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SAFINAMIDE AMELIORATES CEREBRAL ISCHEMIA-REPERFUSION INJURY IN RATS BY ATTENUATING OXIDATIVE STRESS, INFLAMMATION AND APOPTOSIS
Abstract
Background and Aims
With spectacular failure in searching an adjunctive neuroprotective agent for ischemic stroke, exploring and repurposing an already approved drug has become a lower risk alternative. Safinamide, a recently approved drug for Parkinson’s disease, has shown neuroprotective effects in various diseases. The present study investigated the effect of safinamide in experimental model of ischemic stroke in rats.
Methods
Middle cerebral artery occlusion (MCAo) was performed in Sprague Dawley rats. Dose-selection (20, 40 and 80 mg/kg), therapeutic-time-window (ischemia/reperfusion I/R, post-reperfusion 0h/2h and post-reperfusion 2h/4h) and sub-acute (3-days) studies were performed. Effective dose and time-point were selected based on neurobehavioral parameters and infarct size reduction assessed 24h post-reperfusion. Study was extended for 72h. Effects on neurobehavioral parameters and infarct size reduction (MRI) were assessed. To explore the basis of neuroprotection, oxidative stress (MDA, GSH, SOD, NOX-2), inflammatory cytokines (TNF-α, IL-1β, IL-10) and apoptosis (Bax, Bcl-2, cleaved-caspase-3 expression and TUNEL staining) were studied.
Results
Safinamide (80 mg/kg) given post-ischemia and -reperfusion (Saf I/R) and post-reperfusion (Saf 0h/2h) showed significant reduction in infarct size and improvement in neurobehavioral parameters. Safinamide (80 mg/kg) was administered post-reperfusion for 3-days. Significant improvement in motor-coordination and infarct size reduction (TTC staining and MRI) was observed. Additionally, safinamide treatment significantly improved altered redox homeostasis and inflammatory cytokine levels. The deranged expression of apoptotic markers and increased TUNEL positive cells in cortex after MCAo were significantly normalized with safinamide treatment.
Conclusions
The results demonstrated neuroprotective potential of safinamide in cerebral I/R injury and can be considered for repurposing in ischemic stroke.