| Project/Area Number |
03454376
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| Research Category |
Grant-in-Aid for General Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
麻酔学
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| Research Institution | Yamaguchi University |
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Principal Investigator |
SAKABE Takefumi Yamaguchi University, School of Medicine Professor, 医学部, 教授 (40035225)
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| Co-Investigator(Kenkyū-buntansha) |
NAKAKIMURA Kazuhiko Yamaguchi University, School of Medicine Research Associate, 医学部, 助手 (50180261)
DAIKAI Sadamitsu Yamaguchi University, Hospital Assistant Professor, 医学部・附属病院, 講師 (10187164)
MAEKAWA Tsuyoshi Yamaguchi University, Hospital Professor, 医学部・附属病院, 教授 (60034972)
ISHIKAWA Toshizoh Yamaguchi University, School of Medicine Research Associate, 医学部, 助手 (90034991)
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| Project Period (FY) |
1991 – 1992
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| Project Status |
Completed (Fiscal Year 1992)
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| Budget Amount *help |
¥5,200,000 (Direct Cost: ¥5,200,000)
Fiscal Year 1992: ¥1,900,000 (Direct Cost: ¥1,900,000)
Fiscal Year 1991: ¥3,300,000 (Direct Cost: ¥3,300,000)
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| Keywords | brain ischemia / delayed neuronal death / neurotransmitter derangements / intracellular signal transduction / microdialysis / neurobehavioral disturbance / hypothermia / drug theraphy / 海馬CA_1 / 神経伝達物質 / 記憶障害 / セカンドメッセンジャ- |
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| Research Abstract |
The present study was designed to gain further insight into the role of excitonic mechanisms due to overactivity of the neurotransmitters associated with perturbation of intracellular signal transduction may be responsible for brain damage after transient ischemia or hypoxia in rats. 1. Brain ischemia: After transient forebrain ischemia induced by bilateral carotid artery occlusion and hemorrhagic hypotension(BP 50mmHg), the excessive release of DA in striatum due to the increased Ca^<++> influx into presynaptic neurons (opening of the N type Ca channel) was inhibited by the mild hypothermia(-3 ﾟC), staurosporine (protein kinase C inhibitor), and pentobarbital(PB:GABA agonist). By using in vitro autoradiography, the changes of intracellular signal transduction in the hippocampus CA_1 were found during early period of recirculation. The binding sites for^3H-PDBu(protein kinase C) increased while ^3H-forskolin(adenylate cyclase) and ^3H-PN200-110(L type Ca channel) decreased. Mild hypoth
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ermia and PB prevent these perturbations. Ca accumulation in hippocampus CA1 7 days following ischemia were less severe in rats with mild hypothermia, PB, and sadenosyl methionine(SAMe: accelerator of synthesis of phosphatidyl choline). These results suggest that the marked alteration of intracellular signal transduction precedes the delayed neuronal death in the hippocampus CA_1. Memory dysfunction tested by conditioned avoidance response for 7 days after ischemia was also prevented by these treatments.
2. Hypoxia: The neurologic disturbances(gait, hypoactivity) and spatial learning deficits were observed after 0.3% CO exposure. The significant decrease of binding sites for ^3H-GTP and ^3H-PN200-110 in hippocampus and cerebral cortex, and ^3H-forskolin and ^3H-PDBu in extrapyramidal system were found 3 and 14 days after CO exposure. These results suggest that perturbation of intracellular signal transduction may be induced in association with neurobehavioral dysfunction in patients with CO intoxication. In conclusion, mild hypothermia and barbiturates ameliorate the excessive neurotransmitter release, derangements of intracellular signal transduction and Ca(i) elevation in the vulnerable brain regions after transient brain hypoxia/ischemia. The GABA agonist, Ca entry blocker, and acceleration of resynthesis of phosphatidyl choline may be beneficial to prevent the delayed neuronal death. Less
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