2002 Fiscal Year Final Research Report Summary
Pathophysiology and treatment for the acute phase of ischemic cerebrovascular disease
| Project/Area Number |
13470137
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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 |
Neurology
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| Research Institution | Tokai University |
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Principal Investigator |
SHINOHARA Yukito Tokai University, School of Medicine, Professor, 医学部, 教授 (60051504)
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| Co-Investigator(Kenkyū-buntansha) |
MATSUDA Hiroshi Tokai University, School of Medicine, Assistant Researcher, 医学部, 助手 (20317811)
HIRABAYASHI Hisayuki Tokai University, School of Medicine, Assistant Researcher, 医学部, 助手 (60328143)
TAKIZAWA Shunya Tokai University, School of Medicine, Associate Professor, 医学部, 助教授 (70197234)
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| Project Period (FY) |
2001 – 2002
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| Keywords | myeloperoxidase / cerebral ischemia / infarct volume / nitric oxide / 3-nitro-L-tyrosine / peroxynitrite / brain edema / knockout mouse |
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| Research Abstract |
Peroxynitrite has been shown to be responsible for nitration in vivo, while myeloperoxidase (MPO) can also catalyze protein nitration in the presence of high NO2- levels. Recent reports of MPO-mediated enzyme inactivation or lipid peroxidation have suggested a role of MPO in various pathological conditions. As the first study in this project, we measured nitrotyrosine formation and infarct volume in MPO-deficient or wild-type mice subjected to 2-hour focal cerebral ischemia-reperfusion, to clarify the role of MPO in ischemia brain injury. Twenty-four hours after reperfusion, infarct volume in MPO-deficient mice was significantly larger than that in the wild- type mice (81±20 mm3 vs. 52±13 mm3; p<0.01), and nitrotyrosine levels in the infarct region showed a tendency to be higher in the MPO-deficient mice than in the wild-type mice (13.4±6.1 vs. 9.8±4.4 μg/mg; p=0.13). At 14 hours after reperfusion, the nitrotyrosine level was significantly higher in MPO-deficient mice, compared with th
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at in the wild-type mice (3.3±2.9 vs. 1.4±0.4 μg/mg; p<0.05). We conclude that the absence of MPO increases ischemic neuronal damage in vivo, and the MPO-mediated pathway is not responsible for the nitration reaction in cerebral ischemia-reperfusion.
Furthermore, widespread interest in the benefit of thrombolysis has been discussed, but little attention has been paid to reperfusion injury. The purpose of the second study in this project is to evaluate the difference in nitrotyrosine formation and infarct volume between permanent and transient focal ischemia in rats. Permanent (n=14) or transient (n=12) focal ischemia was induced by permanent or 2-hour occlusion of the middle cerebral artery, respectively, with the permanent ligation of the bilateral common carotid arteries in Sprague-Dawley rats. All animals were killed at 24-hour after the start of occlusion in both models. The ratio of nitrotyrosine in the pen-infarct and core-of-infarct regions in transient focal ischemia was significantly higher than in permanent focal ischemia (p<0.01). Infarct volume in cortex, in neither caudoputamen nor whole brain, was significantly larger in transient ischemia than in permanent ischemia (p<0.05), with significant expansion of brain swelling. These results may be caused by the higher production of superoxide and nitric oxide owing to reperfusion, and suggest the necessity to administer neuroprotective drugs as well as thrombolytic agents in the treatment of acute ischemic cerebral damage. Less
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Research Products
(2 results)
