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
- A Precision Medicine Approach to Cerebral Edema and Intracranial Hypertension after Severe Traumatic Brain Injury: Quo Vadis?
- Authors: Jha RM, Kochanek PM
- Issue date: 2018 Nov 7
- Cerebral Edema in Traumatic Brain Injury: Pathophysiology and Prospective Therapeutic Targets.
- Authors: Winkler EA, Minter D, Yue JK, Manley GT
- Issue date: 2016 Oct
- Reduction of Cerebral Edema via an Osmotic Transport Device Improves Functional Outcome after Traumatic Brain Injury in Mice.
- Authors: McBride DW, Donovan V, Hsu MS, Obenaus A, Rodgers VG, Binder DK
- Issue date: 2016
- ABCC8 Single Nucleotide Polymorphisms are Associated with Cerebral Edema in Severe TBI.
- Authors: Jha RM, Puccio AM, Okonkwo DO, Zusman BE, Park SY, Wallisch J, Empey PE, Shutter LA, Clark RS, Kochanek PM, Conley YP
- Issue date: 2017 Apr
- Simulating cerebral edema and delayed fatality after traumatic brain injury using triphasic swelling biomechanics.
- Authors: Basilio AV, Xu P, Takahashi Y, Yanaoka T, Sugaya H, Ateshian GA, Morrison B 3rd
- Issue date: 2019
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SUR1-TRPM4 channels, not K(ATP), mediate brain swelling following cerebral ischemiaWoo, S.K.; Tsymbalyuk, N.; Tsymbalyuk, O.; Ivanova, S.; Gerzanich, V.; Simard, J.M. (Elsevier, 2020)BACKGROUND: Preclinical and emerging clinical data show that glibenclamide reduces space occupying edema and brain swelling following cerebral ischemia. Glibenclamide is a potent inhibitor of numerous sulfonylurea receptor (SUR)-regulated channels, including KATP (SUR1-KIR6.2, SUR2A-KIR6.2, SUR2B-KIR6.2, SUR2B-KIR6.1) and SUR1-TRPM4. Here, we used molecularly specific oligodeoxynucleotides (ODNs) to investigate the role of various SUR-regulated ion channel subunits in post-ischemic brain swelling. METHODS: Focal cerebral ischemia was induced in adult male rats by permanent middle cerebral artery occlusion (pMCAo). We used this model to study the effects of antisense-ODNs (AS-ODNs) directed against Abcc8/SUR1, Trpm4/TRPM4, Kcnj8/KIR6.1 and Kcnj11/KIR6.2 on hemispheric swelling, with sense or scrambled ODNs used as controls. We used antibody-based Förster resonance energy transfer (immuno-FRET) and co-immunoprecipitation to study the co-assembly of SUR1-TRPM4 heteromers. RESULTS: In the combined control groups administered sense or scrambled ODNs, pMCAo resulted in uniformly large infarct volumes (mean ± SD: 57.4 ± 8.8 %; n = 34) at 24 h after onset of ischemia, with no effect of AS-ODNs on infarct size. In controls, hemispheric swelling was 23.9 ± 4.1 % (n = 34), and swelling was linearly related to infarct volume (P < 0.02). In the groups administered anti-Abcc8/SUR1 or anti-Trpm4/TRPM4 AS-ODN, hemispheric swelling was significantly less, 11.6 ± 3.9 % and 12.8 ± 5.8 % respectively (P < 0.0001), and the relationship between infarct volume and swelling was reduced and not significant. AS-ODNs directed against Kcnj8/KIR6.1 and Kcnj11/KIR6.2 had no significant effect on hemispheric swelling (23.3 ± 5.4 % and 22.9 ± 5.8 % respectively). Post-ischemic tissues showed co-assembly of SUR1-TRPM4 heteromers. CONCLUSIONS: Post-ischemic hemispheric swelling can be decoupled from infarct volume. SUR1-TRPM4 channels, not KATP, mediate post-ischemic brain swelling. Copyright 2019 The Author(s).
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.
Role of Sulfonylurea Receptor 1 and Glibenclamide in Traumatic Brain Injury: A Review of the EvidenceJha, R.M.; Bell, J.; Simard, J.M. (MDPI, 2020)Cerebral edema and contusion expansion are major determinants of morbidity and mortality after TBI. Current treatment options are reactive, suboptimal and associated with significant side effects. First discovered in models of focal cerebral ischemia, there is increasing evidence that the sulfonylurea receptor 1 (SUR1)-Transient receptor potential melastatin 4 (TRPM4) channel plays a key role in these critical secondary injury processes after TBI. Targeted SUR1-TRPM4 channel inhibition with glibenclamide has been shown to reduce edema and progression of hemorrhage, particularly in preclinical models of contusional TBI. Results from small clinical trials evaluating glibenclamide in TBI have been encouraging. A Phase-2 study evaluating the safety and efficacy of intravenous glibenclamide (BIIB093) in brain contusion is actively enrolling subjects. In this comprehensive narrative review, we summarize the molecular basis of SUR1-TRPM4 related pathology and discuss TBI-specific expression patterns, biomarker potential, genetic variation, preclinical experiments, and clinical studies evaluating the utility of treatment with glibenclamide in this disease.