| Project/Area Number |
02557091
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| Research Category |
Grant-in-Aid for Developmental Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
Biological pharmacy
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| Research Institution | Tokyo Medical and Dental University |
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Principal Investigator |
MUROTA Sei-itsu Tokyo Med.&Dent.Univ., Department of Physiological Chemistry, Graduate School, Professor, 歯学部, 教授 (50072989)
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| Co-Investigator(Kenkyū-buntansha) |
IWANO Masao Mitsubishi Kasei Corp., Research Development Divis Sinior Researcher, 医薬開発部, 部員
IKEDA Junichi Tokyo Med.&Dent.Univ., Department of Physiological Chemistry, Graduate School, A, 歯学部, 助手 (60222882)
ISHIZAKI Yasuki Tokyo Med.&Dent.Univ., Department of Physiological Chemistry, Graduate School, A, 歯学部, 助手 (90183003)
MORITA Ikuo Tokyo Med.&Dent.Univ., Department of Physiological Chemistry, Graduate School, A, 歯学部, 助教授 (60100129)
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| Project Period (FY) |
1990 – 1992
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| Project Status |
Completed (Fiscal Year 1992)
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| Budget Amount *help |
¥11,200,000 (Direct Cost: ¥11,200,000)
Fiscal Year 1992: ¥2,800,000 (Direct Cost: ¥2,800,000)
Fiscal Year 1991: ¥2,700,000 (Direct Cost: ¥2,700,000)
Fiscal Year 1990: ¥5,700,000 (Direct Cost: ¥5,700,000)
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| Keywords | neuron / glutamic acid / lipid peroxide / glutathione / neuronal cell death / 神経細胞障害 |
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| Research Abstract |
The injury of endothelial cells and neuronal cells is deeply involved in the initiation of atherogenesis and senile dementia, respectively. Therefore, it is important to know what the mechanism of the cell injury is, and how to protect these cells from the injury. We found the HPETEs (hydroperoxyeicosatetraenoic acid) had a potent capacity to cause severe cell injury. During the cours of search for cytoprotective drugs, we found MCI-186 having a remarkable cytoprotective effect on the endothelial cell injury due to HPETEs. 3x10^<-5> M 15-HPETE caused cell death by 60%. But the cytotoxicity was almost completely abolished by the treatment of endothelial cells with 10^<-5> M MCI-186. On the other hand, effects of 15-HPETE on cultured nueronal cells prepared from hippocampi of 19-day-old rat embryos were examines. When neurons were exposure, however, disintegration of both cell bodies and neueites was apparent, which was preceded in many cases by swelling of the soma. Reduced glutathione
… More
effectively prevented the neuronal injury by 15-HPETE.Ebselen, apparently prevented the swelling of the soma, but was not effective in preventing the disintegration of the neurites.
Neurons which contain nicotinamide adenine dinucleotide phosphate diaphorase(NADPH-d) are know to be spared in several neurological disease in which glutamate neurotoxicity is hypothesized to be involved. Since glutamate neurotoxicity has been largely attributed to an excess loading of calcium ion in neuronal cytoplasm([Ca^<2+>]), we evaluated the changes in [Ca^<2+>] of NADPH-d positive cells after glutamate exposure, In light of recent evidence that neuronal NADPH-d is a nitric oxide synthase(NOS), we futjer evaluated the effect of inhibitor of NOS on glutamate induced calcium influx.
We found 8 NADPH-d positive neurons in 63 experiment (about 3000 neurons). In 4 NADPH-d positive neurons evaluated without L-NMMA, rise in [Ca^<2+>] induced by glutamate revealed to be less than that of LNMMA, however, there was no apparent difference in the time cours of [Ca^<2+>] between NADPH-d positive neurons and 4 negative cells.
Our results indicate that nitric oxide may play an important role in modulating calcium influx through glutamate recepter, providing a new possible therapeutic approach for glutamate neurotoxicity. Less
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