JPH1143432A - Medicine for suppressing and treating ageing of brain - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a medicine for suppressing ageing of brain such as Alzheimer's disease by including a specific organogermanium compound as an active ingredient. SOLUTION: This medicine is obtained by including an organogermanium compound shown by the formula [R1 -R3 are each H, methyl, ethyl, etc.; X is OH, an O-lower alkyl, etc.], as an active ingredient. The medicine can be administered orally, parenterally, or locally. The medicine can be prepared, for example, in (A) tablet, powder, or capsule for oral administration, (B) injection for parenteral administration, or (C) lotion or ointment for topical application. The content of the organogermanium compound can be, for example, 5-500 mg per administration unit as needed. The dose of the compound can be, for example, 1-100 mg/kg.d or so depending on the condition and so on.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to an agent for inhibiting and treating brain aging, and more particularly, it comprises a specific organogermanium compound as an active ingredient and exhibits an excellent effect on brain aging such as Alzheimer's disease. The present invention relates to an agent for suppressing and treating brain aging.

[0002]

2. Description of the Related Art The average life expectancy of Japanese is over 75 years for both males and females, and as the elderly population increases, the number of elderly people with dementia is also increasing rapidly.
It was 60,000, but in 2000 it was 1.56 million, 2010
It is estimated that the number will reach 2.26 million a year, and the diagnosis and treatment of senile dementia, the care for the elderly with dementia, and the establishment of a medical supply system are important issues that must be addressed not only in the medical community but also in society. It has become.

[0003] Dementia is defined as an impairment of memory and intelligence that occurs in adults, and is essentially an impairment of information transmission due to degeneration and death of nerve cells. It is said that the causative diseases of dementia reach 70, but cerebrovascular dementia and Alzheimer's disease are more common in the elderly, and both account for 80 to 90% of senile dementia. For men, the former is 55
%, The latter 22%, and the former 35% and the latter 39 in women
%.

[0004] The cerebrovascular dementia is a condition caused by cerebral infarction occurring frequently in the elderly, that is, cerebrovascular dementia is secondary dementia that occurs through pathological aging of blood vessels. It has been.

On the other hand, Alzheimer's dementia is a degenerative degenerative disease associated with temporary aging of the brain. Of Alzheimer's dementia, the type that develops early under 65 is called Alzheimer's disease, and the type that develops later in life is called Alzheimer's dementia, but both have the same pathological characteristics. Therefore, the name Alzheimer's disease is widely used as a synonym for Alzheimer's disease.

The pathological features of Alzheimer's disease are senile plaques and Alzheimer's neurofibrillary tangles (hereinafter referred to as neurofibrillary tangles). The senile plaques are mainly due to extracellular deposition of β-amyloid protein. Is composed of the amyloid nucleus of β-amyloid protein and the degenerating neurites surrounding it.

[0007] The fact that late stage products of protein saccharification reaction (hereinafter referred to as AGE) are involved in amyloid deposition in the brain.
Vitek et al. First suggested (Proc. Natl. Acad. Sci. USA.,
91: 4766, 1994).
It has been reported that an immune reaction of an antibody against pentosidine, a type of GE or AGE whose structure has been elucidated, is observed not only in amyloid deposition sites but also in senile plaques and neurofibrillary tangles. From these results, it was pointed out that AGE may be involved not only in senile plaques but also in the formation of neurofibrillary tangles, and it was revealed that AGE is involved in the pathogenesis of Alzheimer's disease.

For Alzheimer's disease, cholinergic drugs, neurotransmission drugs, neuropeptide drugs, brain cell protective drugs, etc. have been developed, but no fundamental therapeutic drug is commercially available.

[0009]

SUMMARY OF THE INVENTION The present invention has been made to solve the above-mentioned drawbacks of the prior art, and to provide a drug capable of suppressing aging of the brain such as Alzheimer's disease and treating it. Made for purpose.

[0010]

Means for Solving the Problems In order to achieve the above object, the composition of the agent for inhibiting and treating brain aging adopted by the present invention comprises:
Equation (1)

Embedded image (Wherein, R _{1 to} R ₃ represent a hydrogen atom or a lower alkyl group such as a methyl group or an ethyl group or a substituted or unsubstituted phenyl group, and X represents a hydroxyl group, an O-lower alkyl group, an amino group, or OY. [Y is sodium,
A compound having a basic group such as a metal such as potassium or lysozyme or a basic amino acid] are shown as the active ingredients).

The structures that characterize Alzheimer's disease are senile plaques and neurofibrillary tangles. In particular, senile plaques are deposits of amyloid β protein, and are considered to indicate essential abnormalities of Alzheimer's disease. In addition, the presence of AGE in deposited amyloid has been immunohistologically demonstrated, and as a mechanism of the involvement of AGE in the pathogenesis of Alzheimer's disease, neuronal damage due to reactive oxygen species generated by AGE is considered. And cytotoxicity caused by various activated cytokines generated by AGE.

The inventors of the present invention have been studying the bioactive effects of organogermanium compounds for many years, and as a result, organogermanium compounds can effectively suppress or improve protein saccharification reactions, and The drug was found to be highly safe even for long-term administration, and a patent application has already been filed (Japanese Patent Application No. 4-91685).
No.), the inventors of the present invention further focused on the inhibitory effect of the organogermanium compound on the protein saccharification reaction. Discovered that it was significantly suppressed,
The present invention has been completed.

[0013]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail.

[0014] aging inhibitors and therapeutic agent for cerebral of the present invention, since a specific organogermanium compound as an active ingredient represented by the above formula (1), first will be described for this compound, which is to substituents R ₁ Germanium propionic acid in which a propionic acid derivative having R ₃ and an oxygen functional group OX is bonded to a germanium atom as a basic skeleton, wherein germanium atoms and oxygen atoms in the basic skeleton are bonded in a ratio of 2: 3. is there.

The above substituents R _{1 to} R ₃ are the same or different, and are each a hydrogen atom, a methyl group, an ethyl group,
A so-called lower alkyl group such as a propyl group and a butyl group; a substituted or unsubstituted phenyl group; and a substituent X represents a hydroxyl group, an O-lower alkyl group, an amino group or a salt of a carboxylic acid represented by OY. I have. still,
Y represents a metal such as sodium or potassium (however, it is not limited to a monovalent one), or a compound having basicity represented by a basic amino acid such as lysozyme or lysine.

The organogermanium compound having the above structure is a known compound and can be produced by various methods. One example is that the substituents R _{1 to} R ₃ are a hydrogen atom and the substituent X is As for the compound of a hydroxyl group, trihalogermylpropionic acid such as trichlorogermylpropionic acid may be hydrolyzed as shown in the following reaction formula.

Embedded image

The formula (1) representing the above-mentioned organogermanium compound corresponds to a state in which it is isolated as a crystal. In an aqueous solution, a germanium-oxygen bond undergoes hydrolysis, and for example, the substituents R _{1 to} In a compound in which R ₃ is a hydrogen atom and the substituent X is a hydroxyl group,

Embedded image It has been known that the organic germanium compound has the following structure. Further, the organic germanium compound can be represented by the following formula.

Embedded image

The agent for inhibiting and treating aging of the brain of the present invention contains the above-mentioned organogermanium compound as an active ingredient. The administration method is not particularly limited, and is orally, parenterally or topically. Can be administered in a controlled manner.

The dosage form is not particularly limited, and may be used in combination with known carriers and the like, if necessary, for oral administration such as tablets, powders or capsules, parenteral preparations such as injections, lotions and the like. Or it is formulated into a topical application such as ointment.

The content of the organogermanium compound in the agent for inhibiting and treating aging of the brain according to the present invention may be, if necessary, for example, about 5 to 500 mg / l dosage unit. For example, 1 to 100 mg /
It may be about Kg / day.

[0021] The effects of the therapeutic agent for inhibiting aging of the brain of the present invention have been confirmed through the following experiments.

That is, in an in vitro system in which glucose was added to human serum albumin or bovine serum albumin, the browning, the production of fluorescent substance and the production of pentosidine, which is one of the AGEs, which are characteristics of AGE, were described in Examples described later. Thus, the agent for inhibiting and treating aging of the brain of the present invention significantly inhibited.

In addition, longitudinal sections of the brains of ORET-F rats (Otsuka Long Evance Tokushima Fatty rats: spontaneously obese diabetic rats) and normal rats (LETO rats) bred up to 72 weeks of age were stained with Congo red. Was observed with a polarizing microscope, and the area showing birefringence glowing green was observed as amyloid (senile plaque). Senile plaques were observed in 11 out of 27 mice (40.7%) in the control group to which the brain aging inhibitory and therapeutic agent of the present invention was not administered. Only 3 out of 22 (13.6%) were found. In the normal control group, 0 (0%) of the 18 senile plaques were observed.

From the above results, the agent for suppressing and treating brain aging of the present invention significantly suppresses the development of senile plaques, which are highly correlated with the degree of dementia in brain aging such as Alzheimer's disease. It became clear.

[0025]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described in detail below with reference to embodiments, but this does not limit the present invention in any way.

Example 1 A brain aging inhibitory and therapeutic agent of the present invention (substituents R _{1 to} R ₃ were replaced with a hydrogen atom, substituted with 25 mM / ml human serum albumin or bovine serum albumin and 250 mM glucose). Group X is obtained by dissolving a compound having a hydroxyl group as an active ingredient (hereinafter the same in Examples)) so that the concentration of an organic germanium compound as an active ingredient becomes 50 mM, and culturing at 37 ° C. for 6 weeks; The fluorescence intensity (excitation wavelength 370 nm, fluorescence wavelength 440 nm) was measured. The results are shown in Table 1.

[0027]

[Table 1] As is clear from Table 1, the agent for suppressing and treating brain aging of the present invention significantly suppressed the production of fluorescent substances produced by the reaction between serum albumin and glucose.

Example 2 A brain aging inhibitory and therapeutic agent of the present invention was added to a reaction solution obtained by adding 250 mM glucose to 25 mg / ml human serum albumin so that the concentration of an organic germanium compound as an active ingredient became 50 mM. After lysing and culturing at 37 ° C. for 6 weeks, browning (dual wavelength: 4
15 nm / 610 nm) and compared with the absorbance. The results are shown in Table 2.

[0029]

[Table 2] As is clear from Table 2, the brain aging inhibitory and therapeutic agent of the present invention inhibited the browning of the reaction solution after the third week.

Example 3 A reaction solution obtained by adding 250 mM glucose to 25 mg / ml human serum albumin or bovine serum albumin was treated with the agent for suppressing and treating brain aging of the present invention, and the concentration of an organic germanium compound as an active ingredient was reduced to 50 mM. And cultured at 37 ° C. for 6 weeks. The culture solution is hydrolyzed with 6N hydrochloric acid, and the resulting pentosidine is subjected to high performance liquid chromatography (excitation wavelength 335 nm, fluorescence wavelength 385 nm).
Was measured. The results are shown in Table 3.

[0031]

[Table 3] As is clear from Table 3, the agent for suppressing and treating brain aging of the present invention completely inhibited the production of pentosidine.

Example 4 OLET-F rats and LETO rats were bred up to 72 weeks of age.
The brain aging inhibitory and therapeutic agent of the present invention was administered at a dose of 100 mg / kg (body weight) from 25 to 72 weeks of age. Longitudinal sections of the sacrificed rat brain were stained with Congolet and observed with a polarizing microscope, and the expression range of senile plaques was-, ±, +, +
+ And +++, and the expression frequency was expressed as the number of expressed animals / number of animals (%). The results are shown in Table 4.

[0033]

[Table 4] As is clear from Table 4, the number of rats in which senile plaques developed by administration of the brain aging inhibitor and the therapeutic agent of the present invention was significantly 13.6% as compared with 40.7% in the non-administration group. A decrease was observed, and the effects of the present invention on suppressing aging of the brain and remarkably suppressing the development of senile plaques by the therapeutic agent were shown.

Claims (3)

[Claims] (1) Formula (1) (Wherein, R _{1 to} R ₃ represent a hydrogen atom or a lower alkyl group such as a methyl group or an ethyl group or a substituted or unsubstituted phenyl group, and X represents a hydroxyl group, an O-lower alkyl group, an amino group, or OY. [Y is sodium,
A compound having a metal such as potassium or a compound having a basic group such as lysozyme or a basic amino acid] is used as an active ingredient. 2. The agent for suppressing and treating aging of the brain according to claim 1, wherein in formula (1), an organic germanium compound in which R _{1 to} R ₃ are a hydrogen atom and X is a hydroxyl group is an active ingredient. 3. An agent for suppressing and treating Alzheimer's disease, comprising the organic germanium compound represented by the formula (1) according to claim 1 as an active ingredient.