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

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. Whi...

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Autores principales:	Tiffany F C Kung, Cassandra M Wilkinson, Christine A Dirks, Glen C Jickling, Frederick Colbourne
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/aa5fe3b5564147809f58863890600c95
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spelling	oai:doaj.org-article:aa5fe3b5564147809f58863890600c952021-12-02T20:11:05ZGlibenclamide does not improve outcome following severe collagenase-induced intracerebral hemorrhage in rats.1932-620310.1371/journal.pone.0252584https://doaj.org/article/aa5fe3b5564147809f58863890600c952021-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0252584https://doaj.org/toc/1932-6203Intracerebral 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.Tiffany F C KungCassandra M WilkinsonChristine A DirksGlen C JicklingFrederick ColbournePublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 16, Iss 6, p e0252584 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Tiffany F C Kung Cassandra M Wilkinson Christine A Dirks Glen C Jickling Frederick Colbourne Glibenclamide does not improve outcome following severe collagenase-induced intracerebral hemorrhage in rats.
description	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.
format	article
author	Tiffany F C Kung Cassandra M Wilkinson Christine A Dirks Glen C Jickling Frederick Colbourne
author_facet	Tiffany F C Kung Cassandra M Wilkinson Christine A Dirks Glen C Jickling Frederick Colbourne
author_sort	Tiffany F C Kung
title	Glibenclamide does not improve outcome following severe collagenase-induced intracerebral hemorrhage in rats.
title_short	Glibenclamide does not improve outcome following severe collagenase-induced intracerebral hemorrhage in rats.
title_full	Glibenclamide does not improve outcome following severe collagenase-induced intracerebral hemorrhage in rats.
title_fullStr	Glibenclamide does not improve outcome following severe collagenase-induced intracerebral hemorrhage in rats.
title_full_unstemmed	Glibenclamide does not improve outcome following severe collagenase-induced intracerebral hemorrhage in rats.
title_sort	glibenclamide does not improve outcome following severe collagenase-induced intracerebral hemorrhage in rats.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/aa5fe3b5564147809f58863890600c95
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Glibenclamide does not improve outcome following severe collagenase-induced intracerebral hemorrhage in rats.

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