Frontiers in Neuroscience (Oct 2022)

Therapeutic efficacy of matrix metalloproteinase-12 suppression on neurological recovery after ischemic stroke: Optimal treatment timing and duration

  • Siva Reddy Challa,
  • Siva Reddy Challa,
  • Koteswara Rao Nalamolu,
  • Casimir A. Fornal,
  • Billy C. Wang,
  • Billy C. Wang,
  • Billy C. Wang,
  • Ryan C. Martin,
  • Elsa A. Olson,
  • Ammar L. Ujjainwala,
  • David M. Pinson,
  • Jeffrey D. Klopfenstein,
  • Jeffrey D. Klopfenstein,
  • Jeffrey D. Klopfenstein,
  • Krishna Kumar Veeravalli,
  • Krishna Kumar Veeravalli,
  • Krishna Kumar Veeravalli,
  • Krishna Kumar Veeravalli

DOI
https://doi.org/10.3389/fnins.2022.1012812
Journal volume & issue
Vol. 16

Abstract

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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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