Pathophysiology and treatment of cerebral edema in traumatic brain injury
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Date
2019Journal
NeuropharmacologyPublisher
Elsevier LtdType
ReviewMetadata
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Cerebral edema (CE) and resultant intracranial hypertension are associated with unfavorable prognosis in traumatic brain injury (TBI). CE is a leading cause of in-hospital mortality, occurring in >60% of patients with mass lesions, and ∼15% of those with normal initial computed tomography scans. After treatment of mass lesions in severe TBI, an important focus of acute neurocritical care is evaluating and managing the secondary injury process of CE and resultant intracranial hypertension. This review focuses on a contemporary understanding of various pathophysiologic pathways contributing to CE, with a subsequent description of potential targeted therapies. There is a discussion of identified cellular/cytotoxic contributors to CE, as well as mechanisms that influence blood-brain-barrier (BBB) disruption/vasogenic edema, with the caveat that this distinction may be somewhat artificial since molecular processes contributing to these pathways are interrelated. While an exhaustive discussion of all pathways with putative contributions to CE is beyond the scope of this review, the roles of some key contributors are highlighted, and references are provided for further details. Potential future molecular targets for treating CE are presented based on pathophysiologic mechanisms. We thus aim to provide a translational synopsis of present and future strategies targeting CE after TBI in the context of a paradigm shift towards precision medicine. This article is part of the Special Issue entitled "Novel Treatments for Traumatic Brain Injury". Copyright 2018 The AuthorsSponsors
RMJ is supported by grants from the National Institute of Neurological Disorders and Stroke ( K23NS101036 ) and a UPP foundation award. PMK is supported by grants from the NINDS ( R01NS087978 ), the U.S. Department of Defense grant WH81XWH-14-2-0018 , and the Eunice Kennedy Shriver National Institute of Child Health and Human Development ( T32HD040686 ). JMS is supported by grants from the Department of Veterans Affairs ( I01BX002889 ), the Department of Defense ( SCI170199 ), the National Heart, Lung, and Blood Institute ( R01HL082517 ) and the NINDS ( R01NS060801 ; R01NS102589 ; R01NS105633 ).Identifier to cite or link to this item
https://www.scopus.com/inward/record.uri?eid=2-s2.0-85051130625&doi=10.1016%2fj.neuropharm.2018.08.004&partnerID=40&md5=690d971fa564f8e4bb958a8455c0236e; http://hdl.handle.net/10713/8549Scopus Count
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Molecular Mechanisms Governing Aquaporin-4 Mediated Cerebral EdemaCerebral edema, which accompanies all forms of CNS injury, is a pressing clinical problem. Aquaporin-4 (Aqp4), a passive astrocytic transmembrane water channel, has a central role in cerebral edema formation. However, the molecular mechanisms that govern Aqp4 activity after CNS injury are incompletely understood. Here, I sought to characterize the role of two Aqp4-governing mechanisms in Aqp4-mediated cerebral edema: (i) Aqp4 expression and subcellular localization, and (ii) transmembrane osmotic gradients. I determined that, following ischemic stroke, Aqp4 is upregulated to a greater extent in white matter astrocytes versus grey matter astrocytes. I hypothesized that regional heterogeneity in Aqp4 expression generates regional differences in tissue swelling. I report that white matter exhibits greater swelling than grey matter after cerebral ischemia. These results demonstrate a direct correlation between the pattern of Aqp4 expression and the differential propensity of white matter versus grey matter to swell after ischemic insult. Astrocyte swelling occurs after CNS injury and manifests as brain swelling. Mechanisms proffered to explain astrocyte swelling emphasize the importance of either aquaporin-4 (Aqp4), an astrocyte water channel, or of Na+ channels and pumps, which mediate cellular osmolyte influx. However, it is unclear how Na+ and water interact to drive swelling. I hypothesized that, after injury, Aqp4 physically co-associates with newly-expressed Na+ channels, accounting for astrocyte swelling. I report that the Aqp4 water channel physically co-assembles with the Sur1-Trpm4 monovalent cation channel to form a novel heteromultimeric water/ion channel. In vitro functional studies showed that ion and water flux through the Sur1-Trpm4-Aqp4 complex synergize to mediate fast, high-capacity water transport that generates cell swelling. In a murine model of brain edema, astrocytes de novo expressed Sur1-Trpm4, which co-associated with Aqp4. Genetic inactivation of the Sur1-Trpm4-Aqp4 complex via knockout of Trpm4 blocked astrocyte swelling, corroborating in vitro functional studies of cell swelling. Together, these findings demonstrate a novel molecular mechanism involving the Sur1-Trpm4-Aqp4 complex to account for bulk water influx during astrocyte swelling. Furthermore, these data indicate that ion channel antagonists could be used to indirectly modulate Aqp4.
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