JPH06239737A - Brain metabolism promoting and memory improving agent - Google Patents

Abstract

PURPOSE:To obtain a brain metabolism promoting and memory improving agent containing a substance with active oxygen scavenging action as a main ingredient. CONSTITUTION:This brain metabolism promoting and memory improving agent consists essentially of an active oxygen scavenging substance one of whom is a nitrone compound, e.g. alpha-phenyl-N-buthylnitrone, 5,5-dimethylpyrroline N- oxide, alpha-4-pyridyl-1-oxide-t-butylnitrone or a nitroso compound, e.g. t- nitrosobutane or t-butylnitrosobenzene or mixture of one or more of these substances. This compound can activate brain metabolism of aged persons such as metabolism of neurotransmitter and that of proteins, etc., to improve memorizing function and nerve function and is effective for treatment or improvement of cerebral circulation disorders, e.g. cerebral thrombosis, cerebral embolism, cerebral infarction, cerebral hemorrhage and cerebral arteriosclerosis of mammal including human or brain and nerve diseases, e.g. dysmnesia, geriatric dementia and Parkinson's disease which frequently occur in aged persons.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a cerebral metabolism promoting / memory improving agent and a method for promoting cerebral metabolism and improving memory by capturing / eliminating active oxygen.

[0002]

2. Description of the Related Art Conventionally, Avan (Takeda Yakuhin) and the like have been known as agents for improving brain metabolism and mental symptoms, but its main component is idebenone.

[0003]

However, although conventional brain metabolism promoters promote brain metabolism in the short term, they have not fundamentally improved brain metabolism. As side effects of Avan, nervous system disorders such as numbness of limbs, dizziness, lightheadedness, and headaches, agitation, mental disorders such as delirium, restlessness, and insomnia, as well as loose stools, diarrhea, nausea, loss of appetite, stomachache, Disorders of the digestive system such as abdominal discomfort are known.

An object of the present invention is to provide a cerebral metabolism promoting agent which has few side effects and activates cerebral metabolism of elderly people such as metabolism of neurotransmitters and protein metabolism to improve memory and brain function.

[0005]

[Means for Solving the Problems]
As a result of diligent research to solve the above problems, trapping and eliminating active oxygen promotes brain metabolism, improves memory, and either nitrone compound, nitroso compound, etc., or a mixture thereof is active. The present invention has been completed based on the finding that oxygen or free radicals can be trapped / scavenged to activate brain metabolism of elderly people such as metabolism of neurotransmitters and protein metabolism to improve memory and brain function.

The brain metabolism / memory improving agent according to the present invention is
Cerebral thrombosis, cerebral embolism, cerebral infarction, cerebral hemorrhage, cerebral circulatory disorders such as cerebral arteriosclerosis, and memory disorders frequently occurring in the elderly, senile dementia and Parkinson's disease, etc. It will improve.

The cerebral metabolism-promoting / memory-improving agent of the present invention is, as nitrone compounds, PBN (α-phenyl-Nt-butylnitrone), DMPO (5,5-dimethylpyrroline N oxide), POBN (α-4). -Pyridyl 1-oxide-N-t bucil nitrone), or a mixture of one or more thereof, and examples of the nitroso compound include tNB (t-nitrosobutane), BNB (t-
Butylnitrosobenzene) or a mixture of one or more of these.

The present invention also relates to these nitrone compounds,
A composition containing, as a main component, any one of nitroso compounds or a mixture of one or more thereof, and containing PBN, DMPO, etc. as an active ingredient, and a suitable pharmacologically acceptable additive (extending agent). , Diluent) and the like to give a suitable pharmaceutical composition.

Further, since the toxicity of PBN and the like is low and the LD50 in mice and rats is 1.1 g / kg or more, there are few side effects even when used in the human body.

This composition is prepared by mixing the active ingredient with physiologically acceptable carriers, excipients, binders and diluents, for example granules, powders, hard capsules, soft capsules, coatings and syrups. , Orally or parenterally as a suppository or injection.

The dose of the composition of the present invention depends on the type of disease,
It varies depending on the symptoms, age, administration method, etc., but when used orally, it is 0.32-75 mg / kg for rats.
Weight, therefore 19 (60 kg standard weight) per day
The dose is in the range of mg to 4500 mg, preferably 70 to 960 mg. Further, when the composition of the present invention is mixed with physiological saline, it is preferable that both PBN and DMPO are dissolved in a proportion of 0.5 to 1.0%.

[0012]

[Function] When active oxygen is trapped / erased, it becomes difficult to form peroxidative substances, and further, it becomes difficult to crosslink proteins or DNA, resulting in vasodilation and improvement of blood flow, thereby promoting brain metabolism. Conceivable.

The present invention is also directed to PBN or DMPO.
Oral administration or intravenous injection, intraperitoneal injection, etc., to humans or mammals such as pets to trap and eliminate active oxygen or free radicals, and to expand blood vessels to improve blood flow. Cerebral circulation disorders,
Cerebral metabolism is activated by improving blood flow in aged animals, improving memory and neurotransmitter levels.

[0014]

[Effect] The present invention promotes the metabolism of neurotransmitters and proteins of elderly people or elderly pets, and further expands blood vessels to improve blood flow. To improve the memory and brain function by activating cerebral metabolism in the elderly, and cerebral circulation disorders such as cerebral thrombosis, cerebral embolism, cerebral infarction, cerebral hemorrhage, cerebral arteriosclerosis in mammals including humans It is possible to treat or ameliorate brain / nerve diseases such as memory disorders, senile dementia and Parkinson's disease. In addition, this composition is safe because it uses a composition that meets the pharmacological standards.

[0015]

EXAMPLES The present invention will be described more specifically below based on examples.

[Animal] For experiments, 6 to 10 weeks of age and 5
To 6 months old and 24 months old animals, F3
The 44 strain (Charles River) and the Wistar strain (SRL) were used. All animals were fed with food (Oriental yeast, chow) and water in a breeding room with a room temperature of 24 ± 1 ° C and a relative humidity of 55 ± 5% under a 12-hour light-dark cycle (light period from 7 am to 7 pm) after acquisition. It was raised under free intake.

[Pharmaceutical] 3.2 mg of PBN in physiological saline
DMPO was dissolved in physiological saline at a rate of 2 mg / ml [0.2% (w / v)] and administered at a rate of 2 mg / ml [0.32% (w / v)]. The dose was 1.0 ml per 100 g of rat body weight.

[Administration of Drug] Rat 1 administered with PBN
0 mice were used as a PBN administration group, 10 rats treated with DMPO were used as a DMPO administration group, and 10 mice treated with physiological saline alone were used as a control group.

[Experimental experiment on cerebral metabolism in aged rats] The activity variation of proteolytic enzymes in rat cerebral cortex was examined by fluorescence intensity after 40 minutes digestion, and it was found that PBN-administered group was higher in aged animals than control group. . In the control group, 24 months old is less active than 6 months old,
In the PBN group, no difference was observed between 6 months old and 24 months old (Drawing 1). That is, it is considered that PBN increased the activity of proteolytic enzyme, activated the decomposition of unnecessary protein, and promoted the metabolism of protein. From FIG. 1, a statistically significant difference was observed between the 6-month-old control group and the 24-month-old control group (p <0.1), and between the 24-month-old control group and the 24-month-old PBN group (p <0.1). I understand that

Then, the linear body of the rat brain was taken out and the change in the amount of dopamine due to the addition of potassium chloride and oxytocin to PBN of the neurotransmitter was examined, and in the control group, the aged animals had a higher dopamine concentration than the young animals. Although the amount was small, the amount of dopamine in the PBN-administered group was larger than that in the control group, and there was no difference between old and young (Fig. 2). This fact suggests that PBN promotes metabolism of neurotransmitters.

Further, the in vivo dialysis method was used to examine the metabolic changes of dopamine in the striatum of rat brain using PBN and DMPO.
In the control group, the aged animals had a smaller amount of dopamine metabolites (DOPAC) than the young animals, but in the PBN-administered group and the DMPO-administered group, the DOPAC amount in the aged animals was larger than that in the control group, and the difference between the young and old. Is not recognized.

[Table 1] This fact indicates that the metabolism of neurotransmitters is promoted by PBN and DMPO.

[Brief description of drawings]

FIG. 1 is a diagram showing changes in proteolytic enzyme activity.

FIG. 2 is a diagram showing the content of dopamine, which is a neurotransmitter in the brain.

Continuation of the front page (51) Int.Cl. ⁵ Identification code Office reference number FI technical display location C07C 291/04 7188-4H // C07D 207/46 8217-4C 213/89

Claims (6)

[Claims] 1. A cerebral metabolism-promoting substance containing a substance having an action of trapping and eliminating active oxygen such as a nitrone compound or a nitroso compound, or a mixture containing at least one of these compounds as a main component.
Memory improver. 2. A neurotransmitter metabolism-promoting agent comprising a substance having an action of trapping / eliminating active oxygen such as a nitrone compound or a nitroso compound, or a mixture of one or more of these substances as a main component. 3. The nitrone compound is PBN (α-phenyl-Nt-butyl nitrone), DMPO (5,5-dimethylpyrroline N oxide), POBN (α-4-pyridyl 1-oxide-Nt-busyl nitrone). ), Or a mixture of one or more thereof, wherein the nitroso compound is tNB (t-nitrosobutane), BNB (t-butylnitrosobenzene), or a mixture of one or more thereof. The cerebral metabolism promoting / memory improving agent according to claim 1. 4. The nitrone compound is PBN (α-phenyl-Nt-butyl nitrone), DMPO (5,5-dimethylpyrroline N oxide), POBN (α-4-pyridyl 1-oxide-Nt-busyl nitrone). ), Or a mixture of one or more thereof, wherein the nitroso compound is tNB (t-nitrosobutane), BNB (t-butylnitrosobenzene), or one of these.
The neurotransmitter enhancer according to claim 2, which is a mixture of two or more species. 5. A method for promoting brain metabolism and improving memory by capturing / eliminating active oxygen. 6. A method for improving cerebral metabolism promotion and memory by capturing / eliminating active oxygen with any of a nitrone compound, a nitroso compound, or a mixture thereof.