Glibenclamide Produces Region-Dependent Effects on Cerebral Edema in a Combined Injury Model of Traumatic Brain Injury and Hemorrhagic Shock in Mice

Authors

Ruchira M. Jha, 1 Department of Critical Care Medicine, School of Medicine, University of Pittsburgh , Pittsburgh, Pennsylvania.Follow
Bradley J. Molyneaux, 1 Department of Critical Care Medicine, School of Medicine, University of Pittsburgh , Pittsburgh, Pennsylvania.
Travis C. Jackson, 1 Department of Critical Care Medicine, School of Medicine, University of Pittsburgh , Pittsburgh, Pennsylvania.
Jessica S. Wallisch, 1 Department of Critical Care Medicine, School of Medicine, University of Pittsburgh , Pittsburgh, Pennsylvania.
Seo-Young Park, 6 Department of Medicine, School of Medicine, University of Pittsburgh , Pittsburgh, Pennsylvania.
Samuel Poloyac, 8 Department of Pharmacy and Therapeutics, School of Medicine, University of Pittsburgh , Pittsburgh, Pennsylvania.
Vincent A. Vagni, 1 Department of Critical Care Medicine, School of Medicine, University of Pittsburgh , Pittsburgh, Pennsylvania.
Keri L. Janesko-Feldman, 1 Department of Critical Care Medicine, School of Medicine, University of Pittsburgh , Pittsburgh, Pennsylvania.
Keito Hoshitsuki, 8 Department of Pharmacy and Therapeutics, School of Medicine, University of Pittsburgh , Pittsburgh, Pennsylvania.
M Beth Minnigh, 8 Department of Pharmacy and Therapeutics, School of Medicine, University of Pittsburgh , Pittsburgh, Pennsylvania.
Patrick M. Kochanek, 1 Department of Critical Care Medicine, School of Medicine, University of Pittsburgh , Pittsburgh, Pennsylvania.

Document Type

Article

Abstract

Cerebral edema is critical to morbidity/mortality in traumatic brain injury (TBI) and is worsened by hypotension. Glibenclamide may reduce cerebral edema by inhibiting sulfonylurea receptor-1 (Sur1); its effect on diffuse cerebral edema exacerbated by hypotension/resuscitation is unknown. We aimed to determine if glibenclamide improves pericontusional and/or diffuse edema in controlled cortical impact (CCI) (5m/sec, 1 mm depth) plus hemorrhagic shock (HS) (35 min), and compare its effects in CCI alone. C57BL/6 mice were divided into five groups (n = 10/group): naïve, CCI+vehicle, CCI+glibenclamide, CCI+HS+vehicle, and CCI+HS+glibenclamide. Intravenous glibenclamide (10 min post-injury) was followed by a subcutaneous infusion for 24 h. Brain edema in injured and contralateral hemispheres was subsequently quantified (wet-dry weight). This protocol brain water (BW) = 80.4% vehicle vs. 78.3% naïve, p < 0.01) but was not reduced by glibenclamide (I%BW = 80.4%). Ipsilateral edema also developed in CCI alone (I%BW = 80.2% vehicle vs. 78.3% naïve, p < 0.01); again unaffected by glibenclamide (I%BW = 80.5%). Contralateral (C) %BW in CCI+HS was increased in vehicle (78.6%) versus naive (78.3%, p = 0.02) but unchanged in CCI (78.3%). At 24 h, glibenclamide treatment in CCI+HS eliminated contralateral cerebral edema (C%BW = 78.3%) with no difference versus naïve. By 72 h, contralateral cerebral edema had resolved (C%BW = 78.5 ± 0.09% vehicle vs. 78.3 ± 0.05% naïve). Glibenclamide decreased 24 h contralateral cerebral edema in CCI+HS. This beneficial effect merits additional exploration in the important setting of TBI with polytrauma, shock, and resuscitation. Contralateral edema did not develop in CCI alone. Surprisingly, 24 h of glibenclamide treatment failed to decrease ipsilateral edema in either model. Interspecies dosing differences versus prior studies may play an important role in these findings. Mechanisms underlying brain edema may differ regionally, with pericontusional/osmolar swelling refractory to glibenclamide but diffuse edema (via Sur1) from combined injury and/or resuscitation responsive to this therapy. TBI phenotype may mandate precision medicine approaches to treat brain edema.

Medical Subject Headings

Animals; Blood Glucose (metabolism); Brain Edema (drug therapy, etiology); Brain Injuries, Traumatic (complications, drug therapy); Disease Models, Animal; Glyburide (administration & dosage, therapeutic use); Hypoglycemic Agents (administration & dosage, therapeutic use); Infusions, Subcutaneous; Injections, Intravenous; Male; Mice; Mice, Inbred C57BL; Shock, Hemorrhagic (complications, drug therapy)

Publication Date

9-1-2018

Publication Title

Journal of neurotrauma

E-ISSN

1557-9042

Volume

35

Issue

17

First Page

2125

Last Page

2135

PubMed ID

29648981

Digital Object Identifier (DOI)

10.1089/neu.2016.4696

Recommended Citation

Jha, Ruchira M.; Molyneaux, Bradley J.; Jackson, Travis C.; Wallisch, Jessica S.; Park, Seo-Young; Poloyac, Samuel; Vagni, Vincent A.; Janesko-Feldman, Keri L.; Hoshitsuki, Keito; Minnigh, M Beth; and Kochanek, Patrick M., "Glibenclamide Produces Region-Dependent Effects on Cerebral Edema in a Combined Injury Model of Traumatic Brain Injury and Hemorrhagic Shock in Mice" (2018). Neurology. 1341.
https://scholar.barrowneuro.org/neurology/1341