activation of p2x7 promotes cerebral edema and neurological injury after traumatic brain injury in mice激活p2x7促进脑水肿和创伤性脑损伤后神经损伤的老鼠.pdfVIP

Activation of P2X7 Promotes Cerebral Edema and Neurological Injury after Traumatic Brain Injury in Mice 1 1 2 1 1 Donald E. Kimbler , Jessica Shields , Nathan Yanasak , John R. Vender , Krishnan M. Dhandapani * 1 Department of Neurosurgery, Georgia Health Sciences University, Augusta, Georgia, United States of America, 2 Department of Radiology, Georgia Health Sciences University, Augusta, Georgia, United States of America Abstract Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. Cerebral edema, the abnormal accumulation of fluid within the brain parenchyma, contributes to elevated intracranial pressure (ICP) and is a common life- threatening neurological complication following TBI. Unfortunately, neurosurgical approaches to alleviate increased ICP remain controversial and medical therapies are lacking due in part to the absence of viable drug targets. In the present study, genetic inhibition (P2X7 2/ 2 mice) of the purinergic P2x7 receptor attenuated the expression of the pro- inflammatory cytokine, interleukin-1b (IL-1b) and reduced cerebral edema following controlled cortical impact, as compared to wild-type mice. Similarly, brilliant blue G (BBG), a clinically non-toxic P2X7 inhibitor, inhibited IL-1b expression, limited edemic development, and improved neurobehavioral outcomes after TBI. The beneficial effects of BBG followed either prophylactic administration via the drinking water for one week prior to injury or via an intravenous bolus administration up to four hours after TBI, suggesting a clinically-implementable therapeutic window. Notably, P2X7 localized within astr