Article
Apoptosis is mainly induced in astrocyte but not mediated via angiotensin AT1 receptor after cerebral
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Published: | August 8, 2006 |
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Our recent findings suggest that cerebral angiotensin AT2 receptor-mediated neuroprotection is required for the beneficial actions of AT1 receptor antagonist in rat models of brain ischemia. It is unknown whether a direct inhibition of cerebral angiotensin AT1 receptor-mediated actions (i.e. apoptosis) is also contribute to these cerebroprotections of AT1 receptor antagonists. The present study was designed to examine the in vivo role of AT1 receptors in cerebral ischemia-induced apoptosis. We first assessed apoptosis induction in the brain in response to transient unilateral medial cerebral artery occlusion in rats by Western blot analysis and immunofluorescence staining. Forty-eight hours after ischemia, Western blot analysis showed an upregulation of p53 in the peri-infarct zone when compared to sham operated controls. Immunofluorescence staining further revealed that cerebral ischemia induced the expression of cleaved caspase-3 in the peri-infarct zone when compared to c!
ontralateral side or sham operated controls. By double immunofluorescence staining, we could confirm that both AT1 receptor and increased cleaved caspase-3 were mainly located in GFAP+ astrocytes. To clarify the in vivo role of AT1 receptor in astrocyte apoptosis, an AT1 receptor antagonist (candesartan, 0,1 mg/kg) was injected subcutaneously over a period of 5 days before cerebral ischemia. Candesartan significantly improved neurological outcome and reduced the infarct size forty-eight hours after cerebral ischemia. However, the upregulated p53 and cleaved caspase-3 remained unaltered after candesartan treatment. Thus, brain AT1 receptors do not seem to be involved in astrocyte apoptosis following cerebral ischemia. These findings indicate that a direct inhibition of apoptosis in the brain may not play a role in the neuroprotective effects of the AT1 receptor antagonist after cerebral ischemia.