| Project/Area Number |
14370782
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
応用薬理学・医療系薬学
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| Research Institution | Osaka University |
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Principal Investigator |
MATSUDA Toshio Osaka Univ., Grad.Sch.Pharmaceut.Sci., Professor, 薬学研究科, 教授 (00107103)
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| Co-Investigator(Kenkyū-buntansha) |
BABA Akemichi Osaka Univ., Grad.Sch.Pharmaceut.Sci., Professor, 薬学研究科, 教授 (70107100)
KOYAMA Yutaka Osaka Univ., Grad.Sch.Pharmaceut.Sci., Associate Prof., 薬学研究科, 助教授 (00215435)
HASHIMOTO Hitoshi Osaka Univ., Grad.Sch.Pharmaceut.Sci., Associate Prof., 薬学研究科, 助教授 (30240849)
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| Project Period (FY) |
2002 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥13,900,000 (Direct Cost: ¥13,900,000)
Fiscal Year 2005: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2004: ¥2,300,000 (Direct Cost: ¥2,300,000)
Fiscal Year 2003: ¥3,800,000 (Direct Cost: ¥3,800,000)
Fiscal Year 2002: ¥6,800,000 (Direct Cost: ¥6,800,000)
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| Keywords | astrocyte / microglia / apoptosis / cell death / mitochondria / nitric oxide (NO) / SEA0400 / T-817 / 神経細胞 / Na^+ / Ca^<2+>交換系 / 過酸化水素 / cyclic GMP / Ca^<2+> / permeability transition pore (PTP) / プロテインキナーゼ |
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| Research Abstract |
The present study examined the molecular mechanisms of cell death in cultured neurons, astrocytes and microglia and the following results were obtained.
First, we studied the mitochondrial permeability transition pore (mPTP) in rat brain and liver. (1)mPTP responded to reactive oxygen species (ROS) as well as Ca^<2+>. (2)Ca^<2+> induced ROS production in mitochondria. (3)The effect of ROS on mPTP was affected by cGMP and ATP. (4)The effects of ROS and Ca^<2+> on mPTP were accompanied by release of cytochrome c which triggers apoptosis. These results suggest that Ca^<2+>-induced opening of mPTP is mediated by production of ROS. Second, we studied the roles of the Na^+/Ca^<2+> exchanger (NCX) using the inhibitor SEA0400. We demonstrated the protective role of the inhibitor in models of cardiac dysfunction and brain edema and the physiological and pathological roles of NCX in various experimental conditions. Third, we studied the mechanisms of nitric oxide (NO)-induced cytotoxicity in cultured microglia, astrocytes and neurons. NO treatment resulted in cell death and the cytotoxicity was accompanied by mitochondrial dysfunction in cultured neurons, astrocytes and microglia. NO-induced cell toxicity in cultured microglia was attenuated by SEA0400 and edaravone. NO-induced cell toxicity in cultured neurons was attenuated by T-817. In microglia, endoplasmic reticulum stress-induced dysfunction of Ca^<2+> regulation plays a key role in NO-induced cell toxicity. The present results imply that NCX is involved in NO-related diseases.
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