolinic acid under restraint stress (condition C) clearly reduced the spontaneous exercise amount, and no significant change was observed in the other groups”.

  Subsequently, a test of “change in fatigue level due to administration of NMDA receptor antagonist” was conducted in a mental fatigue model.

(Test 3) Action of NMDA receptor antagonist under restraint stress [Test method]
NMDA receptor antagonist memantine hydrochloride (dissolved in physiological saline) was intraperitoneally administered to 5-8 ddY male mice (6 weeks old) per group at a dose of 30 mg / kg for ventilation. The sample was accommodated in a 50 mL polypropylene tube with a perforated hole and subjected to restraint stress. After 1 hour of restraint, quinolinic acid (dissolved in physiological saline) was intraperitoneally administered at a dose of 100 mg / kg, and restraint stress was further applied for 1 hour (condition G). On the other hand, as a control group, physiological saline was administered intraperitoneally instead of memantine hydrochloride (condition H), physiological saline was administered intraperitoneally instead of quinolinic acid (condition J), and intraperitoneal administration was physiological. Saline solution (condition K). Then, immediately after the release, it was placed in the same rotating cage as that used in Test 1, and the number of rotations in a total of 15 hours including a dark period of 12 hours and a light period of 3 hours was measured in a light-dark cycle breeding room. Results are expressed as mean ± standard error. Significant difference between Condition H group (only quinolinic acid) and each group was tested by Student's t-test, and the risk rate was less than 5% (P <0.05) as significant. did.

[Test results]
The results are shown in Table 3. From the results of (Condition H) and (Condition G), it was recognized that “the amount of spontaneous exercise does not decrease if memantine hydrochloride, which is an NMDA receptor antagonist, is administered during restraint stress”. On the other hand, it was also confirmed that “without quinolinic acid administration, the amount of spontaneous exercise is not affected by memantine hydrochloride administration”.

  From the results of Test 2 and Test 3, “Under restraint stress, fatigue symptoms (mental fatigue) are induced even when quinolinic acid is administered peripherally instead of in the brain. However, an NMDA receptor antagonist is administered. It was proved that fatigue symptoms are greatly reduced.

  Next, “relation between quinolinic acid and fatigue in a bacterial infection model” and “whether administration of an NMDA receptor antagonist reduces fatigue” were examined.

  LPS (lipopolysaccharide) was used in establishing a fatigue model associated with bacterial infection. LPS is a bacterial endotoxin that promotes the production of inflammatory cytokines TNF-α and IFN, and as a result, induces IDO to activate the kynurenine pathway and enhance the permeability of BBB in the periphery. We believe that the increased quinolinic acid is likely to enter the brain through the BBB.

(Test 4) Fluctuation in body quinolinic acid concentration and fatigue in a bacterial infection model [Test method]
7 to 8 ddY male mice (6 weeks old) per group were given 0.2 mg / kg (condition M), 0.6 mg / kg (condition N), 2.0 mg / kg (conditions) of LPS derived from Escherichia coli. At the dose of P), physiological saline (condition L) was intraperitoneally administered to the subject group, and 6 hours later, it was placed in the same rotating cage as used in Test 1, and in the light-dark cycle breeding room, the dark period 12 The number of revolutions in a total of 15 hours including time and light period 3 hours was measured. Then, blood was collected 3 hours after the end of the spontaneous movement in the rotating basket, and the serum quinolinic acid concentration was measured. The results are expressed as mean values ± standard error. Significant difference tests between the condition L group (saline solution administration) and each group (LPS administration) are performed by Student's t-test, and the risk rate is less than 5% (P <0. 05) was considered significant.

  The serum quinolinic acid concentration was measured by the following method. After separating the serum and diluting it appropriately with ultrapure water, 80 μL is taken, and 80 μL of 100 nM 3,5-pyridinedicarboxylic acid solution, 40 μL of 5N hydrochloric acid and 200 μL of chloroform are added and vigorously stirred. After centrifugation, 50 μL of 62.5 mM TBAS was added to 100 μL of the supernatant and freeze-dried. The dried pellet was dissolved in 25 μL of a methylene chloride solution containing 7.5% diisopropylethylamine and 3% pentafluorobenzyl bromide, and heated to 60 ° C. And derivatize for 15 minutes. After cooling to room temperature, 50 μL of decane and 750 μL of ultrapure water were added and distributed, and then 1 μL of the organic layer obtained by centrifugation was quantitatively analyzed by GC / MS. In addition, DB-5ms30m was used for the capillary column, and helium and isobutane were used for the carrier gas and the reaction gas, respectively. Ionization was performed at NCI, and quinolinic acid monitored the signal at m / z value 346.

[Test results]
The results are shown in Table 4 and FIG. From this result, it was confirmed that “the amount of locomotor activity decreases while the LPS dose increases, while the serum quinolinic acid concentration increases”. Moreover, as shown in FIG. 1, it was also confirmed that “there is a significant negative correlation between the serum quinolinic acid concentration and the amount of spontaneous exercise” (r = −0.69884, P <0.001). ).

  Subsequently, a test of “change in fatigue level due to administration of an NMDA receptor antagonist” was carried out in a bacterial infection model.

(Test 5) Action of NMDA receptor antagonist under fatigue symptoms by bacterial infection model [Test method]
NMDA receptor antagonist memantine hydrochloride was dissolved in physiological saline and administered intraperitoneally at a dose of 30 mg / kg to 7-8 ddY male mice (6 weeks old) per group. 0.5 hours later, E. coli-derived LPS was intraperitoneally administered at a dose of 0.6 mg / kg, and 6 hours later, memantine hydrochloride was again intraperitoneally administered in the same amount (condition Q). On the other hand, as control groups, physiological saline was administered intraperitoneally instead of memantine hydrochloride (condition R), physiological saline was administered intraperitoneally instead of E. coli-derived LPS (condition S), and intraperitoneal administration Saline solution (condition T). Then, it put into the same rotation cage | basket as what was used in Test 1, and measured the rotation speed in 15 hours in total including the dark period 12 hours and the light period 3 hours in the breeding room of a light-dark cycle. Then, blood was collected 3 hours after the end of the spontaneous movement in the rotating basket, and the serum quinolinic acid concentration was measured by the same method as in Test 4. Results are expressed as mean values ± standard error. Significant difference test between condition R group (only LPS administration) and each group was performed by Student's t-test, and the risk rate was less than 5% (P <0.05) as significant. did.

[Test results]
The results are shown in Table 5. According to the results of (Condition R) and (Condition Q), “If memantine hydrochloride, which is an NMDA receptor antagonist, is administered at the time of LPS administration, the serum quinolinic acid concentration increases, but the locomotor activity does not decrease.” Admitted. On the other hand, it was also confirmed that, unless LPS was administered, locomotor activity and serum quinolinic acid concentration were not affected by memantine hydrochloride administration.

  From the results of Test 4 and Test 5, “the production of quinolinic acid is accelerated in the body by bacterial and viral infection, and fatigue symptoms are induced / accelerated”. However, it was proved that "administration of an NMDA receptor antagonist cannot stop acceleration of quinolinic acid production, but can greatly reduce fatigue symptoms".

  Furthermore, in a bacterial infection model in which fatigue symptoms occur, “the production of quinolinic acid is accelerated in the body, quinolinic acid excessively activates the NMDA receptor and damages brain neurons”, “by administration of an NMDA receptor antagonist It was verified whether or not the cell damage was suppressed.

(Test 6) Effect of NMDA receptor antagonist on brain cell injury caused in bacterial infection model [Test method]
NMDA receptor antagonist memantine hydrochloride was dissolved in physiological saline and administered intraperitoneally at a dose of 30 mg / kg to 7-8 ddY male mice (6 weeks old) per group. 0.5 hours later, E. coli-derived LPS was intraperitoneally administered at a dose of 0.6 mg / kg, and 6 hours later, memantine hydrochloride was again intraperitoneally administered in the same amount (condition W). On the other hand, as control groups, physiological saline was administered intraperitoneally instead of memantine hydrochloride (condition X), physiological saline was administered intraperitoneally instead of E. coli-derived LPS (condition Y), and intraperitoneal administration Saline solution (condition Z). Three days after the intraperitoneal administration of LPS, the mice were perfused with phosphate buffered saline and 4% paraformaldehyde solution from the left ventricle, and then the brain was removed. After the excised brain is fixed with 4% paraformaldehyde solution, paraffin embedding is performed by a conventional method, and this paraffin-embedded block is sliced into 3 μm-thick sections including the hippocampal region with a microtome, and Nissel staining is performed. Cells were dyed separately. The number of neurons existing in the CA1 and CA3 regions of the hippocampus was measured under an optical microscope, and the cell density per mm ³ was calculated. The results are expressed as mean values ± standard error, and the significant difference test between the condition X group (only LPS administration) and each group is performed by Student's t-test, and the risk rate is less than 5% (P <0.05) as significant. did.

  The results of Test 6 demonstrate that in the bacterial infection model by LPS administration, neuronal cell damage is caused in the hippocampal region of the brain, but that cytotoxicity is significantly suppressed by administration of the NMDA receptor antagonist. did it.

  From the above test results, the fatigue mechanism is as follows: “When quinolinic acid increase and BBB weakening occur simultaneously due to bacterial or viral infection, quinolinic acid enters the brain through weakened BBB, It was proved that excessive activation of the NMDA receptor causes brain neuronal injury, resulting in fatigue. In addition, it was proved that “administration of an NMDA receptor antagonist to inactivate the NMDA receptor can suppress brain nerve cell injury and reduce fatigue symptoms”.

  Hereinafter, the present invention will be specifically described with reference to production examples in the case where the present invention is developed as a specific product, but the present invention is not limited to these.

(Example 1) Tablet 25 parts of memantine hydrochloride, 100 parts of anhydrous caffeine, 15 parts of aspartame, 970 parts of mannitol, 66 parts of avicel, 12 parts of menthol, 12 parts of magnesium stearate, and 1200 parts of the total amount are thoroughly mixed according to a conventional method. After that, tableting was performed to obtain one chewable tablet of 400 mg.

(Example 2) Tablets Dextromethorphan cresol sulfonate hydrobromide 25 parts, Anhydrous caffeine 100 parts, Aspartame 15 parts, Mannit 970 parts, Avicel 66 parts, Menthol 12 parts, Magnesium stearate 12 parts, Total amount After thoroughly mixing 1200 parts according to a conventional method, tableting was performed to obtain one 400 mg chewable tablet.

(Example 3) Capsules Ifenprodil tartrate 20.0 mg, anhydrous caffeine 90.0 mg, sodium lauryl sulfate 10.0 mg, lactose 30.0 mg, magnesium stearate 30.0 mg, pregelatinized starch 60.0 mg, low substitution degree After sufficiently mixing 10.0 mg of hydroxypropylcellulose according to a conventional method, granules were prepared, and 20.0 capsules were filled with 250.0 mg per capsule.

(Example 4) Drinking agent Ginkgo biloba extract 1 g, DL-sodium tartrate 100 mg, succinic acid 9 mg, liquid sugar 800 g, citric acid 12 g, vitamin C 10 g, nicotinic acid amide 120 mg, thiamine nitrate 100 mg, pyridoxine hydrochloride 50 mg, phosphoric acid Riboflavin sodium (30 mg), anhydrous caffeine (500 mg), and fragrance (15 mL) were dissolved in distilled water (8 L), distilled water was added to make a total volume of 10 L, filtered through a filter, and 100 mL each was aseptically filled into brown bottles to produce a drink.

(Example 5) Drinking agent Green tea extract 20 g, DL-sodium tartrate 100 mg, succinic acid 9 mg, liquid sugar 800 g, citric acid 12 g, nicotinic acid amide 120 mg, vitamin C 10 g, flavor 12 ml, potassium chloride 1 g, magnesium sulfate 0. 5 g was dissolved in 8 L of distilled water, and distilled water was added to make the total volume 10 L, followed by filter filtration, and aseptic filling into brown bottles 100 mL each to produce a drink.

(Example 6) Jelly agent Theanine 1.5g, valine 1g, leucine 1g, isoleucine 1g, gel-up SA3C 0.2g, gel-up KS 0.1g, trehalose 12g, starch 2g, water 60.7g Dissolve in a warm bath. After cooling to 70 ° C., 20 mL of 1% curdlan dispersion was added and further stirred, and filled in a pouch. Boil sterilization was performed at 100 ° C. for 20 minutes to obtain a jelly agent.

Correlation between serum quinolinic acid concentration and locomotor activity in a bacterial infection model

Claims (5)

A fatigue prevention / treatment composition comprising an N-methyl-D-aspartate (NMDA) receptor antagonist as an active ingredient. NMDA receptor antagonists are NMDA receptor antagonistic memantine, dizocilpine (MK801), phencyclidine (PCP), dextromethorphan, amantadine, ifenprodil, 3- (2-carboxypiperazin-4-yl) propyl- 1-phosphate (CPP), ketamine, thiretamine, budipine, flupirtine, N- [1- (2-thienyl) cyclohexyl] piperidine (TCP), D (-)-2-amino-5-phosphonovaleric acid (D-AP5 ), D (−)-2-amino-7-phosphonoheptanoic acid (D-AP7), kynurenic acid, 6-hydroxykynurenic acid, 7-chlorokynurenic acid, theanine (L-glutamic acid-γ-ethylamide), etc. The prevention / fatigue according to claim 1, wherein one or more compounds are selected from the group consisting of a compound or a derivative of the compound. Care composition. The composition for preventing or treating fatigue according to claim 1, wherein the NMDA receptor antagonist is selected from the group consisting of extracts from ginkgo biloba leaves, green tea, black tea and the like having NMDA receptor antagonistic activity. object. A food or beverage comprising the fatigue prevention / treatment composition according to claim 1. A method for preventing and treating fatigue using any one of claims 1 to 4.