• Therapeutic Targeting of P2X7 After Traumatic Brain Injury

      Kimbler, Donald E.; Department of Neurosurgery (2012-02)
      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-/- mice) of the purinergic P2X7 receptor attenuated the expression of the pro-inflammatory cytokine, interleukin-iP (IL-ip) and reduced cerebral edema following controlled cortical impact, as compared to wild-type mice. Similarly, the clinically useful P2X7 inhibitor, brilliant blue G (BBG), inhibited the expression of IL-ip, limited edemic development and prevented the development of post-traumatic depression and anxiety. The beneficial effects of BBG were observed following 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 astrocytic end feet and administration of BBG decreased the expression of glial fibrillary acidic protein (GFAP), a reactive astrocyte marker, and reduced the expression of aquaporin-4 (AQP4), an astrocytic water channel that promotes cellular edema. Together, these data implicate P2X7 as a novel therapeutic target to prevent secondary neurological injury after TBI, a finding that warrants further investigation.