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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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.
Magnetic resonance imaging pilot study of intravenous glyburide in traumatic brain injuryEisenberg, H.M.; Simard, J.M.; Aldrich, C.; Hayman, E.G. (Mary Ann Liebert Inc., 2020)Pre-clinical studies of traumatic brain injury (TBI) show that glyburide reduces edema and hemorrhagic progression of contusions. We conducted a small Phase II, three-institution, randomized placebo-controlled trial of subjects with TBI to assess the safety and efficacy of intravenous (IV) glyburide. Twenty-eight subjects were randomized and underwent a 72-h infusion of IV glyburide or placebo, beginning within 10 h of trauma. Of the 28 subjects, 25 had Glasgow Coma Scale (GCS) scores of 6-10, and 14 had contusions. There were no differences in adverse events (AEs) or severe adverse events (ASEs) between groups. The magnetic resonance imaging (MRI) percent change at 72-168 h from screening/baseline was compared between the glyburide and placebo groups. Analysis of contusions (7 per group) showed that lesion volumes (hemorrhage plus edema) increased 1036% with placebo versus 136% with glyburide (p = 0.15), and that hemorrhage volumes increased 11.6% with placebo but decreased 29.6% with glyburide (p = 0.62). Three diffusion MRI measures of edema were quantified: mean diffusivity (MD), free water (FW), and tissue MD (MDt), corresponding to overall, extracellular, and intracellular water, respectively. The percent change with time for each measure was compared in lesions (n = 14) versus uninjured white matter (n = 24) in subjects receiving placebo (n = 20) or glyburide (n = 18). For placebo, the percent change in lesions for all three measures was significantly different compared with uninjured white matter (analysis of variance [ANOVA], p < 0.02), consistent with worsening of edema in untreated contusions. In contrast, for glyburide, the percent change in lesions for all three measures was not significantly different compared with uninjured white matter. Further study of IV glyburide in contusion TBI is warranted. Copyright Howard M. Eisenberg et al., 2019.
Cryo-Electron Microscopy Structure Determination of the Anthrax Toxin Protective Antigen Bound to its Lethal and Edema FactorsHardenbrook, Nathan; Krantz, Bryan A. (2020)Protein translocation is an essential function within all living cells. Translocons are dedicated protein translocation machinery, responsible for the unfolding and translocation of proteins. Due to the thermostability of most proteins in their native states, these translocons utilize various different forms of energy to drive the translocation of their substrates. This process is mediated by polypeptide clamps responsible for catalyzing the unfolding and translocation of the protein. Using lipid nanodiscs and cryo-electron microscopy (cryoEM), we have determined structures of heptameric anthrax lethal toxin and edema toxin channels to 4.6 and 3.2-Å resolution, respectively. Additionally, using cryoEM we have determined the first atomic structures of PA8 prechannel bound to full-length EF and LF to 3.3 and 3.7-Å resolution, respectively. In this pre-translocation state, the first α helix and β strand of LF and EF unfold and the α clamp, which resides at the interface of two PA subunits. The α clamp-helix interactions exhibit structural plasticity when comparing the structures of lethal and edema toxins, supporting previous work indicating that the α-clamp engages substrate α-helices repeatedly during translocation. A PA loop in the binding interface is displaced between the prechannel and channel. This results in the loss of a salt bridge and leading to the weakening of the binding interface prior to translocation in the PA7EF structure. Lastly, EF undergoes a largescale conformational rearrangement when forming the complex with PA, compared the solution structure of EF bound to calmodulin. Recruitment to the PA prechannel exposes an originally buried β strand and enables domain organization of EF. Many interactions are formed on domain interfaces in both PA prechannel-bound EF and LF, leading to toxin compaction prior to translocation. This work has resulted in the first structures of PA bound by edema factor, as well as the first structures of PA bound to a full-length substrate. These structures have provided insight into important biophysical steps occurring in preparation for translocation They reveal structural plasticity within the binding α-clamp binding site, allowing the translocating substrate to be engaged multiple times. This provides a greater understanding of how anthrax toxin can invade the host cytosol.