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dc.contributor.authorKimbler, Donald E.
dc.contributor.authorShields, Jessica
dc.contributor.authorYanasak, Nathan
dc.contributor.authorVender, John R.
dc.contributor.authorDhandapani, Krishnan M.
dc.date.accessioned2012-10-26T20:30:47Z
dc.date.available2012-10-26T20:30:47Z
dc.date.issued2012-07-17en_US
dc.identifier.citationPLoS One. 2012 Jul 17; 7(7):e41229en_US
dc.identifier.issn1932-6203en_US
dc.identifier.pmid22815977en_US
dc.identifier.doi10.1371/journal.pone.0041229en_US
dc.identifier.urihttp://hdl.handle.net/10675.2/808
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 (P2X7â /â mice) of the purinergic P2x7 receptor attenuated the expression of the pro-inflammatory cytokine, interleukin-1β (IL-1β) 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-1β 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 astrocytic end feet and administration of BBG decreased the expression of glial fibrillary acidic protein (GFAP), a reactive astrocyte marker, and attenuated 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.
dc.rightsKimbler et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.en_US
dc.subjectResearch Articleen_US
dc.subjectBiologyen_US
dc.subjectModel Organismsen_US
dc.subjectAnimal Modelsen_US
dc.subjectMouseen_US
dc.subjectNeuroscienceen_US
dc.subjectCellular Neuroscienceen_US
dc.subjectMolecular Neuroscienceen_US
dc.subjectNeurochemistryen_US
dc.subjectNeuropsychologyen_US
dc.subjectMedicineen_US
dc.subjectNeurologyen_US
dc.subjectCerebrovascular Diseasesen_US
dc.subjectHead Injuryen_US
dc.subjectNeurointensive Careen_US
dc.subjectNeuropharmacologyen_US
dc.subjectNeurorehabilitation and Traumaen_US
dc.subjectSurgeryen_US
dc.subjectNeurosurgeryen_US
dc.subjectTrauma Surgeryen_US
dc.titleActivation of P2X7 Promotes Cerebral Edema and Neurological Injury after Traumatic Brain Injury in Miceen_US
dc.typeArticleen_US
dc.identifier.pmcidPMC3398891en_US
dc.contributor.corporatenameDepartment of Neurosurgery
dc.contributor.corporatenameDepartment of Radiology
refterms.dateFOA2019-04-10T00:56:16Z
html.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 (P2X7â /â mice) of the purinergic P2x7 receptor attenuated the expression of the pro-inflammatory cytokine, interleukin-1β (IL-1β) 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-1β 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 astrocytic end feet and administration of BBG decreased the expression of glial fibrillary acidic protein (GFAP), a reactive astrocyte marker, and attenuated 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.


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