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

Abstract

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.

Implications of MMP-12 in the pathophysiology of ischaemic stroke

“…MMP-12 may be a potential target for IS treatment MMP-12's negative role on post-stroke brain damage and pathogenesis (ie, blood-brain barrier (BBB) breakdown, infarct development, inflammation, apoptosis and demyelination) as well as in neurological and functional impairments and recovery has been observed in rodent models of IS. [35][36][37][38][39] In these studies, suppressing MMP-12 gene expression shortly after IS decreased brain injury and promoted the recovery of sensorimotor and cognitive function. Reduced BBB breakdown and neuroinflammation in MMP-12-suppressed animals indicate that MMP-12 inhibition can be a promising strategy for preventing the haemorrhagic transformation caused by delayed tPA therapy, thereby allowing more patients to receive tPA treatment.…”

Dexmedetomidine Increases MMP-12 and MBP Concentrations after Coronary Artery Bypass Graft Surgery with Extracorporeal Circulation Anaesthesia without Impacting Cognitive Function: A Randomised Control Trial

“…Other studies have demonstrated that MMP-12 induces brain injury by damaging the BBB after focal cerebral ischemia, while MMP-12 knockdown attenuates this effect [ 15 , 42 ]. Recent reports have revealed that MMP-12 suppression can improve neurological outcomes in animal models of brain ischemia, making MMP-12 a promising therapeutic target [ 24 , 31 ]. The patterns of change in MMP-12 and MBP concentrations observed in the present study are in accordance with those reported in previous studies, suggesting that the activation of MMP-12 induces MBP degradation [ 27 ].…”

“…The activation of MMP-12 also induces the degradation of myelin basic protein (MBP) [ 27 ] and other substrates such as pro-TNFα, a1-antitrypsin, tissue factor pathway inhibitor, plasminogen, and N-cadherin [ 27 , 28 , 29 , 30 ]. Brain ischaemia and reperfusion during cardiac surgery with ECC can promote these pathological processes, highlighting MMP-12 a promising biomarker of brain injury and a potential treatment target [ 15 , 24 , 31 ].…”

Microglia at the scene of the crime: what their transcriptomics reveal about brain health

“…In murine models of stroke, microglia can be protective or disruptive for BBB function depending on their activation state. Pro-inflammatory microgliaderived cytokines such as tumor necrosis factor (TNF) and reactive oxygen specifies acting on astrocytes to induce expression of matrix metalloproteases (MMPs), with MMP inhibitors currently being assessed for their therapeutic potential in stroke recovery [48,49]. Microglia also secrete antiinflammatory cytokines including IL-4, IL-10, arginase 1, and TGFb, which can promote resolution of inflammation and stroke recovery [reviewed in [50]].…”