Glibenclamide does not improve outcome following severe collagenase-induced intracerebral hemorrhage in rats

Abstract

Intracerebral hemorrhage (ICH) is a devastating insult with few effective treatments. Edema and raised intracranial pressure contribute to poor outcome after ICH. Glibenclamide blocks the sulfonylurea 1 transient receptor potential melastatin 4 (Sur1-Trpm4) channel implicated in edema formation. While glibenclamide has been found to improve outcome and reduce mortality in animal models of severe ischemic stroke, in ICH the effects are less clear. In our previous study, we found no benefit after a moderate-sized bleed, while others have reported benefit. Here we tested the hypothesis that glibenclamide may only be effective in severe ICH, where edema is an important contributor to outcome. Glibenclamide (10 μg/kg loading dose, 200 ng/h continuous infusion) was administered 2 hours post-ICH induced by collagenase injection into the striatum of adult rats. A survival period of 24 hours was maintained for experiments 1–3, and 72 hours for experiment 4. Glibenclamide did not affect hematoma volume (~81 μL) or other safety endpoints (e.g., glucose levels), suggesting the drug is safe. However, glibenclamide did not lessen striatal edema (~83% brain water content), ionic dyshomeostasis (Na+, K+), or functional impairment (e.g., neurological deficits (median = 10 out of 14), etc.) at 24 hours. It also did not affect edema at 72 h (~86% brain water content), or overall mortality rates (25% and 29.4% overall in vehicle vs. glibenclamide-treated severe strokes). Furthermore, glibenclamide appears to worsen cytotoxic edema in the peri-hematoma region (cell bodies were 46% larger at 24 h, p = 0.0017), but no effect on cell volume or density was noted elsewhere. Overall, these findings refute our hypothesis, as glibenclamide produced no favorable effects following severe ICH.

Sulfonylurea Receptor 1 in Central Nervous System Injury: An Updated Review

“…The evaluation of SUR1 ± TRPM4 and pharmacological inhibition of the channel by glibenclamide in primary ICH is less mature than current data in disease subtypes of ischemic stroke and TBI. Existing studies in ICH have yielded mixed results ( Table 7 ) [ 143 , 160 , 172 , 173 , 174 , 175 , 176 , 177 ].…”

“…Two recent preclinical reports have suggested no benefit from glibenclamide treatment after ICH [ 173 , 174 ]. Both studies were performed in rats with collagenase-induced ICH; one involved severe ICH [ 173 ], and the other was more modest ICH without mortality [ 174 ].…”

“…Two recent preclinical reports have suggested no benefit from glibenclamide treatment after ICH [ 173 , 174 ]. Both studies were performed in rats with collagenase-induced ICH; one involved severe ICH [ 173 ], and the other was more modest ICH without mortality [ 174 ]. In both reports, glibenclamide was well tolerated, but did not improve edema measures, hematoma volume, or functional outcomes at any timepoint.…”

“…It is challenging to reconcile the discrepant results between these two studies and the previous body of work, particularly since both the species (rat) and the drug dosing (10 mg/kg, 200 ng/h continuous infusion) appear to have been consistent across studies. One possibility is the timing of administration: in the studies demonstrating benefit [ 143 , 172 , 175 ], glibenclamide was loaded either 30 min before or immediately after injury, whereas in those where no benefit was observed, drug was initiated 2 h after injury [ 173 , 174 ]. However, for ultra-early administration to be clinically translatable, it would require drug infusion in a prehospital setting.…”

“…It is also possible that the collagenase-induced ICH models did not activate pathways that upregulate/trigger SUR1-TRPM4. Indeed, in the severe ICH model, there was no increase in Abcc8 or Trpm4 mRNA in the perihematomal region (protein expression was not evaluated) [ 173 ]. Another possibility is that, particularly in severe ICH, the injury is too overwhelming for any drug to demonstrate functional benefit, particularly if administration is delayed.…”