Glibenclamide Treatment in Traumatic Brain Injury: Operation Brain Trauma Therapy

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

Angol nyelvű Tudományos Szakcikk (Folyóiratcikk)
Megjelent: JOURNAL OF NEUROTRAUMA 0897-7151 38 (5) pp. 628-645 2021
  • SJR Scopus - Neurology (clinical): Q1
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-mu g/kg intraperitoneal loading dose at 10 min post-injury, followed by a continuous 7-day subcutaneous infusion [0.2 mu g/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.
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2022-01-25 00:03