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

Cassandra M Wilkinson,Celine J Balay,Paul S Brar,Frederick Colbourne,Ken Arai

doi:10.1371/journal.pone.0215952

Cassandra M Wilkinson, Celine J Balay + Show 3 more

Open Access

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

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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.

Highlights

Intracerebral hemorrhage (ICH) is a devastating stroke with a 40% mortality rate [1]
In experiment 2, 1 animal in the glibenclamide group and 3 animals in the vehicle group were excluded from Gd analysis due to technical problems with the Gd injection
The failure to affect blood-brain barrier (BBB) injury, ion alterations and edema suggests that glibenclamide will not mitigate brain swelling or intracranial pressure rises after ICH in patients

Summary

Introduction

Intracerebral hemorrhage (ICH) is a devastating stroke with a 40% mortality rate [1]. Sur 1 and Trpm are both upregulated and co-expressed as the heteromeric Sur1-Trpm channel after brain injury, such as ICH, ischemic stroke, and traumatic brain injury [9,10] These channels allow for Na entry into cells, thereby contributing to cytotoxic edema [11] and likely persistent ionic dyshomeostasis. Another study, using the collagenase model of ICH in rats, reported that glibenclamide reduced oxidative stress, inhibited apoptosis, and improved neurological deficits [17]. Neither of these studies measured ion concentrations nor did they assess lesion size. The effect of glibenclamide on edema, BBB integrity, and ion homeostasis have only been assessed using the autologous whole blood model of ICH. We evaluated the long-term effects of glibenclamide on skilled reaching, walking ability, blood glucose, and lesion volume

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