2004 Fiscal Year Final Research Report Summary
The role of platelet-derived spasmogens and Rho/Rho-kinase pathway in the pathogenesis of cerebral vasospasm.
| Project/Area Number |
14207053
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Cerebral neurosurgery
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| Research Institution | KYUSHU UNIVERSITY |
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Principal Investigator |
SASAKI Tomio Kyushu university, Dept of Neurosurgery, Professor, 医学研究院, 教授 (10134561)
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| Co-Investigator(Kenkyū-buntansha) |
YOKOYAMA Nobuhiko Kyushu university, Dept of Neurosurgery, Assistant Professor, 病院・講師 (50294939)
MIYAGI Yasushi Kyushu university, Dept of Neurosurgery, Research Associate, 病院・助手 (10380403)
SAITO Nobuhito Gunma university, Dept of Neurosurgery, Professor, 医学部, 教授 (60262002)
TOSAKA Masahiko Gunma university, Dept of Neurosurgery, Research Associate, 医学部, 助手 (40323357)
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| Project Period (FY) |
2002 – 2004
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| Keywords | subarachnoid hemorrhage / cerebral vasospasm / Rho / Rho-kinase pathway / sohingosine-1-phosphate / thrombin / thrombin receptor / Ca2+ sensitization / oxidative stress |
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| Research Abstract |
Cerebral vasospasm is one of the major critical determinants of the prognosis alter subarachnoid hemorrhage (SAH). As shown in our previous discovery that sphingosine-1-phosphate activates the Rho/Rho-kinase pathway in cerebral vasospasm, the activation and up-regulation of Rho and Rhokinase have been suggested to play an important role in the pathogenesis of cerebral vasospasm,
In the present study, we investigated the roles of thrombin, one of the other potent spasmogens, and the roles of Rho/Rho-kinase pathway in cerebral vasospasm. First, we investigated the effect of thrombin and its receptor expression in the hypercontractil response of spastic basilar artery of a rabbit SAH model. Thrombin up-regulated the expression of thrombin receptor and induced a hypercontractile response to thrombin itself in the spastic artery. The impaired desensitization of thrombin receptor also contributed to the hyperoontractiliy of the spastic artery. Second, we investigated the role of Rhokinase in Ca^<2+> sensitization in bovine middle cerebral artery. Thromboxane A_2 analogue, one of the patent spasmogens, induced the sustained contraction with enhanced Ca^<2+> sensitivity of the artery, which was achieved both in myosin fight chain phosphorylation-dependent and -independent manners. Third, we discovered that oxidative stress induced the contractile response of cerebral artery to bradykinin, a physiological vasorelaxant, through the activation of Rho/Rho-kinase pathway and endothelial dysfunction, which thus suggested a loss of endothelium-dependent relaxation under an oxidative stress alter SAH.
Our basic researches showed the importance of Rho/Rho-kinase pathway activation in the molecular mechanisms underlying pathogenesis of cerebral vasospasm. In particular, the regulation of thrombin receptor in the upstream of Rho/Rho-kinase pathways was indicated to be a novel therapeutic target for the prophylactic managemert of cerebral vasospasm.
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