KOYAMA Yutaka Osaka Univ., Grad. Sch. of Pharmaceutical Sci. Associate Prof., 薬学研究科, 助教授 (00215435)
SHIGENAGA Yoshio Osaka Univ., Grad. Sch. of Dentistry. Prof., 歯学研究科, 教授 (90028770)
MATSUDA Toshio Osaka Univ., Grad. Sch. of Pharmaceutical Sci. Prof., 薬学研究科, 教授 (00107103)
HASHIMOTO Hitoshi Osaka Univ., Grad. Sch. of Pharmaceutical Sci. Associate Prof., 薬学研究科, 助教授 (30240849)
|Budget Amount *help
¥13,500,000 (Direct Cost: ¥13,500,000)
Fiscal Year 2001: ¥2,700,000 (Direct Cost: ¥2,700,000)
Fiscal Year 2000: ¥4,700,000 (Direct Cost: ¥4,700,000)
Fiscal Year 1999: ¥6,100,000 (Direct Cost: ¥6,100,000)
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.