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Glibenclamide Treatment in Traumatic Brain Injury: Operation Brain Trauma Therapy.

ABSTRACT: Glibenclamide (GLY) is the sixth drug tested by the Operation Brain Trauma Therapy (OBTT) consortium based on substantial pre-clinical evidence of benefit in traumatic brain injury (TBI). Adult Sprague-Dawley rats underwent fluid percussion injury (FPI; n = 45), controlled cortical impact (CCI; n = 30), or penetrating ballistic-like brain injury (PBBI; n = 36). Efficacy of GLY treatment (10-μg/kg intraperitoneal loading dose at 10 min post-injury, followed by a continuous 7-day subcutaneous infusion [0.2 μg/h]) on motor, cognitive, neuropathological, and biomarker outcomes was assessed across models. GLY improved motor outcome versus vehicle in FPI (cylinder task, p < 0.05) and CCI (beam balance, p < 0.05; beam walk, p < 0.05). In FPI, GLY did not benefit any other outcome, whereas in CCI, it reduced 21-day lesion volume versus vehicle (p < 0.05). On Morris water maze testing in CCI, GLY worsened performance on hidden platform latency testing versus sham (p < 0.05), but not versus TBI vehicle. In PBBI, GLY did not improve any outcome. Blood levels of glial fibrillary acidic protein and ubiquitin carboxyl terminal hydrolase-1 at 24 h did not show significant treatment-induced changes. In summary, GLY showed the greatest benefit in CCI, with positive effects on motor and neuropathological outcomes. GLY is the second-highest-scoring agent overall tested by OBTT and the only drug to reduce lesion volume after CCI. Our findings suggest that leveraging the use of a TBI model-based phenotype to guide treatment (i.e., GLY in contusion) might represent a strategic choice to accelerate drug development in clinical trials and, ultimately, achieve precision medicine in TBI.

SUBMITTER: Jha RM

PROVIDER: S-EPMC8418525 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Glibenclamide Treatment in Traumatic Brain Injury: Operation Brain Trauma Therapy.

Jha Ruchira M RM Mondello Stefania S Bramlett Helen M HM Dixon C Edward CE Shear Deborah A DA Dietrich W Dalton WD Wang Kevin K W KKW Yang Zhihui Z Hayes Ronald L RL Poloyac Samuel M SM Empey Philip E PE Lafrenaye Audrey D AD Yan Hong Q HQ Carlson Shaun W SW Povlishock John T JT Gilsdorf Janice S JS Kochanek Patrick M PM

Journal of neurotrauma 20201218 5

Glibenclamide (GLY) is the sixth drug tested by the Operation Brain Trauma Therapy (OBTT) consortium based on substantial pre-clinical evidence of benefit in traumatic brain injury (TBI). Adult Sprague-Dawley rats underwent fluid percussion injury (FPI; n = 45), controlled cortical impact (CCI; n = 30), or penetrating ballistic-like brain injury (PBBI; n = 36). Efficacy of GLY treatment (10-μg/kg intraperitoneal loading dose at 10 min post-injury, followed by a continuous 7- ...[more]

PMID: 33203303

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Project description:Traumatic brain injury (TBI) is a leading cause of death and disability. Yet, despite immense research efforts, treatment options remain elusive. Translational failures in TBI are often attributed to the heterogeneity of the TBI population and limited methods to capture these individual variabilities. Advances in machine learning (ML) have the potential to further personalized treatment strategies and better inform translational research. However, the use of ML has yet to be widely assessed in pre-clinical neurotrauma research, where data are strictly limited in subject number. To better establish ML's feasibility, we utilized the fluid percussion injury (FPI) portion of the rich, rat data set collected by Operation Brain Trauma Therapy (OBTT), which tested multiple pharmacological treatments. Previous work has provided confidence that both unsupervised and supervised ML techniques can uncover useful insights from this OBTT pre-clinical research data set. As a proof-of-concept, we aimed to better evaluate the multi-variate recovery profiles afforded by the administration of nine different experimental therapies. We assessed supervised pairwise classifiers trained on a pre-processed data set that incorporated metrics from four feature groups to determine their ability to correctly identify specific drug treatments. In all but one of the possible pairwise combinations of minocycline, levetiracetam, erythropoietin, nicotinamide, and amantadine, the baseline was outperformed by one or more supervised classifiers, the exception being nicotinamide versus amantadine. Further, when the same methods were employed to assess different doses of the same treatment, the ML classifiers had greater difficulty in understanding which treatment each sample received. Our data serve as a critical first step toward identifying optimal treatments for specific subgroups of samples that are dependent on factors such as types and severity of traumatic injuries, as well as informing the prediction of therapeutic combinations that may lead to greater treatment effects than individual therapies.

Project description:Cerebral edema is critical to morbidity/mortality in traumatic brain injury (TBI) and is worsened by hypotension. Glibenclamide may reduce cerebral edema by inhibiting sulfonylurea receptor-1 (Sur1); its effect on diffuse cerebral edema exacerbated by hypotension/resuscitation is unknown. We aimed to determine if glibenclamide improves pericontusional and/or diffuse edema in controlled cortical impact (CCI) (5m/sec, 1?mm depth) plus hemorrhagic shock (HS) (35?min), and compare its effects in CCI alone. C57BL/6 mice were divided into five groups (n?=?10/group): naïve, CCI+vehicle, CCI+glibenclamide, CCI+HS+vehicle, and CCI+HS+glibenclamide. Intravenous glibenclamide (10?min post-injury) was followed by a subcutaneous infusion for 24?h. Brain edema in injured and contralateral hemispheres was subsequently quantified (wet-dry weight). This protocol brain water (BW)?=?80.4% vehicle vs. 78.3% naïve, p?<?0.01) but was not reduced by glibenclamide (I%BW?=?80.4%). Ipsilateral edema also developed in CCI alone (I%BW?=?80.2% vehicle vs. 78.3% naïve, p?<?0.01); again unaffected by glibenclamide (I%BW?=?80.5%). Contralateral (C) %BW in CCI+HS was increased in vehicle (78.6%) versus naive (78.3%, p?=?0.02) but unchanged in CCI (78.3%). At 24?h, glibenclamide treatment in CCI+HS eliminated contralateral cerebral edema (C%BW?=?78.3%) with no difference versus naïve. By 72?h, contralateral cerebral edema had resolved (C%BW?=?78.5?±?0.09% vehicle vs. 78.3?±?0.05% naïve). Glibenclamide decreased 24?h contralateral cerebral edema in CCI+HS. This beneficial effect merits additional exploration in the important setting of TBI with polytrauma, shock, and resuscitation. Contralateral edema did not develop in CCI alone. Surprisingly, 24?h of glibenclamide treatment failed to decrease ipsilateral edema in either model. Interspecies dosing differences versus prior studies may play an important role in these findings. Mechanisms underlying brain edema may differ regionally, with pericontusional/osmolar swelling refractory to glibenclamide but diffuse edema (via Sur1) from combined injury and/or resuscitation responsive to this therapy. TBI phenotype may mandate precision medicine approaches to treat brain edema.

Dataset Information

Glibenclamide Treatment in Traumatic Brain Injury: Operation Brain Trauma Therapy.

Publications

Glibenclamide Treatment in Traumatic Brain Injury: Operation Brain Trauma Therapy.

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