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.

• Authors: 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
• Journal: Journal of neurotrauma (J Neurotrauma) Vol. 38 Issue 5 Pg. 628-645 (03 2021) ISSN: 1557-9042 [Electronic] United States
• PMID: 33203303 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Blood Glucose
• Hypoglycemic Agents
• Glyburide

Topics

• Animals
• Blood Glucose (drug effects, metabolism)
• Brain Injuries, Traumatic (blood, drug therapy)
• Glyburide (pharmacology, therapeutic use)
• Hypoglycemic Agents (pharmacology, therapeutic use)
• Male
• Maze Learning (drug effects, physiology)
• Rats
• Rats, Sprague-Dawley
• Treatment Outcome