Objective Emerging epidemiological and clinical evidence indicates that microgtia-induced neurotoxicity may be a factor contributing to the development of ischemia or neurodegeneration in response to pathological signals.The current study focused on the temporal, morphological and biochemical aspects of FasL and its expression during the pathological process of cerebral microemboli in vivo.We characterized a mechanism whereby activated microglia mediate neuronal cell death via P2X7 purinergic receptors and FasL/Fas signaling in response to ischemia.Methods The intracellutar events following microsphere embolism were identified by immunohistochemistry study and Western blot assay.The role of P2X7-FasL signaling was addressed by pharmacological approaches and FasL-deficient (gld/ gld) mice.Results 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 caspases.This, in turn, further exaggerates P2X7-mediated microglial activation and triggers a vicious circle of neuronal cell death.Our findings show that FasL is a necessary component of microglia-induced cell death in vitro and in vivo and introduce a novel apoptotic stimulus that works through a P2X7-dependent mechanism.Conclusion These results highlight the potential of a novel therapeutic neuroprotective approach using pharmacological blockade of sustained microglial activation and the death-inducing ligand.