Pathophysiology and treatment of cerebral edema in traumatic brain injury
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AbstractCerebral 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 Authors
SponsorsRMJ 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 itemhttps://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/10713/8549
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Molecular Mechanisms Governing Aquaporin-4 Mediated Cerebral EdemaStokum, Jesse A.; Simard, J. Marc; 0000-0002-8547-9334 (2017)Cerebral 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.
Mechanisms Regulating Edema in Anterior Ischemic Optic Neuropathy and Approaches to TreatmentNicholson, James Daniel; Bernstein, Steven L. (2012)There are few clinically effective approaches that reduce CNS white matter (WM) injury. Following WM infarct, nuclear factor κB (NFκB)-driven pro-inflammatory signaling can amplify vascular injury, resulting in progressive endothelial dysfunction and a severe ischemic lesion. I evaluated whether amplification of vascular injury in WM could be reduced using complementary approaches related to NFκB signaling: 1) I administered the anti-inflammatory compound 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), a prostaglandin known to inhibit NFκB nuclear translocation; 2) I investigate the role of sulfonylurea receptor 1 (SUR1), which is reported to contribute to vascular dysfunction by opening a non-specific cation channel in response to NFκB signaling. I evaluated the effects of 15d-PGJ2 in the rodent anterior ischemic optic neuropathy (rAION) model, an in vivo optic nerve (ON) ischemia model that shares many characteristics with the clinical condition non-arteritic anterior ischemic optic neuropathy (NAION). I found that 15d-PGJ2 administered intravenously, either acutely or 5 hours post-insult, reduced tissue edema and significantly increased survival of retinal ganglion cells (RGCs) 30 days post-rAION. I developed a novel quantitative capillary vascular analytical technique which allowed me to show that 15d-PGJ2 improves ON capillary perfusion at 1 day post-infarct. To investigate the mechanism of 15d-PGJ2 action, I developed an immunohistochemical technique that enabled me to directly determine that 15d-PGJ2 acts to reduce NFκB signaling in white matter by preventing nuclear localization of the NFκB p65 subunit. Western blot analysis and qRT-PCR gene expression analysis confirmed the 15d-PGJ2-associated reduction of NFκB signaling. SUR1 upregulation after other types of CNS focal ischemic events has been associated with edema formation. Because edema is associated with rAION, I evaluated SUR1 expression post-ON infarct using immunohistochemistry, western blot analysis, and quantitative real time polymerase chain reaction (qRT-PCR). I found no evidence that SUR1 is upregulated in WM after rAION. Using the SUR1 modulator glibenclamide, a drug approved by the U.S. Food and Drug Administration (FDA) for the treatment of type 2 diabetes, I found no difference in ON edema with and without glibenclamide treatment. My results show that, while 15d-PGJ2-associated NFκB modulation may be a useful approach for reducing ON ischemic injuries, increased NFκB signaling apparently does not result in sulfonylurea receptor 1 (SUR1) upregulation in the ON under the conditions tested. These studies may have importance for improved clinical treatment of NAION and other WM ischemic events.
Profile of intravenous glyburide for the prevention of cerebral edema following large hemispheric infarction: Evidence to dateKing, Z.A.; Sheth, K.N.; Kimberly, W.T. (Dove Medical Press Ltd., 2018)Glyburide (also known as glibenclamide) is a second-generation sulfonylurea drug that inhibits sulfonylurea receptor 1 (Sur1) at nanomolar concentrations. Long used to target KATP (Sur1–Kir6.2) channels for the treatment of diabetes mellitus type 2, glyburide was recently repurposed to target Sur1–transient receptor potential melastatin 4 (Trpm4) channels in acute central nervous system injury. Discovered nearly two decades ago, SUR1–TRPM4 has emerged as a critical target in stroke, specifically in large hemispheric infarction, which is characterized by edema formation and life-threatening brain swelling. Following ischemia, SUR1–TRPM4 channels are transcriptionally upregulated in all cells of the neurovascular unit, including neurons, astrocytes, microglia, oligodendrocytes and microvascular endothelial cells. Work by several independent laboratories has linked SUR1–TRPM4 to edema formation, with blockade by glyburide reducing brain swelling and death in preclinical models. Recent work showed that, following ischemia, SUR1–TRPM4 co-assembles with aquaporin-4 to mediate cellular swelling of astrocytes, which contributes to brain swelling. Additionally, recent work linked SUR1–TRPM4 to secretion of matrix metalloproteinase-9 (MMP-9) induced by recombinant tissue plasminogen activator in activated brain endothelial cells, with blockade of SUR1–TRPM4 by glyburide reducing MMP-9 and hemorrhagic transformation in preclinical models with recombinant tissue plasminogen activator. The recently completed GAMES (Glyburide Advantage in Malignant Edema and Stroke) clinical trials on patients with large hemispheric infarctions treated with intravenous glyburide (RP-1127) revealed promising findings with regard to brain swelling (midline shift), MMP-9, functional outcomes and mortality. Here, we review key elements of the basic science, preclinical experiments and clinical studies, both retrospective and prospective, on glyburide in focal cerebral ischemia and stroke.