Therapeutic Window: From the Standpoint of Molecular Biology

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Cerebral ischemia has a relatively simple cause: occlusion of supplying blood vessels. The best treatment, therefore, is to remove the cause. If cerebral blood flow is restored within a short time, the brain is not damaged. The recent advent of thrombolytic agents such as t-PA enabled us to attain this therapeutic goal. This mode of treatment, however, is not always possible, because there is a time window during which therapy must be administered. It is well established that ischemic brain damage depends to a great extent on the duration and degree of flow reduction. If flow reduction is mild or ischemic period lasts only a few hours, patients are likely to recover. What happens when flow reduction is not mild or the duration of ischemia is longer? Ischemia, then, causes irreversible brain damage. To counter this problem, the mechanisms of ischemic brain damage have been investigated for many years, yet they still remain unknown. Glutamate has been postulated as one of the major causes of neuronal vulnerability to ischemia. Indeed, extensive evidence has been accumulated that supports this hypothesis, but anti-glutamatergic drugs have been largely unsuccessful. Recent experiments in this field have been done on the hypothesis that at least a part of ischemic brain damage progresses through apoptosis. When apoptosis is used to mean a cell death process that requires gene expression, it is quite possible that this is the case. Downstream to the main cascade of apoptosis, mitochondria are now believed to play a pivotal role. Loss of mitochondrial membrane potential and leakage of pro-apoptotic substances from the mitochondria are essential steps in apoptosis. On the other hand, loss of ATP and breakdown of mitochondrial energy metabolism are well-known characteristics of classic ischemic necrosis. Investigation of mitochondrial alteration will be the most important goal in elucidating ischemic brain damage in the next several years.
The Japanese Society on Surgery for Cerebral Strokeの論文

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桐野高明
東京大学医学部脳神経外科

Therapeutic Window: From the Standpoint of Molecular Biology

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