Glibenclamide Treatment in Traumatic Brain Injury: Operation Brain Trauma Therapy

Authors

• Ruchira M. Jha, Safar Center for Resuscitation Research, Department of Critical Care Medicine, Anesthesiology, and Clinical and Translational Science, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.Follow
• Stefania Mondello, Department of Neurosciences, University of Messina, Messina, Italy.
• Helen M. Bramlett, Department of Neurological Surgery, The Miami Project to Cure Paralysis, Miller School of Medicine, University of Miami, and Bruce W. Carter Department of Veterans Affairs Medical Center, Miami, Florida, USA.
• C Edward Dixon, Department of Neurological Surgery, Brain Trauma Research Center, Anesthesiology, and Clinical and Translational Science, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
• Deborah A. Shear, Brain Trauma Neuroprotection Branch, Center for Military Psychiatry and Neuroscience, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA.
• W Dalton Dietrich, Department of Neurological Surgery, Brain Trauma Research Center, Anesthesiology, and Clinical and Translational Science, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
• Kevin K. Wang, Program for Neurotrauma, Neuroproteomics & Biomarkers Research, Department of Emergency Medicine, McKnight Brin Institute of the University of Florida, Gainesville, Florida, USA.
• Zhihui Yang, Program for Neurotrauma, Neuroproteomics & Biomarkers Research, Department of Emergency Medicine, McKnight Brin Institute of the University of Florida, Gainesville, Florida, USA.
• Ronald L. Hayes, Center for Innovative Research, Center for Proteomics and Biomarkers Research, Banyan Biomarkers, Inc., Alachua, Florida, USA.
• Samuel M. Poloyac, Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, Pennsylvania, USA.
• Philip E. Empey, Department of Pharmacy and Therapeutics, University of Pittsburgh School of Pharmacy, Pittsburgh, Pennsylvania, USA.
• Audrey D. Lafrenaye, Department of Anatomy and Neurobiology, Virginia Commonwealth University, Richmond, Virginia, USA.
• Hong Q. Yan, Department of Neurological Surgery, Brain Trauma Research Center, Anesthesiology, and Clinical and Translational Science, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
• Shaun W. Carlson, Department of Neurological Surgery, Brain Trauma Research Center, Anesthesiology, and Clinical and Translational Science, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
• John T. Povlishock, Department of Anatomy and Neurobiology, Virginia Commonwealth University, Richmond, Virginia, USA.
• Janice S. Gilsdorf, Brain Trauma Neuroprotection Branch, Center for Military Psychiatry and Neuroscience, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA.
• Patrick M. Kochanek, Safar Center for Resuscitation Research, Department of Critical Care Medicine, Anesthesiology, and Clinical and Translational Science, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.

Document Type

Article

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;  = 45), controlled cortical impact (CCI;  = 30), or penetrating ballistic-like brain injury (PBBI;  = 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,  < 0.05) and CCI (beam balance,  < 0.05; beam walk,  < 0.05). In FPI, GLY did not benefit any other outcome, whereas in CCI, it reduced 21-day lesion volume versus vehicle ( < 0.05). On Morris water maze testing in CCI, GLY worsened performance on hidden platform latency testing versus sham ( < 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.

Medical Subject Headings

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

Publication Date

3-1-2021

Publication Title

Journal of neurotrauma

E-ISSN

1557-9042

Volume

38

Issue

5

First Page

628

Last Page

645

PubMed ID

33203303

Digital Object Identifier (DOI)

10.1089/neu.2020.7421

Recommended Citation

Jha, Ruchira M.; Mondello, Stefania; Bramlett, Helen M.; Dixon, C Edward; Shear, Deborah A.; Dietrich, W Dalton; Wang, Kevin K.; 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.; and Kochanek, Patrick M., "Glibenclamide Treatment in Traumatic Brain Injury: Operation Brain Trauma Therapy" (2021). Neurology. 1342.
https://scholar.barrowneuro.org/neurology/1342