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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
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.
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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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