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Research and Development of Neuroprotective Drugs Based on the Neuron-Glia Interactions

基于神经元-胶质细胞相互作用的神经保护药物的研发

基本信息

批准号：
11557004
负责人：
BABA Akemichi
金额：
$ 8.64万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-11557004/
关键词：
Brain injury Microglia Astrocyte Nerve Degeneration Apoptosis 脳障害

项目摘要

Neuroprotective Actions of Novel Drugs; SEA400, a Na/Ca exchange inhibitor decreased the brain infract volume induced by MCA occlusion (Jpharmacol. Exp. Ther., 298,249-256,2001). SEA400 also had an inhibitory effect on brain edema (increases in water content) in heat lesion-induced brain injury. The anti-edema effect was partly brought from protection of BBB. T-588, a novel drug aimed for therapy of Alzheimer disease, prevented damages of cultured astrocytes by oxidartive stress, which was mediated by the activation of ERK (extracellular-regulated protein kinase) (Eur. Jpharmacol 399,1-8,2000). Injection of T-588 increased ERK activity in rat brain. An immunochemical study, showed that the increase in ERK activation by T-588 is due to the neuronal component. These findings suggest a possibility that SEA400 and T-588 could be neuroprotective drugs against brain injury and neurodegenerative diseases.Mechanisms of Glial Death; Serum-deprivation-induced death of cultured microglia was mediated by expression: of Bax, an pro-apoptotic protein (Jpn. Jpharmacol. 83,351-154,2000). Mechanisms of apoptosis of cultured astrocytes were examined. We found that induction of astrocytes apoptosis was closely related with reduction of mitochondrial membrane potential. Several drugs (T-588, Ibudilast, CV-2619.SEA400) prevented. The astrocytic apoptosis Br.Jpharmacol., 133,841-578, 2001; Jpharmacol. Exp. Ther., 298,249-256,2001). Intracelluair signals mediated by cGMP were involved in the regulation mitochondrial membrane potential to protect astrocytic apoptosis.

新药的神经保护作用；钠/钙交换抑制剂SEA400减少大脑中动脉闭塞所致的脑梗塞体积(J。实验298,249-256,2001)。SEA400对热损伤所致脑损伤的脑水肿(含水量增加)也有抑制作用。抗水肿作用部分来自血脑屏障的保护作用。T-588是一种用于治疗阿尔茨海默病的新药，它通过激活细胞外调节蛋白激酶(ERK)来预防氧化应激对培养星形胶质细胞的损伤。药剂399，1-8,2000)。注射T-588可增加大鼠脑内ERK活性。一项免疫化学研究表明，T-588对ERK激活的增加是由于神经元成分所致。这些发现提示SEA400和T-588可能是脑损伤和神经退行性疾病的神经保护药物。胶质细胞死亡的机制；血清剥夺诱导培养的小胶质细胞死亡是由促凋亡蛋白Bax的表达介导的。乔拉莫尔。83,351-154,2000)。对培养的星形胶质细胞的凋亡机制进行研究。我们发现，诱导星形胶质细胞的凋亡与线粒体膜电位的降低密切相关。几种药物(T-588、异丁司特、CV-2619.SEA400)可预防。《星形细胞凋亡》杂志，133,841-578,2001；实验298,249-256,2001)。CGMP介导的细胞内信号参与了线粒体膜电位的调节，从而保护星形胶质细胞的凋亡。