Research Article: Glibenclamide, a Sur1-Trpm4 antagonist, does not improve outcome after collagenase-induced intracerebral hemorrhage

Date Published: May 1, 2019

Publisher: Public Library of Science

Author(s): Cassandra M. Wilkinson, Paul S. Brar, Celine J. Balay, Frederick Colbourne, Ken Arai.

http://doi.org/10.1371/journal.pone.0215952

Abstract

The sulfonylurea 1 transient receptor potential melastatin 4 (Sur1-Trpm4) receptor is selectively expressed after intracerebral hemorrhage (ICH). This upregulation contributes to increases in intracellular sodium. Water follows sodium through aquaporin channels, leading to cytotoxic edema. Even after edema is thought to have resolved, ionic dyshomeostasis persists, as does blood-brain barrier (BBB) damage. Glibenclamide, a hypoglycemic agent that inhibits Sur1-Trpm4, has been shown to reduce BBB damage and edema following infusion of autologous blood into the brain (ICH) as well as after other brain injuries. In order to further assess efficacy, we used the collagenase ICH model in rats to test whether glibenclamide reduces edema, attenuates ion dyshomeostasis, improves BBB damage, and reduces lesion volume. We tested a widely-used glibenclamide dose shown effective in other studies (10 μg/kg loading dose followed by 200 ng/hr for up to 7 days). Early initiation of glibenclamide did not significantly impact edema (72 hours), BBB permeability (72 hours), or lesion volume after ICH (28 days). Recovery from neurological impairments was also not improved by glibenclamide. These results suggest that glibenclamide will not improve outcome in ICH. However, the treatment appeared to be safe as there was no effect on bleeding or other physiological variables.

Partial Text

Intracerebral hemorrhage (ICH) is a devastating stroke with a 40% mortality rate [1]. In the hours after an ICH, ionic homeostasis becomes disrupted, and this dyshomeostasis can persist for weeks [2–4]. Sodium (Na) and chloride (Cl) concentration increase whereas potassium (K) concentration declines. These ionic perturbations are greatest near the hematoma, but extend well into the perihematoma zone [4]. Perhaps because of this, and other factors, there is considerable cellular injury (e.g., loss of dendrites [5]) and death in the perihematoma region [6]. Likely these ionic perturbations also directly impair neural function, and could lead to seizures, commonly seen in preclinical work and in patients [7,8]. Further indirect support comes from our research that shows that rehabilitation normalizes Cl levels in the peri-hematoma zone after experimental ICH [3], which might underlie how rehabilitation improves behavioral recovery. These data also suggest that pharmacological therapies to restore ion homeostasis may improve outcome after ICH.

Glibenclamide, a Sur1-Trpm4 inhibitor and hypoglycemic agent, has shown promising results in ischemic and hemorrhagic stroke, including reducing edema, mortality, and functional deficits [12,14,16,17]. In contrast to those findings, glibenclamide did not reduce BBB permeability, element concentration alterations, edema, behavioral impairment or brain injury after collagenase-induced ICH in our experiments. The failure to affect BBB injury, ion alterations and edema suggests that glibenclamide will not mitigate brain swelling or intracranial pressure rises after ICH in patients. Furthermore, the lack of benefit against functional impairments and brain injury after ICH does not support the clinical use of glibenclamide as a neuroprotectant after ICH. Fortunately, physiological measures, including core temperature, activity, and blood glucose were not affected by glibenclamide. As well, hematoma volume was not affected.

 

Source:

http://doi.org/10.1371/journal.pone.0215952

 

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