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Therapeutic efficacy of matrix metalloproteinase-12 suppression on neurological recovery after ischemic stroke: Optimal treatment timing and duration
We recently showed that the post-ischemic induction of matrix metalloproteinase-12 (MMP-12) in the brain degrades tight junction proteins, increases MMP-9 and TNFα expression, and contributes to the blood-brain barrier (BBB) disruption, apoptosis, demyelination, and infarct volume development. The o...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2022
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9577328/ https://www.ncbi.nlm.nih.gov/pubmed/36267234 http://dx.doi.org/10.3389/fnins.2022.1012812 |
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author | Challa, Siva Reddy Nalamolu, Koteswara Rao Fornal, Casimir A. Wang, Billy C. Martin, Ryan C. Olson, Elsa A. Ujjainwala, Ammar L. Pinson, David M. Klopfenstein, Jeffrey D. Veeravalli, Krishna Kumar |
author_facet | Challa, Siva Reddy Nalamolu, Koteswara Rao Fornal, Casimir A. Wang, Billy C. Martin, Ryan C. Olson, Elsa A. Ujjainwala, Ammar L. Pinson, David M. Klopfenstein, Jeffrey D. Veeravalli, Krishna Kumar |
author_sort | Challa, Siva Reddy |
collection | PubMed |
description | We recently showed that the post-ischemic induction of matrix metalloproteinase-12 (MMP-12) in the brain degrades tight junction proteins, increases MMP-9 and TNFα expression, and contributes to the blood-brain barrier (BBB) disruption, apoptosis, demyelination, and infarct volume development. The objectives of this study were to (1) determine the effect of MMP-12 suppression by shRNA-mediated gene silencing on neurological/functional recovery, (2) establish the optimal timing of MMP-12shRNA treatment that provides maximum therapeutic benefit, (3) compare the effectiveness of acute versus chronic MMP-12 suppression, and (4) evaluate potential sex-related differences in treatment outcomes. Young male and female Sprague-Dawley rats were subjected to transient middle cerebral artery occlusion and reperfusion. Cohorts of rats were administered either MMP-12shRNA or scrambled shRNA sequence (control) expressing plasmids (1 mg/kg; i.v.) formulated as nanoparticles. At designated time points after reperfusion, rats from various groups were subjected to a battery of neurological tests to assess their reflex, balance, sensory, and motor functions. Suppression of MMP-12 promoted the neurological recovery of stroke-induced male and female rats, although the effect was less apparent in females. Immediate treatment after reperfusion resulted in a better recovery of sensory and motor function than delayed treatments. Chronic MMP-12 suppression neither enhanced nor diminished the therapeutic effects of acute MMP-12 suppression, indicating that a single dose of plasmid may be sufficient. We conclude that suppressing MMP-12 after an ischemic stroke is a promising therapeutic strategy for promoting the recovery of neurological function. |
format | Online Article Text |
id | pubmed-9577328 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-95773282022-10-19 Therapeutic efficacy of matrix metalloproteinase-12 suppression on neurological recovery after ischemic stroke: Optimal treatment timing and duration Challa, Siva Reddy Nalamolu, Koteswara Rao Fornal, Casimir A. Wang, Billy C. Martin, Ryan C. Olson, Elsa A. Ujjainwala, Ammar L. Pinson, David M. Klopfenstein, Jeffrey D. Veeravalli, Krishna Kumar Front Neurosci Neuroscience We recently showed that the post-ischemic induction of matrix metalloproteinase-12 (MMP-12) in the brain degrades tight junction proteins, increases MMP-9 and TNFα expression, and contributes to the blood-brain barrier (BBB) disruption, apoptosis, demyelination, and infarct volume development. The objectives of this study were to (1) determine the effect of MMP-12 suppression by shRNA-mediated gene silencing on neurological/functional recovery, (2) establish the optimal timing of MMP-12shRNA treatment that provides maximum therapeutic benefit, (3) compare the effectiveness of acute versus chronic MMP-12 suppression, and (4) evaluate potential sex-related differences in treatment outcomes. Young male and female Sprague-Dawley rats were subjected to transient middle cerebral artery occlusion and reperfusion. Cohorts of rats were administered either MMP-12shRNA or scrambled shRNA sequence (control) expressing plasmids (1 mg/kg; i.v.) formulated as nanoparticles. At designated time points after reperfusion, rats from various groups were subjected to a battery of neurological tests to assess their reflex, balance, sensory, and motor functions. Suppression of MMP-12 promoted the neurological recovery of stroke-induced male and female rats, although the effect was less apparent in females. Immediate treatment after reperfusion resulted in a better recovery of sensory and motor function than delayed treatments. Chronic MMP-12 suppression neither enhanced nor diminished the therapeutic effects of acute MMP-12 suppression, indicating that a single dose of plasmid may be sufficient. We conclude that suppressing MMP-12 after an ischemic stroke is a promising therapeutic strategy for promoting the recovery of neurological function. Frontiers Media S.A. 2022-10-04 /pmc/articles/PMC9577328/ /pubmed/36267234 http://dx.doi.org/10.3389/fnins.2022.1012812 Text en Copyright © 2022 Challa, Nalamolu, Fornal, Wang, Martin, Olson, Ujjainwala, Pinson, Klopfenstein and Veeravalli. 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 | Neuroscience Challa, Siva Reddy Nalamolu, Koteswara Rao Fornal, Casimir A. Wang, Billy C. Martin, Ryan C. Olson, Elsa A. Ujjainwala, Ammar L. Pinson, David M. Klopfenstein, Jeffrey D. Veeravalli, Krishna Kumar Therapeutic efficacy of matrix metalloproteinase-12 suppression on neurological recovery after ischemic stroke: Optimal treatment timing and duration |
title | Therapeutic efficacy of matrix metalloproteinase-12 suppression on neurological recovery after ischemic stroke: Optimal treatment timing and duration |
title_full | Therapeutic efficacy of matrix metalloproteinase-12 suppression on neurological recovery after ischemic stroke: Optimal treatment timing and duration |
title_fullStr | Therapeutic efficacy of matrix metalloproteinase-12 suppression on neurological recovery after ischemic stroke: Optimal treatment timing and duration |
title_full_unstemmed | Therapeutic efficacy of matrix metalloproteinase-12 suppression on neurological recovery after ischemic stroke: Optimal treatment timing and duration |
title_short | Therapeutic efficacy of matrix metalloproteinase-12 suppression on neurological recovery after ischemic stroke: Optimal treatment timing and duration |
title_sort | therapeutic efficacy of matrix metalloproteinase-12 suppression on neurological recovery after ischemic stroke: optimal treatment timing and duration |
topic | Neuroscience |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9577328/ https://www.ncbi.nlm.nih.gov/pubmed/36267234 http://dx.doi.org/10.3389/fnins.2022.1012812 |
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