MMP‐12 knockdown during acute and chronic phases promotes post‐stroke neurological recovery

Abstract

Matrix metalloproteinases (MMPs) are known modulators of ischemic brain damage. We recently showed that ischemic stroke in adult rodents induces MMP‐12 in brain during both acute and chronic phases of ischemic stroke. We also showed that MMP‐12 is detrimental during acute phase as it promotes BBB disruption leading to brain damage. In the present study, we evaluated the significance of elevated MMP‐12 during the chronic phase after focal ischemia on neurological recovery. Adult male Sprague‐Dawley rats were subjected to a 2h transient middle cerebral artery occlusion (MCAO). These rats were administered with either a single dose (at 10–15 min of reperfusion) or 3 doses (at 10–15 min, 7 days and 14 days of reperfusion) of plasmids expressing either MMP‐12 shRNA or a scrambled control shRNA (1 mg/Kg; i.v.; n = 9–11/group) in nanoparticle formulation. To assess reflexes, balance, sensory and motor functions, rats were subjected to modified neurological severity scoring, adhesive removal test, beam walk test and rotarod test at 1, 7, 14 and 21 days after reperfusion. The cohort of rats treated with a single dose of MMP‐12 shRNA showed significantly better functional recovery as compared to control shRNA cohort. Longer‐term suppression of MMP‐12 also resulted in better functional recovery than control shRNA cohort. Thus, these studies indicate that induction of MMP‐12 during both acute and chronic phases after focal ischemia contributes to neurological deficits and hinders recovery.Support or Funding InformationThis work was supported by the NIH Grant 1R01NS102573‐01A1 to KKV