P2X7 Receptor-Associated Programmed Cell Death in the Pathophysiology of Hemorrhagic Stroke

Hemorrhagic stroke is a life-threatening disease characterized by a sudden rupture of cerebral blood vessels, and cell death is widely believed to occur after exposure to blood metabolites or subsequently damaged cells. Recently, programmed cell death, such as apoptosis, autophagy, necroptosis, pyroptosis, and ferroptosis, has been demonstrated to play crucial roles in the pathophysiology of stroke. However, the detailed mechanisms of these novel kinds of cell death are still unclear. The P2X7 receptor, previously known for its cytotoxic activity, is an ATP-gated, nonselective cation channel that belongs to the family of ionotropic P2X receptors. Evolving evidence indicates that the P2X7 receptor plays a pivotal role in central nervous system pathology; genetic deletion and pharmacological blockade of the P2X7 receptor provide neuroprotection in various neurological disorders, including intracerebral hemorrhage and subarachnoid hemorrhage. The P2X7 receptor may regulate programmed cell death via (I) exocytosis of secretory lysosomes, (II) exocytosis of autophagosomes or autophagolysosomes during formation of the initial autophagic isolation membrane or omegasome, and (III) direct release of cytosolic IL-1β secondary to regulated cell death by pyroptosis or necroptosis. In this review, we present an overview of P2X7 receptor- associated programmed cell death for further understanding of hemorrhagic stroke pathophysiology, as well as potential therapeutic targets for its treatment.