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Intra-arterial verapamil improves functional outcomes of thrombectomy in a preclinical model of extended hyperglycemic stroke
The abrupt hyperglycemic reperfusion following thrombectomy has been shown to harm the efficacy of the intervention in stroke patients with large vessel occlusion. Studies of ours and others have shown thioredoxin-interacting protein (TXNIP) is critically involved in hyperglycemic stroke injury. We...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2023
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10134451/ https://www.ncbi.nlm.nih.gov/pubmed/37124219 http://dx.doi.org/10.3389/fphar.2023.1161999 |
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author | Nasoohi, Sanaz Alehossein, Parsa Jorjani, Masoumeh Brown, Candice M. Ishrat, Tauheed |
author_facet | Nasoohi, Sanaz Alehossein, Parsa Jorjani, Masoumeh Brown, Candice M. Ishrat, Tauheed |
author_sort | Nasoohi, Sanaz |
collection | PubMed |
description | The abrupt hyperglycemic reperfusion following thrombectomy has been shown to harm the efficacy of the intervention in stroke patients with large vessel occlusion. Studies of ours and others have shown thioredoxin-interacting protein (TXNIP) is critically involved in hyperglycemic stroke injury. We recently found verapamil ameliorates cerebrovascular toxicity of tissue plasminogen activators in hyperglycemic stroke. The present study aims to answer if verapamil exerts direct neuroprotective effects and alleviates glucose toxicity following thrombectomy in a preclinical model of hyperglycemic stroke. Primary cortical neural (PCN) cultures were exposed to hyperglycemic reperfusion following oxygen-glucose deprivation (OGD), with or without verapamil treatment. In a mouse model of intraluminal stroke, animals were subjected to 4 h middle cerebral artery occlusion (MCAO) and intravenous glucose infusion. Glucose infusion lasted one more hour at reperfusion, along with intra-arterial (i.a.) verapamil infusion. Animals were subjected to sensorimotor function tests and histological analysis of microglial phenotype at 72 h post-stroke. According to our findings, glucose concentrations (2.5–20 mM) directly correlated with TXNIP expression in OGD-exposed PCN cultures. Verapamil (100 nM) effectively improved PCN cell neurite growth and reduced TXNIP expression as well as interaction with NOD-like receptor pyrin domain-containing-3 (NLRP3) inflammasome, as determined by immunoblotting and immunoprecipitation. In our mouse model of extended hyperglycemic MCAO, i.a. verapamil (0.5 mg/kg) could attenuate neurological deficits induced by hyperglycemic stroke. This was associated with reduced microglial pro-inflammatory transition. This finding encourages pertinent studies in hyperglycemic patients undergoing thrombectomy where the robust reperfusion may exacerbate glucose toxicity. |
format | Online Article Text |
id | pubmed-10134451 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-101344512023-04-28 Intra-arterial verapamil improves functional outcomes of thrombectomy in a preclinical model of extended hyperglycemic stroke Nasoohi, Sanaz Alehossein, Parsa Jorjani, Masoumeh Brown, Candice M. Ishrat, Tauheed Front Pharmacol Pharmacology The abrupt hyperglycemic reperfusion following thrombectomy has been shown to harm the efficacy of the intervention in stroke patients with large vessel occlusion. Studies of ours and others have shown thioredoxin-interacting protein (TXNIP) is critically involved in hyperglycemic stroke injury. We recently found verapamil ameliorates cerebrovascular toxicity of tissue plasminogen activators in hyperglycemic stroke. The present study aims to answer if verapamil exerts direct neuroprotective effects and alleviates glucose toxicity following thrombectomy in a preclinical model of hyperglycemic stroke. Primary cortical neural (PCN) cultures were exposed to hyperglycemic reperfusion following oxygen-glucose deprivation (OGD), with or without verapamil treatment. In a mouse model of intraluminal stroke, animals were subjected to 4 h middle cerebral artery occlusion (MCAO) and intravenous glucose infusion. Glucose infusion lasted one more hour at reperfusion, along with intra-arterial (i.a.) verapamil infusion. Animals were subjected to sensorimotor function tests and histological analysis of microglial phenotype at 72 h post-stroke. According to our findings, glucose concentrations (2.5–20 mM) directly correlated with TXNIP expression in OGD-exposed PCN cultures. Verapamil (100 nM) effectively improved PCN cell neurite growth and reduced TXNIP expression as well as interaction with NOD-like receptor pyrin domain-containing-3 (NLRP3) inflammasome, as determined by immunoblotting and immunoprecipitation. In our mouse model of extended hyperglycemic MCAO, i.a. verapamil (0.5 mg/kg) could attenuate neurological deficits induced by hyperglycemic stroke. This was associated with reduced microglial pro-inflammatory transition. This finding encourages pertinent studies in hyperglycemic patients undergoing thrombectomy where the robust reperfusion may exacerbate glucose toxicity. Frontiers Media S.A. 2023-04-13 /pmc/articles/PMC10134451/ /pubmed/37124219 http://dx.doi.org/10.3389/fphar.2023.1161999 Text en Copyright © 2023 Nasoohi, Alehossein, Jorjani, Brown and Ishrat. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Pharmacology Nasoohi, Sanaz Alehossein, Parsa Jorjani, Masoumeh Brown, Candice M. Ishrat, Tauheed Intra-arterial verapamil improves functional outcomes of thrombectomy in a preclinical model of extended hyperglycemic stroke |
title | Intra-arterial verapamil improves functional outcomes of thrombectomy in a preclinical model of extended hyperglycemic stroke |
title_full | Intra-arterial verapamil improves functional outcomes of thrombectomy in a preclinical model of extended hyperglycemic stroke |
title_fullStr | Intra-arterial verapamil improves functional outcomes of thrombectomy in a preclinical model of extended hyperglycemic stroke |
title_full_unstemmed | Intra-arterial verapamil improves functional outcomes of thrombectomy in a preclinical model of extended hyperglycemic stroke |
title_short | Intra-arterial verapamil improves functional outcomes of thrombectomy in a preclinical model of extended hyperglycemic stroke |
title_sort | intra-arterial verapamil improves functional outcomes of thrombectomy in a preclinical model of extended hyperglycemic stroke |
topic | Pharmacology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10134451/ https://www.ncbi.nlm.nih.gov/pubmed/37124219 http://dx.doi.org/10.3389/fphar.2023.1161999 |
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