Therapeutic Targeting of P2X7 After Traumatic Brain Injury

Hdl Handle:
http://hdl.handle.net/10675.2/346822
Title:
Therapeutic Targeting of P2X7 After Traumatic Brain Injury
Authors:
Kimbler, Donald E.
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-/- 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.
Affiliation:
Department of Neurosurgery
Issue Date:
Feb-2012
URI:
http://hdl.handle.net/10675.2/346822
Additional Links:
http://ezproxy.gru.edu/login?url=http://search.proquest.com/docview/1017709853?accountid=12365
Type:
Dissertation
Appears in Collections:
Theses and Dissertations

Full metadata record

DC FieldValue Language
dc.contributor.authorKimbler, Donald E.en
dc.date.accessioned2015-03-18T03:40:32Zen
dc.date.available2015-03-18T03:40:32Zen
dc.date.issued2012-02en
dc.identifier.urihttp://hdl.handle.net/10675.2/346822en
dc.description.abstractTraumatic 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.en
dc.relation.urlhttp://ezproxy.gru.edu/login?url=http://search.proquest.com/docview/1017709853?accountid=12365en
dc.rightsCopyright protected. Unauthorized reproduction or use beyond the exceptions granted by the Fair Use clause of U.S. Copyright law may violate federal law.en
dc.subjectneurotraumaen
dc.subjectIntracranial Pressureen
dc.subjectInnate Immunityen
dc.subjectNeuroinflammationen
dc.subjectATPen
dc.subjectPurinergicen
dc.subjectBrilliant Blue Gen
dc.subjectControlled Cortical Impacten
dc.titleTherapeutic Targeting of P2X7 After Traumatic Brain Injuryen
dc.typeDissertationen
dc.contributor.departmentDepartment of Neurosurgeryen
dc.description.advisorDhandapani, Krishnanen
dc.description.committeeBrann, Darrell; McClusky, Lynnette; Vender, John; Schumacher, Autumnen
dc.description.degreeDoctor of Philosophy (Ph.D.)en
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