- Glibenclamide Treatment in Traumatic Brain Injury: Operation Brain Trauma Therapy.
Glibenclamide Treatment in Traumatic Brain Injury: Operation Brain Trauma Therapy.
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; nā=ā45), controlled cortical impact (CCI; nā=ā30), or penetrating ballistic-like brain injury (PBBI; nā=ā36). Efficacy of GLY treatment (10-μg/kg intraperitoneal loading dose at 10āmin post-injury, followed by a continuous 7-day subcutaneous infusion [0.2āμg/h]) on motor, cognitive, neuropathological, and biomarker outcomes was assessed across models. GLY improved motor outcome versus vehicle in FPI (cylinder task, pā<ā0.05) and CCI (beam balance, pā<ā0.05; beam walk, pā<ā0.05). In FPI, GLY did not benefit any other outcome, whereas in CCI, it reduced 21-day lesion volume versus vehicle (pā<ā0.05). On Morris water maze testing in CCI, GLY worsened performance on hidden platform latency testing versus sham (pā<ā0.05), 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 24āh 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.