【発明の詳細な説明】［産業上の利用分野］本発明は、酸性フィブロブラスト成長因子（ａＦＧＦ）
若しくはその関連物質又は酸性フィブロブラスト成長因
子分泌活性を有するグルコースおよび（または）Ｌ−ア
ルギニン、Ｌ−ロイシン、Ｌ−インロイシン及びＬ−バ
リンがら選ばれる少なくとも１種のアミノ酸を有効成分
として含有する副作用のない抗痴呆薬に関する。[Detailed Description of the Invention] [Industrial Application Field] The present invention provides acid fibroblast growth factor (aFGF)
or a related substance thereof, or a side effect containing as an active ingredient at least one amino acid selected from glucose and/or L-arginine, L-leucine, L-inleucine, and L-valine having acidic fibroblast growth factor secretion activity. Regarding anti-dementia drugs without.
［従来の技術］わが国における人口の高齢化は急速に進行している。６
５歳以上の老年者の人口は、現在総人口の約■０，５％
であるが、２１世世紀類には約１６％にまで増加すると
予測されている。それに伴って、老年期痴呆患者も急増
し、２１世世紀類には現在の約２倍の百数十万人を越え
るものと思われる。その患者数の多さ、また家庭や医療
機関、国家の経済に対する負担の大きさからみても、痴
呆の治療は、癌やＡＩＤＳのそれと並んで、医学の最も
重要な課題である。[Background Art] The aging of the population in Japan is progressing rapidly. 6
The population of elderly people aged 5 and over is currently approximately 0.5% of the total population.
However, it is predicted to increase to approximately 16% by the 21st century. Along with this, the number of senile dementia patients is rapidly increasing, and is expected to exceed 100,000, twice the current number, by the 21st century. Considering the large number of patients and the heavy burden it places on families, medical institutions, and the national economy, the treatment of dementia is one of the most important challenges in medicine, along with those of cancer and AIDS.
現在、わが国においては、痴呆をきたす疾患の中で最も
多いのは脳血管性痴呆である。脳血管性痴呆は、ひとた
び痴呆が完成したあとでは治療は困難である。しかし、
脳血管性痴呆は主として脳梗塞、ＣＯ中毒、心不全や事
故等による大量失血に伴う脳虚血および低血糖症や強い
持続的ａ１１発作に伴う脳内エネルギー代謝の乱れによ
って生じるものであり、その危険因子を管理することに
より予防ノテきる痴呆（ｐｒｅｖｅｎｔａｂｌｅ ｄｅ
ｍｅｎｔｉａｌであるといえる。痴呆発症の防止は言う
までもなく脳虚血や脳内グルコース低下による脳内神経
細胞壊死の抑止および生存神経細胞の可塑性による神経
回路網の再構築にある。Currently, in Japan, cerebrovascular dementia is the most common disease that causes dementia. It is difficult to treat cerebrovascular dementia once the dementia is complete. but,
Cerebrovascular dementia is mainly caused by cerebral infarction, CO poisoning, cerebral ischemia and hypoglycemia associated with massive blood loss due to heart failure, accidents, etc., and disturbances in energy metabolism in the brain associated with strong and persistent A11 attacks, and the risks associated with this disease are high. Dementia can be prevented by managing factors.
It can be said that it is mental. Needless to say, prevention of the onset of dementia lies in suppressing neuronal necrosis in the brain due to cerebral ischemia and low intracerebral glucose, and in rebuilding neural networks through the plasticity of surviving neurons.
脳は体重の約２％の臓器だが、安静時の全心拍出量の１
５％、全酸素消費量の２０％は脳に用いられる。脳のエ
ネルギー代謝のほとんどすべてが血中グルコースの好気
的酸化によっていて、全グルコース消費量の２５％は脳
によって消費される。しかし、脳のさかんなエネルギー
代謝を支える酸素、グルコースの脳内備蓄はほとんどな
く、供給が止まると数十秒のうちにエネルギー代謝のみ
ならず、脳の機能も停止する。さらに供給が途絶した状
態が持続すれば、不可逆的な細胞傷害が発生する。The brain is an organ that accounts for approximately 2% of body weight, but accounts for 1% of total cardiac output at rest.
5% and 20% of total oxygen consumption is used by the brain. Almost all of the brain's energy metabolism is through aerobic oxidation of blood glucose, with 25% of total glucose consumption being consumed by the brain. However, there are almost no reserves of oxygen and glucose in the brain, which support the brain's active energy metabolism, and if the supply stops, not only energy metabolism but also brain function will stop within a few tens of seconds. Furthermore, if the supply continues to be disrupted, irreversible cell damage will occur.
即ち、脳はエネルギー代謝の障害に特に脆弱な臓器であ
る。代表的な病態は脳虚血（脳無酸素症）、低血糖症お
よびエネルギー消費が異常に亢進する強いけいれん発作
状態である。これらはいずれも神経細胞傷害を起こし、
その分布のパクーンおよび組織像が相互に類似している
。この神経細胞の壊死はエネルギー代謝を含めたさまざ
まな代謝障害に伴って過剰に放出されるＬ−グルタミン
酸、Ｌ−アスパラギン酸などの興奮性神経伝達物質によ
ってもたらされる現象であると考えられ、これら神経伝
達物質の拮抗阻害剤が開発されているが、発作時の脳障
害の抑制は不充分であり痴呆を含めた脳機能障害は防止
出来ない。That is, the brain is an organ that is particularly vulnerable to disturbances in energy metabolism. Typical pathological conditions include cerebral ischemia (cerebral anoxia), hypoglycemia, and a severe seizure state in which energy consumption is abnormally increased. All of these cause nerve cell damage,
Their distribution pattern and histology are similar to each other. This necrosis of nerve cells is thought to be a phenomenon caused by excitatory neurotransmitters such as L-glutamic acid and L-aspartic acid that are released in excess due to various metabolic disorders including energy metabolism. Competitive inhibitors of transmitters have been developed, but they are insufficient to suppress brain damage during seizures, and brain dysfunction including dementia cannot be prevented.
脳虚血による障害の中心は神経細胞壊死であり、海馬の
ＣＡｌｆｌ域、小脳ＰＩＩｒｋｉｎｊｅ細胞、線条体外
側部、大脳皮質３．５．６層などに生じやすく、選択的
脆弱性がある（ＩＦｉｒｉａｏ、 Ｔ、 ＋ Ｂｒａ
ｉｎ Ｒｅｓ、、 ２３９５７ Ｆ１９Ｂ２）等）。The main cause of damage caused by cerebral ischemia is neuronal necrosis, which tends to occur in the CAfl area of the hippocampus, the cerebellar PIIrkinje cells, the lateral part of the striatum, and layers 3, 5, and 6 of the cerebral cortex, and is selectively vulnerable (IFiriao). , T, + Bra
in Res, 23957 F19B2) etc.).
特に、海馬は歯状図、海馬ＣＡ３、海馬ＣＡＬよりなり
、記憶や情報認知の重要な場として考えられている。In particular, the hippocampus consists of the dentate, hippocampal CA3, and hippocampal CAL, and is considered to be an important site for memory and information recognition.
短時間の脳虚血の後に血流を再開すると、海鳥も含め脳
内の栄養生理的恒常性も回復し、エネルギー代謝も正常
化するとともに、脳虚血により情夫した錐体細胞の活動
電位も回復する（ＭｏｎａｇｈａｎＤ、 Ｈ，、ｅｆ
！ｌ ： Ｎａｔｕｒｅ、 ３０６．１７６ ｆ１９
８３））。When blood flow is resumed after a short period of cerebral ischemia, nutritional and physiological homeostasis in the brain is restored, including in seabirds, energy metabolism is normalized, and the action potentials of pyramidal neurons affected by cerebral ischemia are also reduced. Recover (Monaghan D, H,, ef
! l: Nature, 306.176 f19
83)).
しかし、脳虚血から３〜４日後には島馬ＣＡＬ領域に人
力する軸索やダリア細胞にはなんら障害を生じないにも
かかわらず、錐体細胞は壊死する（Ｐｅｌｉｌｏ、 ｃ
、 Ｋ、、 ｅｔ ！ｌ ｌ Ｎｅｕ＋ｏｌｏｇ７
．３７．１２８１（１９Ｂ？））。これは、脳虚血によ
り興奮性アミノ酸のグルタミン酸が大量に放出され、か
つ細胞外からの取込みが低下することにより、細胞外濃
度の著しい上昇が起こり、ついで神経細胞の異常な興奮
と細胞外からのＣａ２＋の細胞内流入が生じるとともに
、神経細胞内の蛋白質や脂質の分解が進行し、最終的に
ミトコンドリアの障害を生じて壊死に至ると考えられテ
ィるｆＢｅｎｖｅａｉＮ！Ｈｅｔ ＪＪ、 Ｎｅｕｒ
ｏｃｈｅｍ、、４３．１３６９（１９８４）、Ｄｕｃｅ
１． Ｒｅｌ ！ｌ ： ［ｔ＋ａｉｎ Ｒｅｓ、
、 ２６３．７Ｎ１９８３））。However, 3 to 4 days after cerebral ischemia, pyramidal cells become necrotic, although there is no damage to the axons and dahlia cells that feed into the insular CAL region (Pelilo, c.
, K,, etc! l l Neu+olog7
．． 37.1281 (19B?)). This is because a large amount of the excitatory amino acid glutamate is released due to cerebral ischemia, and its uptake from the outside of the cell is reduced, resulting in a significant increase in the extracellular concentration, which then causes abnormal excitation of neurons and the release of glutamate from the outside of the cell. In addition to the influx of Ca2+ into cells, the decomposition of proteins and lipids within nerve cells progresses, which is thought to eventually cause mitochondrial damage and lead to necrosis. Het JJ, Neur
ochem, 43.1369 (1984), Duce
1. Rel! l: [t+ain Res,
, 263.7N1983)).
［発明が解決しようとする課題］本発明の課題は、−時的または継続的な脳虚血による脳
内グルタミン酸の著しい上昇が生じた際に脳のグルタミ
ン酸に対する耐性を高め、延いては神経細胞壊死を抑止
し、生存神経細胞の可塑性による神経回路網の再構築に
より脳障害の治療をすることができる副作用のない治療
薬を提供することにある。[Problems to be Solved by the Invention] An object of the present invention is to: - Increase the tolerance of the brain to glutamate when a significant increase in intracerebral glutamate occurs due to temporal or continuous cerebral ischemia, The object of the present invention is to provide a therapeutic drug that has no side effects and can treat brain disorders by inhibiting necrosis and reconstructing neural networks through the plasticity of surviving neurons.
［課題を解決するための手段］脳虚血や脳内グルコースの著明な低下により惹起される
神経細胞壊死の脳内分布の内で最も高い脆弱性を示すの
が海馬ＣＡＬ錐体細胞である。[Means for solving the problem] Hippocampal CAL pyramidal neurons exhibit the highest vulnerability to neuronal necrosis induced by cerebral ischemia or a marked decrease in intracerebral glucose. .
実験動物に短時間（砂ネズミで５分、ラットで１０〜３
０分）の前脳虚血処置を施すことによって前脳全体が均
一で高度の脳虚血に陥り、虚血を解除すると血流がほぼ
完全に再開される。エネルギー代謝の指標としてのＡＴ
Ｐ含量やエネルギーチャージは虚血中に著明に低下する
が、虚血後には速やかに回復する。虚血直後から虚血後
１日までの間には海馬ＣＡＬ錐体細胞には組織学的変化
はみられない。この時期には海馬ＣＡＬ領域より電気的
活動が記録でき、細胞外の単位発射の数はむしろ正常よ
り増加している。短時間の虚血後世なくとも１日の間は
様々な観点から海馬ＣＡＬ錐体細胞は明らかに生存して
いる。しかし、虚血後２日目には電気生理学的活動は停
止し、機能的死（ｆｕｎｃｔｉｏｎａｌ ｄｅａｔｈ）
の状態となる。虚血を負荷して３〜４日には海馬ＣＡＬ
錐体細胞の大部分が壊死となり崩壊する。病変の進行は
きわめて緩やかに遅れて進行する（連発性神経細胞壊死
、ｄｅｌａ７ｅｄ ｎｅＩｌ＋ｏｏａｌ ｄｅａｔｈ）
。Test animals for a short period of time (5 minutes for sand mice, 10-3 minutes for rats)
By administering forebrain ischemia treatment for 0 minutes), the entire forebrain falls into uniform and severe cerebral ischemia, and when the ischemia is removed, blood flow is almost completely resumed. AT as an indicator of energy metabolism
P content and energy charge drop markedly during ischemia, but quickly recover after ischemia. No histological changes were observed in hippocampal CAL pyramidal cells from immediately after ischemia to 1 day after ischemia. At this stage, electrical activity can be recorded from the hippocampal CAL region, and the number of extracellular unit firings is actually higher than normal. From various viewpoints, hippocampal CAL pyramidal neurons clearly survive for at least one day after a short period of ischemia. However, on the second day after ischemia, electrophysiological activity ceases and functional death occurs.
The state will be as follows. 3 to 4 days after ischemia, hippocampal CAL
Most of the pyramidal cells become necrotic and collapse. Progression of the lesion is extremely slow and delayed (recurrent neuronal necrosis, dela7ed neIl+ooal death)
.
脳障害が生じる可能性の高い脳血栓にともなう脳梗塞、
Ｃ○中毒、心不全、大量失血による脳虚血、および低血
糖症や強い持続的けいれん発作による脳内エネルギー代
謝の乱れが生じる場合に可及的すみやかに神経細胞のグ
ルタミン酸を中心とした神経興奮物質に対する耐性を高
め、エネルギー代謝を含めた脳内恒常性を維持すること
により病変の進行を抑えかつ予後の改善に資すると考え
られる。Cerebral infarction due to cerebral thrombosis, which is likely to cause brain damage;
In the event of C○ poisoning, heart failure, cerebral ischemia due to massive blood loss, or disturbance of energy metabolism in the brain due to hypoglycemia or strong sustained convulsions, the use of neurostimulants, mainly glutamate, in nerve cells as soon as possible. It is thought that increasing resistance to the disease and maintaining brain homeostasis, including energy metabolism, will suppress the progression of lesions and contribute to improving prognosis.
因みに、日常生活においては、脳虚血で生じるような脳
内グルタミン酸の著しい上昇や脳の障害は生じない。Incidentally, in daily life, there is no significant increase in intracerebral glutamate or brain damage that occurs in cerebral ischemia.
第工図は、雄性ラット（Ｓｐｒａｇｕ＋−Ｄａｖｌｅｙ
系３５０ｇ）にＬ−グルタミン酸６．８％含有の飼料を
自由摂取させた（ｎ＝ｌｌ）ときの、摂取行動と血漿お
よび脳内グルタミン酸濃度の日内変動を示すグラフであ
る。このグラフから、食事とともに摂食蛋白質由来の大
量のグルタミン酸やアスパラギン酸が小腸より大量に吸
収されるが、血中や脳内での両者の濃度には口内変動が
ほとんどないことがわかる。The first drawing is a male rat (Spragu+-Davley).
Fig. 3 is a graph showing ingestion behavior and diurnal fluctuations in plasma and brain glutamate concentrations when (n = 11) animals (350 g) were allowed to freely ingest feed containing 6.8% L-glutamic acid (n = 11). This graph shows that large amounts of glutamic acid and aspartic acid derived from ingested proteins are absorbed from the small intestine with meals, but there is almost no intraoral variation in the concentrations of both in the blood and brain.
また、マウスの飼料に３ｏ％Ｌ−グルタミン酸ナトリウ
ム（ＭＳＧ）を添加しても、血中や脳内グルタミン酸は
上昇せず、たとえ実験的に妊娠あるいは授乳中の母数の
血中グルタミン酸濃度を異常に上昇させても胎盤を通過
せず、母乳へ移行はないことが知られている。これは、
摂食に伴って小腸より消化吸収されるＬ−グルタミン酸
が、アラニンやグルタミンへと代謝されるとともに、消
化管、脳、胎盤、乳腺のグルタミン酸に対するバリヤー
により、母数、胎児、新生仔の脳内グルタミン酸が正常
範囲内に保たれるためである。Furthermore, even if 3o% monosodium L-glutamate (MSG) was added to mouse feed, blood or brain glutamate did not increase, and even if experimentally the blood glutamate concentration was abnormally increased in pregnant or lactating mothers. It is known that even if the concentration is increased to 50%, it does not cross the placenta and is not transferred to breast milk. this is,
L-glutamic acid, which is digested and absorbed from the small intestine during ingestion, is metabolized to alanine and glutamine, and the barrier to glutamic acid in the gastrointestinal tract, brain, placenta, and mammary glands allows it to be absorbed in the brains of mothers, fetuses, and newborns. This is because glutamate is kept within the normal range.
これに対して、バリヤーの未発達な幼若マウス（９〜１
０日齢）では、高濃度のＬ−グルタミン酸水溶液を実験
的に大量（４ｇ／ｋｇ体重）に腹腔内や強制経口投与す
ると、酸性アミノ酸が小腸より濃度依存的に吸収される
がら、血中や脳内のグルタミン酸濃度が正常値の数百倍
以上に上昇し、海馬、黒質、最後野、扁桃体、嗅球、視
床下部（室傍核、弓状核、正中隆起）の部位において神
経細胞の壊死が散在的に生じ、脳虚血と同様選択的脆弱
性が認められる。In contrast, young mice with underdeveloped barriers (9-1
When a large amount (4 g/kg body weight) of a highly concentrated aqueous L-glutamic acid solution is experimentally administered intraperitoneally or by force orally, acidic amino acids are absorbed from the small intestine in a concentration-dependent manner; Glutamate concentration in the brain increases to more than several hundred times the normal value, resulting in necrosis of neurons in the hippocampus, substantia nigra, cortex postrema, amygdala, olfactory bulb, and hypothalamus (paraventricular nucleus, arcuate nucleus, median eminence). Occurs sporadically, and selective vulnerability is observed, similar to cerebral ischemia.
ところが、 １０日齢マウスに人工乳を与えたり、離乳
直後のマウスに１時間摂食させた後、同様の処置を行う
と、血中グルタミン酸は、栄養素を摂取していない場合
と同様、異常に上昇するにもかかわらず、弓状核などの
障害は著しく減弱する。However, when a 10-day-old mouse is given artificial milk, or a newly weaned mouse is given a similar treatment after being fed for an hour, blood glutamate levels become abnormal, similar to when no nutrients are taken. Despite the increase, lesions such as the arcuate nucleus are markedly attenuated.
これは、摂食時、味覚や嗅覚刺激ついで栄養素の消化吸
収と並行して分泌されるホルモンや神経栄養因子が、脳
内で作用した可能性が考えられる。This is thought to be due to the action of hormones and neurotrophic factors secreted in the brain during ingestion, which are stimulated by taste and smell, and are secreted in parallel with the digestion and absorption of nutrients.
本発明者は、以上のような知見に基いて、ラットおよび
サルで摂食に伴って血中及び脳内レベルが変化する神経
栄養因子として、摂食後１．５時間で酸性フィブロブラ
スト成長因子（ａＦＧＦ）は１０倍に上昇するが血小板
由来成長因子は１／８に低下することを見い出した。こ
の両戚長因子は神経細胞を培養する際、培地に添加する
と神経突起を発芽させることが知られている。Based on the above findings, the present inventors determined that acid fibroblast growth factor ( aFGF) was increased 10 times, but platelet-derived growth factor was found to be decreased 1/8. It is known that when added to the medium when culturing nerve cells, this long-length factor causes neurites to sprout.
さらに、摂食に伴って分泌されることより食欲に及ぼす
効果を調べたところ、ａＦＧＦのみに食欲抑制を見い出
しかつグルコースにより抑制され、グルタミン酸により
興奮する摂食中枢の視床下部外側野（ＬＨＡ）神経細胞
（グルコース感受性神経細胞）は、ａＦＧＦの脳内投与
によって長時間にわたって抑制された。第２図及び第３
Ａ−Ｃ図参照。第２１！Ｉは、ａ ＦＧＦ第３脳室投与
（２２０ｎｔ／ラツト）により食欲（摂食量）が有意に
抑制された（Ｐ＜０．０１）結果を示し、第３Ａ−Ｃ図
は摂食中枢グルコース感受性神経細胞におけるａＦＧＦ
の作用を示す。更に詳しくは、第３図は、視床下部外側
野（摂食中枢）に微小電極を刺入れ電気泳動的にグルコ
ース、ａＦＧＦ、Ｌ−グルタミン酸を投与した（図中に
、電流量で示されている）結果を示し、この図からａ
ＦＧＦ投与後８．５分の潜時の後に強い抑制が生じ、１
５分程度持続したことがわかる。因みに、第３Ａ−Ｃ図
は、第３Ａ図の右に第３Ｂ図、第３Ｂ図の右に第３Ｃ図
をつなげてみるもので、縦軸はパルス（放電７秒）を示
し、横軸は経過時間を示す。Furthermore, when we investigated the effect of aFGF on appetite due to its secretion during feeding, we found that only aFGF suppressed appetite, and the lateral hypothalamic area (LHA) nerve of the feeding center, which is suppressed by glucose and excited by glutamate, was found to suppress appetite. cells (glucose-sensitive neurons) were suppressed for a long time by intracerebral administration of aFGF. Figures 2 and 3
See diagrams A-C. 21st! Figures 3A and 3C show that appetite (food intake) was significantly suppressed (P<0.01) by administering FGF to the third ventricle (220 nt/rat); aFGF in cells
This shows the effect of More specifically, Figure 3 shows that a microelectrode was inserted into the lateral hypothalamus (feeding center) and glucose, aFGF, and L-glutamate were administered electrophoretically (indicated by the amount of current in the figure). ) results and from this figure a
Strong suppression occurred after a latency of 8.5 min after FGF administration, and 1
It can be seen that it lasted about 5 minutes. Incidentally, Figures 3A-C connect Figure 3B to the right of Figure 3A, and Figure 3C to the right of Figure 3B, where the vertical axis represents the pulse (7 seconds of discharge) and the horizontal axis represents the pulse (7 seconds of discharge). Indicates elapsed time.
そこで、プロティンキナーゼＣを直接活性化させる１−
ｏｌｅｏＹｌ −２−ｓｃｅｊ７１２−５ｃｅｊ７１−
（ホルボールエステルの合成物質）を電気泳動的にグ
ルコース感受性神経細胞に作用させると、同じような潜
時と持続時間で抑制をひき起こすことができる。Therefore, 1-, which directly activates protein kinase C,
oleoYl -2-scej712-5cej71-
(a synthetic phorbol ester) electrophoretically applied to glucose-sensitive neurons can induce inhibition with similar latency and duration.
逆にイミブラミンでプロティンキナーゼＣ活性を抑える
と、 １−ｏ１ｅｏ７１−２−ｓｃｅ（１１２−５ｃｅ
（１１−の作用は出てこない。つまりａＦＧＦはプロテ
ィンキナーゼＣを介して効果を発揮しているようである
。Conversely, when protein kinase C activity is suppressed with imibramine, 1-o1eo71-2-sce (112-5ce
(No effect of 11- is observed. In other words, aFGF seems to exert its effect via protein kinase C.
ａＦＧＦの全構造に対する抗体で脳切片を染色してみる
と、摂食後２時間で視床下部外側野（ＬＨＡ） 、不確
帯、海馬、扁桃体、孤束核などの神経細胞が染色される
。しかし、摂食前では脳室壁の上衣細胞や脳室前壁のＡ
Ｖ３Ｖや下目器官の細胞が染色でき、上記神経細胞群は
染色できないのに、摂食後は上衣細胞のａ ＦＧＦは空
になって脳実質の方に流れている。ａＦＧＦのＮ末端か
ら３０塩基（１０個のアミノ酸残基）までのｃ ＤＮＡ
プローブを用い、ｉｎ ｉｉ＋ｕハイブリダイゼーショ
ン法で検索すると、脳室周囲の上衣細胞はａ ＦＧＦの
ｍＲＮＡをもっているが、ＬＨＡの神経細胞などにはな
い。このことはグルコース投与後、上衣細胞から脳を髄
液中および脳内に放出されたａＦＧＦがＬＨＡの神経細
胞などに取り込まれたことを示している。When brain sections are stained with antibodies against all aFGF structures, neurons in the lateral hypothalamic area (LHA), zona incerta, hippocampus, amygdala, nucleus solitarius, and other areas are stained 2 hours after feeding. However, before feeding, ependymal cells on the ventricular wall and A on the anterior ventricular wall
V3V and cells of the lower eye organ can be stained, but the above neuronal groups cannot be stained, but after feeding, aFGF in ependymal cells is emptied and flows toward the brain parenchyma. c DNA from the N-terminus of aFGF to 30 bases (10 amino acid residues)
Searching using a probe and in ii+u hybridization revealed that periventricular ependymal cells have aFGF mRNA, but LHA neurons do not. This indicates that aFGF released from ependymal cells into the cerebrospinal fluid and into the brain after glucose administration was taken up by LHA neurons and the like.
以上のことは、ａ ＦＧＦが神経細胞の生存および機能
維持に重要な関わりを持ち、培養神経細胞の神経突起を
伸展させることより脳障害発症後の神経回路網構築に到
る可塑性発現にも関わっている可能性がある。The above results indicate that aFGF has an important role in maintaining the survival and function of neurons, and is also involved in the expression of plasticity that leads to the construction of neural networks after the onset of brain damage by extending the neurites of cultured neurons. There is a possibility that
そこで、＾１！ｅ【の浸透圧ミニポンプをスナネズミの
側脳室に留置し、ａＦＧＦ（２０即／ｄ、ヘパリン（５
０１１ｇ／ｄ）含有生理食塩水にて希釈）を１週間微量
連続脳室内投与（２Ｈｎｇ／動物／日）した。So, ^1! An osmotic mini-pump of [e] was placed in the lateral ventricle of the gerbil, and aFGF (20 i/d) and heparin (5 d/d) were added to the gerbil's lateral ventricle.
011 g/d) (diluted with physiological saline) was continuously administered intracerebroventricularly (2 Hng/animal/day) for one week.
尚、対照は同様の処置を行ない、生理的食塩水のみを投
与した。処置３日後に５分間両側の頚動脈を結紮し、前
脳虚血状態にした。その後速やかに血行を再開し、５日
後に脳を層流固定し、海馬を含む領域を病理組織学的検
索したところ、対照では海馬ＣＡＬ錐体細胞全体に壊死
を認めたが（第８図及び第９図参照。両図より、対照で
は広範囲の神経細胞の壊死が認められ、神経繊維の走行
が不明瞭になっている）、ａＦＧＦ投与の場合は全く壊
死を認めなかった。（第１Ｇ図及び第１１図参照。As a control, the same treatment was performed and only physiological saline was administered. Three days after the treatment, both carotid arteries were ligated for 5 minutes to create forebrain ischemia. Thereafter, blood circulation was promptly resumed, and 5 days later, the brain was fixed with laminar flow, and the region including the hippocampus was examined histopathologically. Necrosis was observed throughout the hippocampal CAL pyramidal cells in the control (Fig. 8 and See Figure 9. Both figures show that in the control case, extensive necrosis of nerve cells was observed, and the course of nerve fibers became unclear), while in the case of aFGF administration, no necrosis was observed at all. (See Figure 1G and Figure 11.
この場合、神経細胞、神経繊維になんら異常も認められ
ない）。さらに、対照に生じた自発運動の抑制を含む行
動異常はａＦＧＦ投与により完全に抑止した。In this case, no abnormalities are observed in nerve cells or nerve fibers). Furthermore, behavioral abnormalities including suppression of locomotor activity that occurred in controls were completely suppressed by aFGF administration.
一方、ａＦＧＦの脳内分泌は摂食のみならずグルコース
あるいはＬ−アルギニン、Ｌ−ロイシン、Ｌ−イソロイ
シン又はＬ−バリンの経口または静脈投与により促進さ
れ、いずれの場合も投与後２時間に最大レベルに達した
。第４図及び第５図参照。脳虚血や脳内エネルギー代謝
の失調等のショックより回復した後はこれら栄養素の投
与がａ ＦＧＦの代替効果を発揮すると思われる。On the other hand, the intracerebral secretion of aFGF is stimulated not only by ingestion but also by oral or intravenous administration of glucose, L-arginine, L-leucine, L-isoleucine, or L-valine, and in each case reaches its maximum level 2 hours after administration. Reached. See Figures 4 and 5. After recovery from a shock such as cerebral ischemia or imbalance of intracerebral energy metabolism, administration of these nutrients is thought to exert a substitutive effect for aFGF.
さらに記憶能力等の障害に対しても、ａＦＧＦあるいは
これら栄養素投与によるａＦＧＦの分泌により記憶能力
の賦活をラットにおける学習テスト（条件付は忌避行動
）により調べた。すなわち、明暗２室からなるケージに
ラットを収容し、環境に順化させた後グルコース投与２
時間後に明室にラットを静置し、暗室に移動すると微弱
な電気ショックを与え明室内に留まるよう訓練した。対
照には生理的食塩水を同様に投与した。Furthermore, for disorders such as memory ability, the activation of memory ability by aFGF or the secretion of aFGF by administration of these nutrients was investigated using a learning test in rats (conditioned on avoidance behavior). That is, rats were housed in a cage consisting of two light and dark rooms, and after being acclimatized to the environment, glucose was administered 2.
After an hour, the rats were left in the light room, and when they were moved to the dark room, they were given a weak electric shock to train them to stay in the light room. Physiological saline was similarly administered to controls.
翌日、ラットを同じケージの明室に静置し、暗室へ移動
するまでの時間を測定するとグルコース投与ラットにお
いて有意な記憶保持効果を認めた（＊＊、 Ｐ＜０．
０１）。第６図参照。この効果はグルコースに限らずａ
ＦＧＦ分泌活性を有するＬ−アルギニン、Ｌ−ロイシン
、Ｌ−イソロイシン、Ｌ−バリン等のアミノ酸にも同様
に認められ、−０以上の知見により本発明は完成される
に至ったのである。The next day, the rats were placed in the light room of the same cage and the time taken to move to the dark room was measured, and a significant memory retention effect was observed in the glucose-administered rats (**, P<0.
01). See Figure 6. This effect is not limited to glucose.
This is also observed in amino acids such as L-arginine, L-leucine, L-isoleucine, and L-valine, which have FGF secretion activity, and the present invention was completed based on the finding of -0 or more.
すなわち、本発明の抗痴呆薬は、酸性フィブロブラスト
成長因子（ａＦＧＦ）又はａＦＧＦの活性フラグメント
、ａＦＧＦのアナログペプチド、ａ ＦＧＦと活性ドメ
インを同じくするａＦＧＦの構造類似の非ペプチド性有
機化合物などのａＦＧＦ関連物質或いはａＦＧＦ分泌活
性を有するグルコースおよび（または）Ｌ−アルギニン
、Ｌ−ロイシン、Ｌ−イソロイシン及びＬ−バリンなど
の塩基性アミノ酸及び分岐鎖アミノ酸から選ばれる少な
くとも１種のアミノ酸を有効成分とすることを特徴とす
る副作用のない抗痴呆薬である。That is, the anti-dementia drug of the present invention is aFGF, such as acidic fibroblast growth factor (aFGF) or an active fragment of aFGF, an analog peptide of aFGF, or a non-peptidic organic compound having the same active domain as aFGF and having a structure similar to that of aFGF. Contains as an active ingredient at least one amino acid selected from basic amino acids and branched chain amino acids such as glucose and/or L-arginine, L-leucine, L-isoleucine, and L-valine, which have related substances or aFGF secretion activity. It is an anti-dementia drug with no side effects.
上記グルコースおよびアミノ酸は単独でも抗痴呆薬とし
ての効果を示めすか、グルコースとアミノ酸の組合せに
よりその効果はより向上する。これら栄養素による効果
は脳の血行や代謝が正常化した状態で最大の効果を発現
するので、発作発症直後は速やかにａ ＦＧＦの脳内微
量連続投与が望まれる。The above-mentioned glucose and amino acids alone can exhibit an effect as an anti-dementia drug, or the combination of glucose and amino acids can further improve the effect. Since the effects of these nutrients are greatest when cerebral blood circulation and metabolism are normalized, it is desirable to continuously administer small amounts of aFGF into the brain immediately after the onset of a seizure.
本発明の抗痴呆薬の有効成分である酸性フィブロブラス
ト成長因子（ａＦＧＦ）は、公知物質で、例えばａ Ｆ
ＧＦ産生細胞の細胞培養、組み換えＤＮＡなどの方法に
より製造することができる。また、ａＦＧＦの活性フラ
グメントは上記方法により製造したものの酵素分解、化
学処理などにより製造することができる。ａ ＦＧＦの
アナログペプチドとしてはＡ１１−ａ ＦＧＦ、 Ｍｅ
ｔａＦＧＦなどを例示することができ、これらは組み
換えＤＮＡなどの方法により製造することができる。ａ
ＦＧＦと活性ドメインを同じくするａＦＧＦの構造類似
の非ペプチド性有機化合物としては １−ｏｌｅｏ７１
−２−＊ｃｅ＋７１−ｇ１７ｃｅｒｏ１等のホルボール
エステルなど例示することができ、これらは化学的合成
法、酵素処理などの方法で製造することができる。Acid fibroblast growth factor (aFGF), which is the active ingredient of the anti-dementia drug of the present invention, is a known substance, such as aFGF.
It can be produced by methods such as cell culture of GF-producing cells and recombinant DNA. Furthermore, the active fragment of aFGF can be produced by enzymatic decomposition, chemical treatment, etc. of the fragment produced by the above method. a FGF analog peptides include A11-a FGF, Me
Examples include taFGF, which can be produced by methods such as recombinant DNA. a
A non-peptidic organic compound structurally similar to aFGF that has the same active domain as FGF is 1-oleo71.
Examples include phorbol esters such as -2-*ce+71-g17cero1, and these can be produced by chemical synthesis methods, enzyme treatment, and other methods.
本発明の抗痴呆薬をヒトに投与する場合、投与方法、投
与量は脳虚血や脳エネルギー代謝失調発作後の時間的経
過により異なる。例えば、発作直後にはａＦＧＦおよび
（または）同じ活性を有するその関連物質の脳室内微量
連続投与（１１１９〜２００ Ｒ／ ｃａｐｉｌｉ／
ｄａ７）を採用することが好ましい。When administering the anti-dementia drug of the present invention to humans, the administration method and dosage vary depending on the time course after cerebral ischemia or cerebral energy metabolism disorder attack. For example, immediately after an attack, intracerebroventricular microdose continuous administration of aFGF and/or its related substances with the same activity (1119-200 R/capili/
It is preferable to adopt da7).
発作後２日目以降は、上記処置に加えて、グルコースお
よび（または）Ｌ−アルギニン、Ｌ−ロイシン、Ｌ−イ
ソロイシン、Ｌ−バリー等のアミノ酸を成人１日当り
Ｉｇ好ましくは６ｇ以上を例えば経口、静注、経腸的に
投与することが望ましく、上限は１００ｇ程度であり６
０ｇ以下が望まれる。From the 2nd day after the attack, in addition to the above treatment, supplement with glucose and/or amino acids such as L-arginine, L-leucine, L-isoleucine, and L-barry per day for adults.
It is desirable to administer 6 g or more of Ig orally, intravenously, or enterally, and the upper limit is about 100 g.
0g or less is desirable.
本発明の抗痴呆薬は、所望の医薬品又はグルコース、ア
ミノ酸などの栄養素に関しては食品の形態にても提供す
ることが出来る。例えば、医薬品としては、単独で散剤
、顆粒、錠剤、糖衣錠、カプセル、液剤の形態とするこ
とができる。あるいは、経腸栄養剤又は輸液等に添加し
て投与することもできるーただし、ａＦＧＦに関しては
、半減期が短かいので例えばその生理食塩水に溶解した
溶液として浸透圧ポンプ等による連続微量脳室内投与が
望ましい。The anti-dementia drug of the present invention can also be provided in the form of a food with respect to desired pharmaceuticals or nutrients such as glucose and amino acids. For example, the pharmaceutical product may be in the form of powder, granules, tablets, sugar-coated tablets, capsules, or liquids. Alternatively, aFGF can be administered by adding it to enteral nutrients or infusions, etc. However, since aFGF has a short half-life, it can be administered in continuous micro-intracerebroventricular doses using, for example, a solution dissolved in physiological saline using an osmotic pump or the like. Administration is recommended.
［実施例］以下、本発明を実験例により具体的に説明する。[Example]The present invention will be specifically explained below using experimental examples.
実験例１対照としてスナネズミ （雄性、約２５０ｇ）を導入し
、両側頚動脈を短時間（５分間）結紮し、５日後に病理
組織学的検索を実施したところ、海鳥ＣＡ１層の神経細
胞全体が壊死を起こしていたことを確認した（第８図及
び第９図）。Experimental Example 1 A gerbil (male, approximately 250 g) was introduced as a control, and both carotid arteries were ligated for a short period of time (5 minutes). After 5 days, a histopathological search was performed, and all nerve cells in the CA1 layer of the seabird were found to be necrotic. It was confirmed that this had occurred (Figures 8 and 9).
同じコロニー由来のスナネズミ（雄性、約２５０ｇ）に
あらかじめ両側の側転室にカニユーレを留置し、ＡＩ＋
ｒ＋の浸透圧ミニポンプ（モデル２００２゜０．５ｄ／
ｈｌ）を背部皮層に埋め込んだ。ａＦＧＦは５０＃／ａ
ｄのヘパリン含有生理的食塩水に２０埒／−になるよう
調製し投与した。処置３日後に７＼ロセン麻酔下で両側
頚動脈を５分間結紮して前脳虚血状態にし、麻酔はすみ
やかに中断した。虚血処置５時間にネンブタール麻酔下
（２０■／ｋｇ体重、ｉｐ）で脳をアセトアルデヒドに
て潅流固定した。Cannulae were placed in the cartwheel chambers on both sides of a gerbil (male, approximately 250 g) from the same colony, and AI+
r+ osmotic pressure mini pump (model 2002゜0.5d/
hl) was implanted into the dorsal cortex. aFGF is 50#/a
It was prepared and administered to the heparin-containing physiological saline of d at 20 mg/-. Three days after the procedure, both carotid arteries were ligated for 5 minutes under 7\locene anesthesia to create a state of forebrain ischemia, and the anesthesia was immediately discontinued. Five hours after the ischemic treatment, the brain was perfusion-fixed with acetaldehyde under Nembutal anesthesia (20 μg/kg body weight, ip).
脳を摘出し、パラフィンに包埋後前額断連続切片（５ｍ
）を作成し、ニラスル染色後光学顕微鏡にて組織学的評
価を行った。第１０図及び第１１図参照。The brain was removed, embedded in paraffin, and serially sectioned (5 m
) was prepared, and histological evaluation was performed using an optical microscope after Nirasur staining. See Figures 10 and 11.
対照は第８図及び第９図に示すようにＣＡＬ錐体細胞の
壊死を認めたが、ａＦＧＦ投与ては第１Ｏ図及び第１１
図に示すように全く壊死を認めたかった。In the control, necrosis of CAL pyramidal cells was observed as shown in Figs. 8 and 9, but in the case of aFGF administration, necrosis was observed in Figs.
As shown in the figure, no necrosis was observed.
実験例２ラットを夜間絶食した後にラット飼料を摂取させた場合
及びグルコースを腹腔内投与（２ｇ／ｋｇ体重）した場
合のそれぞれについて経時的に脳を髄液中ａＦＧＦをヒ
ドラによるバイオアッセイにて測定した。結果を第４図
に示す。第４図よりラットの飼料摂取ではグルコース投
与よりａＦＧＦの分泌が高い水準で持続時間も長いこと
が理解される。Experimental Example 2 AFGF in the cerebrospinal fluid of the brain was measured over time using a bioassay using Hydra when rats were fed with rat feed after overnight fasting and when glucose was intraperitoneally administered (2 g/kg body weight). did. The results are shown in Figure 4. From FIG. 4, it is understood that aFGF secretion is at a higher level and lasts for a longer time when rats are fed with food than when glucose is administered.
グルコース、グルコース＋Ｌ−アルギニン、Ｌアルギニ
ン及び分枝鎖アミノ酸（Ｌ−バリン＋Ｌ−イソロイシン
）をそれぞれ同様にして各種投与量で腹腔的投与した各
場合について２時間後の脳を髄液中ａＦＧＦを同様にし
て測定した。結果を第５図に示す。第５図より、上記ア
ミノ酸はグルコースと同様の効果と認められ、またこれ
ら栄養素投与量に対し脳を髄液中のａＦＧＦ量は明らか
に用量依存性に直線的に増大したことがわかる。Glucose, glucose + L-arginine, L-arginine, and branched-chain amino acids (L-valine + L-isoleucine) were each administered intraperitoneally at various doses. Two hours later, aFGF in the brain was examined in the same manner. It was measured as follows. The results are shown in Figure 5. From FIG. 5, it can be seen that the above-mentioned amino acids were recognized to have the same effect as glucose, and that the amount of aFGF in the brain and cerebrospinal fluid clearly increased linearly in a dose-dependent manner in response to the administration of these nutrients.
実験例３ラットを夜間絶食させた後にａ ＦＧＦを第３脳室内に
投与（２２０ｎｇ／ ｈｒ） Ｌ、その後の暗期におけ
る摂食量を測定したところ有意に摂食量が抑制された（
Ｐ〈０．１１１）。第２図参照。Experimental Example 3 After the rats were fasted overnight, aFGF was administered into the third ventricle (220 ng/hr), and the amount of food intake during the subsequent dark period was measured, and the amount of food intake was significantly suppressed (
P<0.111). See Figure 2.
そこで、摂食中枢（視床下部外側野）にあるグルコース
感受性神経細胞の神経応答と無麻酔無拘束下で電気泳動
的にａＦＧＦを投与（２０ｎＡ）記録したところＬ−グ
ルタミン酸による興奮については影響を受けないが、８
．５分の潜時後に著明な抑制が生じる。第３図参照。即
ち、Ｌ−グルタミン酸およびグルコースに感受性を有す
る神経細胞の活動をａＦＧＦは抑制すると言える。Therefore, we electrophoretically recorded the neural responses of glucose-sensitive neurons in the feeding center (lateral hypothalamus) by administering aFGF (20 nA) under anesthesia and unrestrained conditions, and found that L-glutamate-induced excitation was not affected. No, but 8
．． Marked suppression occurs after a latency of 5 minutes. See Figure 3. That is, it can be said that aFGF suppresses the activity of nerve cells sensitive to L-glutamate and glucose.
実験例４雄性マウス（４０ｇ）を明暗２室よりなる特殊ケージに
単独収容し５分間放置して実験環境に馴化させた。マウ
スは翌日朝より絶食とし、同量のグルコースとＬ−アル
ギニン（各３１Ｇ■／ｋｇ体重）、グルコース（３００
■／聴体重）又は生理的食塩水を腹腔的投与し２時間後
に特殊ケージの明室内に静置した。マウスが暗室へ移動
した直後に弱い電気ショック（ＩｍＡ、 ３秒）を与え
条件付けを行った（ａｃＢｉｉｉｌｉｏａＤｉａｌ）
。＆の日の同し時刻にマウスを再び特殊ケージの明室内
に静置し、暗室へ移動するまでの時間（１ａｉｅｎｃｙ
）を測定し、前日の条件付けした記憶の残存程度を調へ
たｆ＋ｅｔ＋ｎ＋ｉｏ。Experimental Example 4 A male mouse (40 g) was housed singly in a special cage consisting of two light and dark rooms and left for 5 minutes to acclimatize to the experimental environment. The mice were fasted from the morning of the next day and were given the same amount of glucose and L-arginine (each 31 G/kg body weight), glucose (300
2 hours later, the rats were left standing in a light room of a special cage. Conditioning was performed by giving a weak electric shock (ImA, 3 seconds) immediately after the mouse moved to the dark room (acBiiilioaDial).
. At the same time on days of
) was measured, and the degree of residual conditioned memory from the previous day was investigated.
ｔｅｉｌ）。tail).
結果を第６図に示す。この図から、グルコース投与によ
り記憶賦活効果を認め、グルコースとＬ−アルギニンを
同時に投与した場合はさらに賦活されることがわかる。The results are shown in Figure 6. From this figure, it can be seen that memory activation effect is observed by glucose administration, and memory activation is further enhanced when glucose and L-arginine are administered simultaneously.
実験例５スナネズミ（雄性、約２５（Ｉｇ）を夜間絶食させた後
グルコース（２ｇ ／ ｋｇ体重）、同量のグルコース
とＬ−アルギニン（２，１ｇ／ｋｇ体重）を経口投与し
た。２時間後に両側頚動脈を短時間（５分間）結紮し、
５日後に脳の病理組織学的検査を実施し、同一部位の切
片（５ｍ）での海鳥ＣＡ１層の神経細胞の壊死細胞数を
計測した。Experimental Example 5 Gerbils (male, approximately 25 (Ig)) were fasted overnight, and then glucose (2 g/kg body weight) and the same amount of glucose and L-arginine (2.1 g/kg body weight) were orally administered. 2 hours later. Both carotid arteries were briefly ligated (5 minutes),
Five days later, a histopathological examination of the brain was performed, and the number of necrotic cells in the seabird CA1 layer was measured in a section (5 m) of the same site.
グルコース投与による海馬ＣＡＩ層錐体細胞の壊死細胞
数は対照（生理的食塩水）に比し有意に低下しくＰ＜０
．０１． ｚ 生理的食塩水）、グルコースおよびＬ
−アルギニン併用によりグルコース単独よりさらに改善
（Ｐ＜０．０１． ｖｈ グルコース単独、Ｐ ＜
ｉｌ、 ０ｆ）Ｉ 、 ｘ 生理的食塩水）された。The number of necrotic cells in hippocampal CAI layer pyramidal neurons due to glucose administration was significantly decreased compared to the control (physiological saline), P<0
．． 01. z physiological saline), glucose and L
- Further improvement with arginine combination than with glucose alone (P<0.01. vh Glucose alone, P<
il, 0f) I, x saline).
第７図参照。See Figure 7.
［発明の効果］本発明による抗痴呆薬はａ ＦＧＦ又はその関連物質或
いは脳内ａＦＧＦ分泌活性を有するグルコース及び（ま
たは）Ｌ−アルギニンなどの代表的栄養素を有効成分と
するもので、副作用の心配がなく、脳虚血や脳内エネル
ギー代謝失調の発作時に脳内グルタミン酸およびアスパ
ラギン酸感受性のある神経細胞の、異常に上昇したグル
タミン酸およびアスパラギン酸に対する耐性を高め、生
存をはかることにより発作後に生しる脳機能の低下、特
に記憶や言語障害（失語症等）を防止もしくは治療する
ことが出来る。[Effects of the Invention] The anti-dementia drug according to the present invention contains typical nutrients such as aFGF or related substances or glucose and/or L-arginine that have aFGF secretion activity in the brain as an active ingredient, and there is no concern about side effects. During attacks of cerebral ischemia or intracerebral energy metabolism imbalance, the brain cells that are sensitive to glutamate and aspartate increase their tolerance to the abnormally elevated levels of glutamate and aspartate, thereby ensuring their survival. It can prevent or treat the decline in brain function, especially memory and language disorders (aphasia, etc.).
第１図は、ラットにおける摂食行動と血漿および脳内グ
ルタミン酸濃度の日内変動を示すグラフ、第２図は、食
欲に対するａＦＧＦ第３脳室投与におけるａＦＧＦの作
用を示すグラフ、第４図は、摂食後及び栄養素（グルコ
ース）腹腔内投与後それぞれの脳を髄液中ａ ＦＧＦ量
の変化を示すグラフ、第５図は、各種栄養素投与による脳を髄液中ａＦＧＦに
対する影響を示すグラフ、第６図は、グルコースおよび（または）Ｌ−アルギニン
腹腔内投与による記憶賦活効果を示すグラフ、第７図は、スナネズミ前脳虚血による晦馬ＣＡ１錐体細
胞障害におけるグルコースおよび（または）Ｌ−アルギ
ニンの経口投与の影響を示すグラフ、第８図は、スナネズミの５分間前脳虚血後５日目の海馬
ＣＡＬ錐体細胞（対照、生食水）の顕微鏡写真（ｘ ｔ
３．２’）、第９図は、第８図の写真の○甲部分の拡大顕微鏡写真（
ｘｌｏｏ）、第１０図は、ａＦＧＦ側脳室内連続投与したスナネズミ
の５分、司前脳虚血後５日目の海馬ＣＡＬ錐体細胞（生
食水）の顕微鏡写真（Ｘ１３．２）、第１１図は、第１
Ｏ図の写真の○甲部分の拡大顕微鏡写真（ｘｌＧＯ）を
、それぞれ、示す。明期 時期 明期（ａ）摂食ｔ（
ｇ／１０分）（ｂ）血漿中グルタミン酸濃度（μｍｏｌ／ｄｌ）第４
図（Ｃ）場内グルタミン酸濃度（μｍｏｊ勾濱ｌ量）第図投与量（ｍｃ＋／ｋｃ＋）第５図第６図「木木］第８図第１０図第９図第１１図手続補正書（方式）事件の表示平成２年特許願第６９２４６号発明の名称抗痴呆薬３ 補正をする者事件との関係 特許出願人名称（００６］味の素株式会社４゜５゜代理人補正指令の日付東京都新宿区新宿１丁目１番１４号 山田ビル（郵便番
号１６０）電話（０３） ３５４−８６２３゜（６２
００） 弁理士 川 口 義 雄（ほか３名と７平成２年６月２６日補正の対象明細書７、補正の内容Fig. 1 is a graph showing feeding behavior and diurnal fluctuations in plasma and brain glutamate concentrations in rats; Fig. 2 is a graph showing the effect of aFGF on appetite when aFGF is administered to the third ventricle; Fig. 4 is a graph showing the effects of aFGF on appetite. Figure 5 is a graph showing the changes in the amount of aFGF in the cerebrospinal fluid of the brain after feeding and after intraperitoneal administration of nutrients (glucose). The figure is a graph showing the memory activation effect of intraperitoneal administration of glucose and/or L-arginine. Graph showing the effects of oral administration, Figure 8 is a micrograph of hippocampal CAL pyramidal neurons (control, saline) on day 5 after 5 minutes of forebrain ischemia in gerbils (x t
3.2'), Figure 9 is an enlarged micrograph of the instep part of the photograph in Figure 8 (
Figure 10 is a micrograph (X13.2) of hippocampal CAL pyramidal cells (saline) on day 5 after forebrain ischemia in a gerbil to which aFGF was continuously administered in the lateral ventricle for 5 minutes. The figure shows the first
Enlarged micrographs (xlGO) of the instep part of the photograph in Figure O are shown. Light period Period Light period (a) Feeding t(
g/10 minutes) (b) Plasma glutamate concentration (μmol/dl) 4th
Figure (C) In-house glutamic acid concentration (μmoj gradient amount) Figure Dose (mc+/kc+) ) Display of the case 1990 Patent Application No. 69246 Name of the invention Anti-dementia drug 3 Person making the amendment Relationship to the case Patent applicant name (006) Ajinomoto Co., Ltd. 4゜5゜ Date of agent amendment order Shinjuku, Tokyo Shinjuku 1-1-14 Yamada Building (zip code 160) Telephone (03) 354-8623゜(62)
00) Patent attorney Yoshio Kawaguchi (and 3 others) Specification 7 subject to amendment on June 26, 1990, contents of amendment
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2069246AJPH03275631A (en) | 1990-03-19 | 1990-03-19 | Antidement agent |
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2069246AJPH03275631A (en) | 1990-03-19 | 1990-03-19 | Antidement agent |
| Publication Number | Publication Date |
|---|---|
| JPH03275631Atrue JPH03275631A (en) | 1991-12-06 |
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2069246APendingJPH03275631A (en) | 1990-03-19 | 1990-03-19 | Antidement agent |
| Country | Link |
|---|---|
| JP (1) | JPH03275631A (en) |
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| EP0827744A3 (en)* | 1996-08-12 | 2000-05-17 | Japan Science and Technology Corporation | Use of amino acids for the manufacture of a medicament for inhibiting or activating glutamic acid in the brain |
| WO2006077954A1 (en)* | 2005-01-21 | 2006-07-27 | Kyowa Hakko Kogyo Co., Ltd. | Remedy for neurological disease |
| WO2007043363A1 (en) | 2005-10-12 | 2007-04-19 | Otsuka Pharmaceutical Factory, Inc. | Composition for use in prevention of hypoglycemic condition |
| WO2008044691A1 (en) | 2006-10-10 | 2008-04-17 | Otsuka Pharmaceutical Factory, Inc. | Antidepressant agent |
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|---|---|---|---|---|
| US5891848A (en)* | 1995-04-25 | 1999-04-06 | Nippon Zoki Pharmaceutical Co., Ltd. | Peptide fragments |
| EP0827744A3 (en)* | 1996-08-12 | 2000-05-17 | Japan Science and Technology Corporation | Use of amino acids for the manufacture of a medicament for inhibiting or activating glutamic acid in the brain |
| WO2006077954A1 (en)* | 2005-01-21 | 2006-07-27 | Kyowa Hakko Kogyo Co., Ltd. | Remedy for neurological disease |
| WO2007043363A1 (en) | 2005-10-12 | 2007-04-19 | Otsuka Pharmaceutical Factory, Inc. | Composition for use in prevention of hypoglycemic condition |
| WO2008044691A1 (en) | 2006-10-10 | 2008-04-17 | Otsuka Pharmaceutical Factory, Inc. | Antidepressant agent |
| US9060979B2 (en) | 2006-10-10 | 2015-06-23 | Otsuka Pharmaceutical Factory, Inc. | Antidepressant |
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