Glibenclamide Treatment in Traumatic Brain Injury: Operation Brain Trauma Therapy

Ruchira M. Jha, Stefania Mondello, Helen M. Bramlett, C. Edward Dixon, Deborah A. Shear, W. Dalton Dietrich, Kevin K.W. Wang, Zhihui Yang, Ronald L. Hayes, Samuel M. Poloyac, Philip E. Empey, Audrey D. Lafrenaye, Hong Q. Yan, Shaun W. Carlson, John T. Povlishock, Janice S. Gilsdorf, Patrick M. Kochanek

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)628-645
Number of pages18
JournalJournal of neurotrauma
Volume38
Issue number5
DOIs
StatePublished - Mar 2021

Keywords

  • cerebral edema
  • consortium
  • controlled cortical impact
  • contusion
  • fluid percussion injury
  • glyburide
  • penetrating ballistic-like brain injury
  • rat
  • sulfonylurea receptor-1

ASJC Scopus subject areas

  • Clinical Neurology

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