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OBJECTIVE The present study was desighed to determine the causative links and precise correlations among microglial activation, the ATP-gated P2X7 purinergic receptor cation channel, and neuronal degeneration during cerebral ischemic cell death.METHODS The male rats were subjected to general anesthesia, after which 1000 non-radioactive microspheres were injected into the left carotid artery.The ipsilateral hemisphere was dissected out for morphological and biochemical analysis.RESULTS The activation of microglia significantly increased in the ischemic brain at acute phase of microsphere embolism.A secondary activation of microglia was observed after 72 h and remained elevated through 168 h after microsphere embolism.The current study also focused on the temporal, morphological and biochemical aspects of FasL and its expression during the pathological process of cerebral microemboli in vivo.A significant number of FasL-expressing cells, which were diffusely labeled with a round morphology, were found restricted to the microembolic region 168 h after ME.Intriguingly, enhanced P2X7 immunoreactivity coincided with increased anti-FasL immunore-activity in same ischemic areas.We characterized a mechanism whereby activated microglia mediate neuronal cell death via P2X7 purinergic receptors and FasL/Fas signaling in response to ischemia.In animals treated with minocycline (45 mg·kg-1, less FasL expression and Fluoro-Jade C-positive structures were observed in the ipsilateral brain hemisphere of ischemic rats.CONCLUSION Based on our observations, we predict that the early activation of P2X7 purinoceptors in microglia results in gradual accumulation of FasL and the subsequent activation of downstream cell death signaling.Taken together, these results suggest the potential of a novel therapeutic neuroprotective approach using pharmacological blockade of sustained microglial activation against neurovascular disorders.