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

新型药物的神经保护作用; Na/Ca交换抑制剂SEA 400减少了MCA闭塞诱导的脑梗死体积（Jpharmacol. Exp. Ther.，298，249 - 256，2001）。SEA 400还对热损伤诱导的脑损伤中的脑水肿（水含量增加）具有抑制作用。其抗水肿作用部分来自于对血脑屏障的保护。T-588是一种用于治疗阿尔茨海默病的新药，可防止由氧化应激引起的培养星形胶质细胞损伤，这是通过激活ERK（胞外调节蛋白激酶）（Eur. JPharmacol 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增加ERK激活是由于神经元成分。胶质细胞死亡的机制：培养的小胶质细胞的血清剥夺诱导的死亡是通过Bax，一种促凋亡蛋白的表达介导的（Jpn. J药理学83，351 - 154，2000）。探讨星形胶质细胞凋亡的机制。我们发现星形胶质细胞凋亡的诱导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）预防。星形胶质细胞凋亡Br.Jpharmacol.，133，841 -578，2001; Jpharmacol. Exp. Ther.，298，249 - 256，2001）。cGMP介导的细胞内信号参与调节线粒体膜电位，保护星形胶质细胞凋亡。

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.