| Budget Amount *help |
¥2,100,000 (Direct Cost: ¥2,100,000)
Fiscal Year 1998: ¥400,000 (Direct Cost: ¥400,000)
Fiscal Year 1997: ¥500,000 (Direct Cost: ¥500,000)
Fiscal Year 1996: ¥1,200,000 (Direct Cost: ¥1,200,000)
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| Research Abstract |
Purpose : To clarify the role of anoxic depolarization (AD) in ischemic brain injury, we examined the correlation between AD and ischemia-induced neuronal injury. Involvement of ion channels and an effect of hypothermia in the appearance of AD were also studied to evaluate the therapeutic measures of ischemic brain injury.
Methods : Sprague-Dawley rats underwent transient forebrain ischemia with lowering blood pressure and bilateral carotid occlusion while direct current shifts, electrocorticogram, and cortical blood flow (CoBF) were epidurally recorded from the right parietal cortex. After scheduled interval (from 24 hours to 30 days), the right parietal cortex was studied histopathologically.
Results : (1) In rats exhibiting AD, it usually appeared 0.5-3.0 min after carotid occlusion. When circulation reinitiated 15 min after AD onset, 8 of 11 rats showed severe ischemic neuronal injury in the parietal cortex. Of 10 rats subjected to 10 mm of AD, severe neuronal injury was not observed
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. AD always appeared with CoBF decreasing to less than 10% of the control. When CoBF fell below 20% of the control, 9 of 14 rats exhibited AD.In 5 rats, AD did not appeared despite CoBF falling below 20% of the control and no severe neuronal injury was depicted following 20 min of ischemia. These results indicated that the appearance of AD was more closely correlated with the development of ischemic neuronal injury than degree of CoBF reduction.
(2) Pretreatment with MK8O1 (NMDA antagonist) did not alter the CoBF threshold for the appearance of AD ; however, it could delay the duration of AD for the development of severe neuronal injury by 5 min.
(3) Pretreatment with DNQX (non-NMDA antagonist) could rise the CBF threshold for the appearance of AD, but could not delay the duration of AD for the development of neuronal injury.
(4) When rats were subjected to hypothermia (brain temperature : 30-31ﾟC), AD appeared after CoBF fell below 5% of the control. If AD did not appear despite CoBF falling to 5-10% of the control, no neuronal injury was observed following 30 min of ischemia. In rats exhibiting AD under hypothermia, severe neuronal injury did not appeared following 20 min of ischemia but frequently observed following 30 min of ischemia. The present study well corresponded with previous studies reporting that hypothermia protect against neuronal injury by inhibing the release of glutamate.
Conclusion : Our studies support that the disturbance of ion homeostasis, especially transient overloading of calcium ion into neuronal cells, has a crucial role in the development of neuronal injury. The present studies suggest that AD is a more reliable determinant of irreversible brain injury than degree of CBF reduction, and also demonstrated that 15 min is the critical duration of AD for irreversible brain injury at brain temperatures around 370ﾟC.It is also indicated that mild hypothermia protected against cerebral ischemia through raising the CBF threshold inducing AD. Less
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