WO1999004786A1 - Inhibitor and therapeutic agent for brain aging - Google Patents
Inhibitor and therapeutic agent for brain aging Download PDFInfo
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- WO1999004786A1 WO1999004786A1 PCT/JP1998/003287 JP9803287W WO9904786A1 WO 1999004786 A1 WO1999004786 A1 WO 1999004786A1 JP 9803287 W JP9803287 W JP 9803287W WO 9904786 A1 WO9904786 A1 WO 9904786A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/28—Compounds containing heavy metals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
Definitions
- the present invention relates to an agent for inhibiting and treating brain aging, and more particularly, to an agent for inhibiting and treating brain aging, which comprises a specific organic germanium compound as an active ingredient and exhibits an excellent effect on brain aging such as Alzheimer's disease. It is about. Background art
- the average life expectancy of the Japanese is over 75 years for both males and females, and as the population of the elderly increases, the number of elderly with dementia is also increasing rapidly. As of 1995, the number of elderly with dementia was about 12.6 It is estimated that the number will reach 156,000 in 2000 and 226,000 in 2010, and the diagnosis and treatment of senile dementia and the elderly with dementia The establishment of a nursing care and medical supply system is an important issue that must be addressed not only in the medical community but also in society.
- Dementia is defined as an impairment of memory and intelligence that occurs in adults, the essence of which is impaired communication due to neuronal degeneration and death.
- the cause of dementia is said to be 70, but cerebrovascular dementia and Alzheimer's disease are more common in the elderly, with both accounting for 80-90% of senile dementia.
- the former is 55%
- the latter is 22%
- the former is 35% and the latter is 39% for women.
- the above-mentioned cerebrovascular dementia is a condition caused by cerebral infarction occurring frequently in the elderly, that is, cerebrovascular dementia is considered to be secondary dementia which occurs through pathological aging of blood vessels. ing.
- Alzheimer's disease is a degenerative disease associated with temporary aging of the brain.
- Alzheimer's type dementia the type that develops early under 65 years Alzheimer's disease, a type that develops later in life, is called Alzheimer's disease, but since both have the same pathological characteristics, the name Alzheimer's disease is widely used. Used as a synonym for Ruthheimer-type dementia.
- 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 / 3 amyloid protein.
- the structure consists of the amyloid nucleus of 3) amyloid protein and the degenerating neurites surrounding it.
- Vitek et al. (Proc. Natl. Acad. Sci. USA., 91: 4766, 1994) first suggested that the late stage product of the protein saccharification reaction (AGE) is involved in amyloid deposition in the brain. Since then, many researchers have reported that the immune response of antibodies to pentosidine, an AGE or a type of AGE whose structure has been elucidated, has been observed not only in amyloid deposition sites but also in senile plaques and neurofibrillary tangles Was done. These results point out that AGE may be involved not only in senile plaques but also in the formation of neurofibrillary tangles, indicating that AGE is involved in the pathogenesis of Alzheimer's disease.
- AGE protein saccharification reaction
- An object of the present invention is to solve the above-mentioned disadvantages of the prior art, and to provide an agent capable of suppressing aging of the brain such as Alzheimer's disease and treating it. Disclosure of the invention
- composition of the brain aging inhibitory and therapeutic agent employed by the present invention is represented by the following formula (1) (Ge-C-CH-COX) 2 0 3 (1) R 2
- R 1 to R 3 are a hydrogen atom, a lower alkyl group such as the same or different methyl group or ethyl group, or a substituted or unsubstituted phenyl group, and X is a hydroxyl group, an O-lower alkyl group, an amino group or OY.
- Y represents a compound having a metal such as sodium or potassium, or a compound having a basic group such as lysozyme or basic amino acid), respectively.
- the structures that characterize Alzheimer's disease are senile plaques and neurofibrillary tangles, and especially senile plaques are deposits of amyloid) 3 protein, which are thought to indicate essential abnormalities of Alzheimer's disease.
- AGEs in the deposited amyloid was immunohistologically proved, and as a mechanism of the involvement of AGEs in the pathogenesis of Alzheimer's disease, neuronal damage due to active oxygen generated by AGEs, Two types of cytotoxicity due to various activated cytokines generated by AGE have been proposed.
- the inventors of the present invention have been studying the bioactive effects of organic germanium compounds for many years, and as a result, organic germanium compounds can effectively suppress or improve protein saccharification reactions, and The drug was found to be highly safe during administration, and a patent application has already been filed (Japanese Patent Application No. 4-191685), but the inventors of the present invention have further investigated the use of organogermanium compounds. Further research focused on the inhibitory effect on protein saccharification reactions, and found that administration of a specific organic germanium significantly suppressed the development of senile plaques in the brain, and completed the present invention. That is what led to it. BEST MODE FOR CARRYING OUT THE INVENTION
- the agent for inhibiting and treating aging of the brain of the present invention contains a specific organic germanium compound represented by the above formula (1) as an active ingredient.
- R 3 may be the same or different and each represents a hydrogen atom, a so-called lower alkyl group such as a methyl group, an ethyl group, a propyl group, a butyl group, or a substituted or unsubstituted phenyl group.
- the group X represents a hydroxyl group, a 0-lower alkyl group, an amino group or a salt of a carboxylic acid represented by 0Y.
- Y represents a metal such as sodium or potassium (however, it is not limited to monovalent ones, 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.
- the substituents R i to R 3 are a hydrogen atom
- the substituent X is a hydroxyl group.
- trihalogermylpropionic acid such as trichlorogermylpropionic acid may be hydrolyzed as shown in the following reaction formula.
- the organic germanium compound can also be represented by the formula below.
- the agent for suppressing and treating aging of the brain of the present invention contains the above-mentioned organic germanium compound as an active ingredient, but the administration method is not particularly limited, and is orally, parenterally or It can be administered locally.
- the dosage form is also not particularly limited, and may be used in combination with a known carrier, if necessary, for oral administration such as tablets, powders or capsules, or non-oral preparations such as injections, lotions, or the like. It is formulated into a topical application such as ointment.
- the content of the organogermanium compound in the agent for suppressing and treating aging of the brain of the present invention may be, for example, about 5 to 50 mg / dosage unit as needed.
- the concentration may be about 1 to 10 O mg / K g / day.
- 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 has become.
- 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.
- the brain aging inhibitory and therapeutic agent of the present invention is dissolved in a reaction solution obtained by adding 250 mM glucose to 25 mg / m1 human serum albumin so that the concentration of the organic germanium compound as an active ingredient becomes 5 OmM. After culturing for 6 weeks at 37 ° C, the browning (two wavelengths: 415 nm Z 610 nm) was measured with a micro-mouthed plate reader and compared with the absorbance. The results are shown in Table 2.
- a reaction solution of 25 mg / m1 human serum albumin or pepsin serum albumin and 25 OmM glucose was added to the brain aging inhibitor and therapeutic agent of the present invention, and the concentration of an organic germanium compound as an active ingredient was 5 OmM.
- the cells were dissolved at 37 ° C. for 6 weeks.
- the culture was hydrolyzed with 6 N hydrochloric acid, and the resulting pentosidine was measured by high performance liquid chromatography (excitation wavelength 335 nm, emission wavelength 385 ⁇ m). Table 3 shows the results.
- OLET-F rats and LETO rats were bred up to 72 weeks of age, and lOOmgZkg (body weight) was administered from 25 weeks to 72 weeks of age of the brain aging inhibitory and therapeutic agent of the present invention.
- a longitudinal section of the sacrificed rat brain was stained with a congolet, observed with a polarizing microscope, and evaluated for the range of senile plaques on a scale of 1, 1, 10, 10, +, + + + +
- the expression frequency was represented by the number of expressed animals and the number of animals (%). The results are shown in Table 4. Table 4
- the brain aging inhibitory and therapeutic agent of the present invention containing the organogermanium compound represented by the formula (1) as an active ingredient has a high correlation with the degree of dementia in brain aging such as Alzheimer's disease. It can significantly suppress the development of senile plaques that have been confirmed to have sex.
Abstract
A medicament which can eliminate problems of the prior art and can inhibit and cure brain aging attributable to Alzheimer's disease and the like. It is characterized by containing as the active ingredient an organogermanium compound represented by general formula (1) wherein R1 to R3 represent each a hydrogen atom or may be the same or different and represent each a lower alkyl group such as a methyl or ethyl group, or a substituted or unsubstituted phenyl group; X represents a hydroxyl group, an O-lower alkyl group, an amino group, or a salt represented by OY wherein Y represents a metal such as sodium or potassium, or a compound having a basic group, such as lysozyme or basic amino acid.
Description
明 細 書 脳の老化抑制及び治療剤 技術分野 Description Brain aging inhibitor and therapeutic agent Technical field
本発明は脳の老化抑制及び治療剤に関するものであり、 更に詳しくは、 特定 の有機ゲルマニウム化合物を有効成分とし、 アルツハイマー病等の脳の老化に 対し優れた効果を示す脳の老化抑制及び治療剤に関するものである。 背景技術 The present invention relates to an agent for inhibiting and treating brain aging, and more particularly, to an agent for inhibiting and treating brain aging, which comprises a specific organic germanium compound as an active ingredient and exhibits an excellent effect on brain aging such as Alzheimer's disease. It is about. Background art
日本人の平均寿命は男女共に 7 5才を超え、 高齢者人口が増大すると共に痴 呆性老人も又、 急激に増加していて、 1 9 9 5年現在、 痴呆性老人は約 1 2 6 万人であるが、 2 0 0 0年には 1 5 6万人、 2 0 1 0年には 2 2 6万人に達す ると予測され、 老年期痴呆の診断と治療、 痴呆性老人への介護、 医療供給シス テムの確立は、 医学界のみならず、 社会的にも取り組まなければならない重要 課題となっている。 The average life expectancy of the Japanese is over 75 years for both males and females, and as the population of the elderly increases, the number of elderly with dementia is also increasing rapidly. As of 1995, the number of elderly with dementia was about 12.6 It is estimated that the number will reach 156,000 in 2000 and 226,000 in 2010, and the diagnosis and treatment of senile dementia and the elderly with dementia The establishment of a nursing care and medical supply system is an important issue that must be addressed not only in the medical community but also in society.
痴呆は、 成人に起こる記憶及び知能の障害と定義されるが、 その本質は神経 細胞の変性並びに死による情報伝達障害である。 痴呆の原因疾患は 7 0に及ぶ といわれているが、 高齢者に多いのは脳血管性痴呆とアルツハイマー病で、 両 者によって老年期痴呆の 8、 9割が占めらていて、 両者の比率は、 男性では前 者が 5 5 %、 後者が 2 2 %、 女性では前者が 3 5 %、 後者が 3 9 %である。 上記脳血管性痴呆は、 老年者に高発する脳梗塞に起因して起こる状態で、 即 ち、 脳血管性痴呆は血管の病的な老化を介して起こる、 二次的な痴呆であると されている。 Dementia is defined as an impairment of memory and intelligence that occurs in adults, the essence of which is impaired communication due to neuronal degeneration and death. The cause of dementia is said to be 70, but cerebrovascular dementia and Alzheimer's disease are more common in the elderly, with both accounting for 80-90% of senile dementia. For men, the former is 55%, the latter is 22%, and the former is 35% and the latter is 39% for women. The above-mentioned cerebrovascular dementia is a condition caused by cerebral infarction occurring frequently in the elderly, that is, cerebrovascular dementia is considered to be secondary dementia which occurs through pathological aging of blood vessels. ing.
これに対しアルツハイマー型痴呆は、 脳の一時的老化と関係する退行変性疾 患である。 アルツハイマー型痴呆の内、 6 5才未満の早期に発症するタイプが
ァルツハイマー病、 それ以降の老年期に発症するタイプがァルツハイマー型痴 呆と呼ばれているが、 両者は病理学的には同じ特徴を有することから、 ァルツ ハイマ一病という名称が、 広くァルツハイマー型痴呆の同義語として用いられ ている。 Alzheimer's disease, on the other hand, is a degenerative disease associated with temporary aging of the brain. Of the Alzheimer's type dementia, the type that develops early under 65 years Alzheimer's disease, a type that develops later in life, is called Alzheimer's disease, but since both have the same pathological characteristics, the name Alzheimer's disease is widely used. Used as a synonym for Ruthheimer-type dementia.
アルツハイマー病における病理学的特徴は、 老人斑とアルツハイマー神経原 線維変化 （以下、 神経原線維変化という） であり、 老人斑は主として /3アミ口 イド蛋白の細胞外沈着によるもので、 典型老人斑の構造は、 ）3アミロイド蛋白 のアミロイド核とそれを取り囲む変性神経突起からできている。 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 / 3 amyloid protein. The structure consists of the amyloid nucleus of 3) amyloid protein and the degenerating neurites surrounding it.
脳のアミロイド沈着に蛋白糖化反応後期段階生成物 （以下、 A G Eという） が関与していることを Vitekらが最初に示唆（Proc. Natl. Acad. Sci. USA., 91: 4766, 1994) して以来、 多くの研究者らによって A G Eや A G Eの一種でその 構造が明らかにされているペントシジンに対する抗体の免疫反応がアミロイド 沈着部位のみならず、老人斑や神経原線維変化に認められることが報告された。 これらの結果から A G Eが老人斑だけでなく神経原線維変化の形成にも関与し ている可能性が指摘され、 A G Eがアルツハイマー病の病体形成に関与してい ることが明らかにされた。 Vitek et al. (Proc. Natl. Acad. Sci. USA., 91: 4766, 1994) first suggested that the late stage product of the protein saccharification reaction (AGE) is involved in amyloid deposition in the brain. Since then, many researchers have reported that the immune response of antibodies to pentosidine, an AGE or a type of AGE whose structure has been elucidated, has been observed not only in amyloid deposition sites but also in senile plaques and neurofibrillary tangles Was done. These results point out that AGE may be involved not only in senile plaques but also in the formation of neurofibrillary tangles, indicating that AGE is involved in the pathogenesis of Alzheimer's disease.
アルツハイマー病に対しては、 コリン作動薬、 神経伝達改善薬、 神経べプチ ド系薬、 脳細胞保護薬等が開発されているが、 根本的な治療薬は市販されてい ない。 For Alzheimer's disease, cholinergic drugs, neurotransmitters, neuropeptides, brain cell protective drugs, etc. have been developed, but no fundamental therapeutic drugs are available on the market.
本発明は、 上記のような従来技術の難点を解消し、 アルツハイマー病等の脳 の老化を抑制し、 且つ、 治療をすることのできる薬剤を提供することを目的と してなされた。 発明の開示 An object of the present invention is to solve the above-mentioned disadvantages of the prior art, and to provide an agent capable of suppressing aging of the brain such as Alzheimer's disease and treating it. Disclosure of the invention
上記目的を達成するために本発明が採用した脳の老化抑制及び治療剤の構成 は、 式 （1 )
( Ge-C-CH-COX ) 203 ( 1 ) R2 To achieve the above object, the composition of the brain aging inhibitory and therapeutic agent employed by the present invention is represented by the following formula (1) (Ge-C-CH-COX) 2 0 3 (1) R 2
(式中、 乃至 R 3は水素原子又は同一或いは異なるメチル基、 ェチル基等の 低級アルキル基又は置換若しくは無置換のフエニル基を、 Xは水酸基、 O—低 級アルキル基、 アミノ基又は O Yで表される塩 [Yはナトリウム、 カリウム等 の金属又はリゾチーム、 塩基性ァミノ酸等の塩基性基を有する化合物を示す] をそれぞれ示す） で表される有機ゲルマニウム化合物を有効成分とすることを 特徴とするものである。 (Wherein, R 1 to R 3 are a hydrogen atom, a lower alkyl group such as the same or different methyl group or ethyl group, or a substituted or unsubstituted phenyl group, and X is a hydroxyl group, an O-lower alkyl group, an amino group or OY. (Y represents a compound having a metal such as sodium or potassium, or a compound having a basic group such as lysozyme or basic amino acid), respectively.) It is assumed that.
而して、 アルツハイマー病を特徴づける構造物は、 老人斑と神経原線維変化 であるが、 特に老人斑は、 アミロイド ) 3蛋白沈着物であり、 アルツハイマー病 の本質的異常を示すと考えられていて、 更に沈着アミロイドに A G Eが存在し ていることが免疫組織学的に証明され、 A G Eのアルツハイマー病の病態形成 への関与の機序として、 A G Eにより生成された活性酸素による神経細胞障害 と、 A G Eにより生成された活性化した各種サイトカインによる細胞障害の二 つが提唱されている。 Thus, the structures that characterize Alzheimer's disease are senile plaques and neurofibrillary tangles, and especially senile plaques are deposits of amyloid) 3 protein, which are thought to indicate essential abnormalities of Alzheimer's disease. Furthermore, the presence of AGEs in the deposited amyloid was immunohistologically proved, and as a mechanism of the involvement of AGEs in the pathogenesis of Alzheimer's disease, neuronal damage due to active oxygen generated by AGEs, Two types of cytotoxicity due to various activated cytokines generated by AGE have been proposed.
本発明の発明者らは、 多年にわたり有機ゲルマニウム化合物の生理活性作用 について研究を行っており、 その結果、 有機ゲルマニウム化合物は効果的に蛋 白糖化反応を抑制或いは改善することができ、 しかも長期間投与に際しても安 全性の高い薬剤であることを発見し、 すでに特許出願をしている （特願平 4一 9 1 6 8 5号） が、 本発明の発明者らは更に有機ゲルマニウム化合物の有する 蛋白糖化反応阻害作用に着目して更に研究を進めたところ、 特定の有機ゲルマ 二ゥムを投与することが、 脳の老人斑の発症を顕著に抑制することを発見し、 本発明を完成させるに至ったものである。
発明を実施するための最良の形態 The inventors of the present invention have been studying the bioactive effects of organic germanium compounds for many years, and as a result, organic germanium compounds can effectively suppress or improve protein saccharification reactions, and The drug was found to be highly safe during administration, and a patent application has already been filed (Japanese Patent Application No. 4-191685), but the inventors of the present invention have further investigated the use of organogermanium compounds. Further research focused on the inhibitory effect on protein saccharification reactions, and found that administration of a specific organic germanium significantly suppressed the development of senile plaques in the brain, and completed the present invention. That is what led to it. BEST MODE FOR CARRYING OUT THE INVENTION
以下に本発明を詳細に説明する。 Hereinafter, the present invention will be described in detail.
本発明の脳の老化抑制及び治療剤は、 上記の式 （1 ) で表わされる特定の有 機ゲルマニウム化合物を有効成分としているので、 まずこの化合物について説 明すると、 これは置換基 R！乃至 R 3と酸素官能基 0 Xとを有するプロピオン酸 誘導体とゲルマニウム原子とが結合したゲルミルプロピオン酸を基本骨格とし、 当該基本骨格におけるゲルマニウム原子と酸素原子とが 2 ： 3の割合で結合し たものである。 The agent for inhibiting and treating aging of the brain of the present invention contains a specific organic germanium compound represented by the above formula (1) as an active ingredient. First, this compound will be described. Or a germanyl atom in which a propionic acid derivative having R 3 and an oxygen functional group 0 X is bonded to a germanium atom as a basic skeleton, and a germanium atom and an oxygen atom in the basic skeleton are bonded in a ratio of 2: 3. It is a thing.
上記置換基 乃至 R 3は、 同一或いは異なっており、 それぞれ水素原子や、 メチル基， ェチル基， プロピル基， ブチル基等のいわゆる低級アルキル基、 置 換され若しくは置換されていないフエニル基を、 置換基 Xは水酸基， 0—低級 アルキル基， ァミノ基又は 0 Yで表わされるカルボン酸の塩をそれぞれ示して いる。 尚、 Yはナトリウム、 カリウム等の金属 （但し、 一価のものに限られな レ 、 又は、 リゾチーム、 或いはリジン等の塩基性アミノ酸に代表される塩基 性を有する化合物を示している。 The above substituents to R 3 may be the same or different and each represents a hydrogen atom, a so-called lower alkyl group such as a methyl group, an ethyl group, a propyl group, a butyl group, or a substituted or unsubstituted phenyl group. The group X represents a hydroxyl group, a 0-lower alkyl group, an amino group or a salt of a carboxylic acid represented by 0Y. Y represents a metal such as sodium or potassium (however, it is not limited to monovalent ones, or a compound having basicity represented by a basic amino acid such as lysozyme or lysine).
而して、 上記構造の有機ゲルマニウム化合物はすでに公知の化合物であり、 様々な方法により製造することができるが、 その一例を置換基 R i乃至 R 3が水 素原子、 置換基 Xは水酸基の化合物について示せば、 下記反応式に示すように、 トリクロルゲルミルプロピオン酸等のトリハロゲルミルプロピオン酸を加水分 解すれば良いのである。 Thus, 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 i to R 3 are a hydrogen atom, and the substituent X is a hydroxyl group. As for the compounds, trihalogermylpropionic acid such as trichlorogermylpropionic acid may be hydrolyzed as shown in the following reaction formula.
E O E O
Cl3Ge-CH2-CH2-COOH ► ( 1 ) 尚、 上記有機ゲルマニウム化合物を表わす式 （1 ) は、 それを結晶として単 離した状態に相当するもので、 水溶液中ではゲルマニウム一酸素結合が加水分 解を受け、 例えば置換基 1^乃至 R 3が水素原子、 置換基 Xは水酸基の化合物で
は、 Cl 3 Ge—CH 2 —CH 2 —COOH ► (1) The above-mentioned formula (1) representing the organogermanium compound corresponds to a state in which it is isolated as a crystal. Is hydrolyzed, for example, the substituents 1 ^ to R 3 are hydrogen atoms, and the substituent X is a hydroxyl compound. Is
OH OH
II
HO - Ge - CH2—CH2-COOH OH なる構造をとることがわかっており、 更に、 上記有機ゲルマニウム化合物は以 下の式で表すこともできる。 HO - Ge - CH 2 has been found to take -CH 2 -COOH OH composed structure, further, the organic germanium compound can also be represented by the formula below.
剤形についても特に制限を受けることはなく、 必要に応じ公知の担体等を併 用して、 錠剤、 散剤或いはカプセル剤等の経口投与剤、 又は、 注射剤等の非経 口剤、 ローション又は軟膏等の局所適用剤に製剤されるものである。 The dosage form is also not particularly limited, and may be used in combination with a known carrier, if necessary, for oral administration such as tablets, powders or capsules, or non-oral preparations such as injections, lotions, or the like. It is formulated into a topical application such as ointment.
又、 本発明の脳の老化抑制及び治療剤における有機ゲルマニウム化合物の含 有量は必要に応じ、 例えば 5〜5 0 O m g / 1投与単位程度とすればよく、 投 与量としては、 症状等に応じ、 例えば 1〜 1 0 O m g /K g /日程度とすれば よい。 In addition, the content of the organogermanium compound in the agent for suppressing and treating aging of the brain of the present invention may be, for example, about 5 to 50 mg / dosage unit as needed. For example, the concentration may be about 1 to 10 O mg / K g / day.
而して、 本発明の脳の老化抑制及び治療剤の効果は、 以下のような実験を通 して確認されたものである。 Thus, the effects of the therapeutic agent for inhibiting and treating brain aging of the present invention have been confirmed through the following experiments.
即ち、 ヒト血清アルブミン又はゥシ血清アルブミンにグルコースを添加した in vitroの系において、 A G Eの特徴である褐変化、 蛍光物質産生並びに A G
Eの一つであるペントシジンの産生を、 後述する実施例のように、 本発明の脳 の老化抑制及び治療剤は有意に阻害したのである。 That is, in an in vitro system in which glucose was added to human serum albumin or pepsin serum albumin, browning characteristic of AGE, fluorescent substance production, and AG The production of pentosidine, one of E, was significantly inhibited by the brain aging inhibitory and therapeutic agent of the present invention, as described in Examples below.
又、 7 2週令まで飼育した OLET-Fラット（Otsuka Long EvanceTokushima Fatty rat：自然発症肥満糖尿病ラット） 並びに正常ラット （LE Oラット） の 脳の縦断面標本をコンゴレッドで染色し、 これを偏光顕微鏡で観察して、 緑色 に輝く複屈析を示す部分をアミロイド （老人斑） として観察したところ、 老齢 OLET-F ラットの脳の縦断面標本で、 中脳〜延髄部の神経線維中に老人斑が、 本発明の脳の老化抑制及び治療剤非投与対照群では 2 7匹中 1 1匹 （4 0 . 7 %) に認められたが、 本発明の脳の老化抑制及び治療剤投与群では 2 2匹中 3匹 （1 3 . 6 %) にのみ認められた。 尚、 正常対照群では 1 8匹中老人斑が 観察されたのは 0匹 （0 %) であった。 In addition, longitudinal sections of the brains of OLET-F rats (Otsuka Long Evance Tokushima Fatty rats: spontaneously obese diabetic rats) and normal rats (LE O rats) reared up to 72 weeks of age were stained with Congo red and polarized. When observed under a microscope, the area showing birefringence, which glows green, was observed as amyloid (senile plaque). A longitudinal section of the brain of an aged OLET-F rat showed a neuron in the midbrain to medullary nerve fibers. Plaques were observed in 11 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, but the brain aging inhibitory and therapeutic agent of the present invention group Was found only in 3 out of 2 animals (13.6%). In the normal control group, 0 (0%) of the 18 senile plaques were observed.
以上の結果から、 本発明の脳の老化抑制及び治療剤は、 アルツハイマー病等 の脳の老化において痴呆の程度と高い相関性が認められている老人斑の発現を、 顕著に抑制することが明らかになつたのである。 From the above results, it is clear that 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 has become.
以下に本発明を実施例に基づいて詳細に説明するが、 これは本発明をなんら 制限するものではない。 Hereinafter, the present invention will be described in detail with reference to Examples, but this does not limit the present invention in any way.
実施例 1 Example 1
2 5 m g /m 1のヒト血清アルブミン又はゥシ血清アルブミンに 2 5 O mM グルコースを添加した反応液に、 本発明の脳の老化抑制及び治療剤（置換基 1^ 乃至 R 3が水素原子、 置換基 Xは水酸基の化合物を有効成分とするもの [以下、 実施例において同じ] ) を、 有効成分である有機ゲルマニウム化合物の濃度が 5 O mMとなるように溶解し、 6週間、 3 7 で培養し、 蛍光強度 （励起波長 3 7 0 n m、 蛍光波長 4 4 0 n m) を測定した。 結果を表 1に示した。
表 1 2 5 mg / m to the reaction solution was added 2 5 O mM glucose 1 of human serum albumin or © shea serum albumin, aging inhibitors and therapeutic agent for cerebral of the present invention (substituent 1 ^ to R 3 are hydrogen atoms, Substituent 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 the organic germanium compound as an active ingredient is 5 OmM, and then is dissolved for 6 weeks at 37. After culturing, the fluorescence intensity (excitation wavelength: 370 nm, fluorescence wavelength: 450 nm) was measured. The results are shown in Table 1. table 1
実施例 2 Example 2
25mg/m 1のヒト血清アルブミンに 250 mMグルコースを添加した反 応液に、 本発明の脳の老化抑制及び治療剤を、 有効成分である有機ゲルマニウ ム化合物の濃度が 5 OmMとなるように溶解し、 6週間、 37°Cで培養し、 マ イク口プレートリーダーで褐変化 （二波長： 415 nmZ 610 nm) を測定 し、 吸光度をもって比較検討した。 結果を表 2に示した。 The brain aging inhibitory and therapeutic agent of the present invention is dissolved in a reaction solution obtained by adding 250 mM glucose to 25 mg / m1 human serum albumin so that the concentration of the organic germanium compound as an active ingredient becomes 5 OmM. After culturing for 6 weeks at 37 ° C, the browning (two wavelengths: 415 nm Z 610 nm) was measured with a micro-mouthed plate reader and compared with the absorbance. The results are shown in Table 2.
表 2 Table 2
実施例 3 Example 3
25mg/m 1のヒト血清アルブミン又はゥシ血清アルブミンに 25 OmM グルコースを添加した反応液に、 本発明の脳の老化抑制及び治療剤を、 有効成 分である有機ゲルマニウム化合物の濃度が 5 OmMとなるように溶解し、 3 7°C、 6週間培養した。 培養液は 6 N塩酸で加水分解し、 生成したペントシジ ンを高速液体クロマトグラフィー法 （励起波長 335 nm、 蛍光波長 385 η m) で測定した。 結果を表 3に示した。 A reaction solution of 25 mg / m1 human serum albumin or pepsin serum albumin and 25 OmM glucose was added to the brain aging inhibitor and therapeutic agent of the present invention, and the concentration of an organic germanium compound as an active ingredient was 5 OmM. The cells were dissolved at 37 ° C. for 6 weeks. The culture was hydrolyzed with 6 N hydrochloric acid, and the resulting pentosidine was measured by high performance liquid chromatography (excitation wavelength 335 nm, emission wavelength 385 ηm). Table 3 shows the results.
表 3 Table 3
の産生を完全に抑制した。 Was completely suppressed.
実施例 4 Example 4
OLET-Fラット並びに LETOラットを 72週令まで飼育し、 本発明の脳の老 化抑制及び治療剤を 25週令から 72週令まで、 l O OmgZkg (体重） 投 与した。 屠殺したラット脳の縦断面標本をコンゴ一レットで染色し、 偏光顕微 鏡で観察し、 老人斑の発現範囲を一、 土、 十、 +十、 + + +の 5段階で評価す ると共に、 発現頻度を発現動物数ノ動物数 （％) で表示した。 結果を表 4に示 した。
表 4 OLET-F rats and LETO rats were bred up to 72 weeks of age, and lOOmgZkg (body weight) was administered from 25 weeks to 72 weeks of age of the brain aging inhibitory and therapeutic agent of the present invention. A longitudinal section of the sacrificed rat brain was stained with a congolet, observed with a polarizing microscope, and evaluated for the range of senile plaques on a scale of 1, 1, 10, 10, +, + + + The expression frequency was represented by the number of expressed animals and the number of animals (%). The results are shown in Table 4. Table 4
以上のように、 前記式 （1 ) で表される有機ゲルマニウム化合物を有効成分 とする本発明の脳の老化抑制及び治療剤は、 アルツハイマー病等の脳の老化に おいて痴呆の程度と高い相関性が認められている老人斑の発現を、 顕著に抑制 することができるものである。
As described above, the brain aging inhibitory and therapeutic agent of the present invention containing the organogermanium compound represented by the formula (1) as an active ingredient has a high correlation with the degree of dementia in brain aging such as Alzheimer's disease. It can significantly suppress the development of senile plaques that have been confirmed to have sex.
Claims
1. 式 （1)
1. Equation (1)
R2 (式中、 乃至 R3は水素原子又は同一或いは異なるメチル基、 ェチル基等の 低級アルキル基又は置換若しくは無置換のフエニル基を、 Xは水酸基、 o—低 級アルキル基、 アミノ基又は OYで表される塩 [Υはナトリウム、 カリウム等 の金属又はリゾチーム、 塩基性アミノ酸等の塩基性基を有する化合物を示す] をそれぞれ示す） で表される有機ゲルマニウム化合物を有効成分とすることを 特徴とする脳の老化抑制及び治療剤。 R 2 (wherein, R 3 to R 3 represent a hydrogen atom or a lower alkyl group such as the same or different methyl group or ethyl group or a substituted or unsubstituted phenyl group; X represents a hydroxyl group, an o-lower alkyl group, an amino group or An organic germanium compound represented by a salt represented by OY (indicating a metal such as sodium or potassium or a compound having a basic group such as lysozyme or a basic amino acid) is used as an active ingredient. A characteristic agent for inhibiting and treating brain aging.
2. 式 （1) において、 1^乃至1^3が水素原子、 Xが水酸基である有機ゲル マニウム化合物を有効成分とする請求項 1に記載の脳の老化抑制及び治療剤。2. The agent for suppressing and treating brain aging according to claim 1, wherein in formula (1), an organic germanium compound in which 1 ^ to 1 ^ 3 is a hydrogen atom and X is a hydroxyl group is an active ingredient.
3. 請求項 1に記載の式 （1) で表される有機ゲルマニウム化合物を有効成 分とするアルツハイマー病の抑制及び治療剤。
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.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP9/215618 | 1997-07-25 | ||
| JP9215618A JPH1143432A (en) | 1997-07-25 | 1997-07-25 | Medicine for suppressing and treating ageing of brain |
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| PCT/JP1998/003287 WO1999004786A1 (en) | 1997-07-25 | 1998-07-23 | Inhibitor and therapeutic agent for brain aging |
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| WO (1) | WO1999004786A1 (en) |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5352815A (en) * | 1992-03-16 | 1994-10-04 | Asai Germanium Research Institute Co., Ltd. | Agent for suppression and interception of mailard reaction |
| WO1995028151A1 (en) * | 1994-04-13 | 1995-10-26 | Quadrant Holdings Cambridge Limited | Use of maillard reaction inhibitors for the treatment of amyloidosis-based disease |
-
1997
- 1997-07-25 JP JP9215618A patent/JPH1143432A/en active Pending
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1998
- 1998-07-23 WO PCT/JP1998/003287 patent/WO1999004786A1/en active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5352815A (en) * | 1992-03-16 | 1994-10-04 | Asai Germanium Research Institute Co., Ltd. | Agent for suppression and interception of mailard reaction |
| WO1995028151A1 (en) * | 1994-04-13 | 1995-10-26 | Quadrant Holdings Cambridge Limited | Use of maillard reaction inhibitors for the treatment of amyloidosis-based disease |
Non-Patent Citations (1)
| Title |
|---|
| HARRINGTON C. R., ET AL.: "INHIBITORS OF THE MAILLARD REACTION. POTENTIAL IN THE TREATMENT OF ALZHEIMER'S DISEASE.", CNS DRUGS, ADIS INTERNATIONAL, AUCKLAND, NZ, vol. 06., no. 03., 1 January 1996 (1996-01-01), AUCKLAND, NZ, pages 167 - 177., XP002912935, ISSN: 1172-7047 * |
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