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Jha RM; Mondello S; Bramlett HM; Dixon CE; Shear DA; Dietrich WD; Wang KKW; Yang Z; Hayes RL; Poloyac SM; Empey PE; Lafrenaye AD; Yan HQ; Carlson SW; Povlishock JT; Gilsdorf JS; Kochanek PM
J Neurotrauma 2021[Mar]; 38 (5): 628-645 PMID33203303show ga
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-mug/kg intraperitoneal loading dose at 10 min post-injury, followed by a continuous 7-day subcutaneous infusion [0.2 mug/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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J+Neurotrauma 2021 ; 38 (5): 628-645
