To evaluate the outcome of modulating AMPA receptors after ischemia reperfusion injury by sequential treatment of AMPA antagonist and agonist.

Preclinical studies revealed neuroprotective efficacy of antioxidants, anticonvulsants, ion channel blockers, and immunosuppressants agents against ischemic stroke. However, clinical studies failed to establish the neuroprotective efficacy of these agents. Hence, novel approach against cerebral ischemia is necessary. The current study evaluated, for the first time, a new sequential approach of encumbering and then stimulating AMPA receptors against neurological damage after ischemic stroke.

Experiments were performed after approval from Institutional Animal Ethical Committee. Wistar rats underwent 90 min middle cerebral artery occlusion (MCAo) followed by perampanel administration (1.5 mg/kg i.p.) in antagonist group and aniracetam (50 mg/kg i.p.) in agonist group for different durations at different time points. Infarct percentage, neurological deficits, rota rod and grip strength tests were performed on 7^th day after MCAo. Best time point was selected from antagonist and agonist group for sequential treatment. In sequential treatment group, perampanel (1.5 mg/kg i.p.) was given for 5 days post reperfusion and aniracetam (50 mg/kg i.p.) administered after 5 days of reperfusion till 7 days. After 7 days neurological damage was assessed.

Sequential treatment of perampanel and aniracetam showed maximum protection against neurological damage and diminished infarct size in TTC staining when compared with disease control group. Furthermore, sequential treatment augmented motor coordination and grip strength (p<0.001). However, neurological deficit score, apoptosis (Bax, Bcl-2 and cleaved caspase-3) and proinflammatory cytokines (TNF-α and IL-1β) significantly (p<0.001) diminished in treatment group. Optical density in immunohistochemical analysis for GluR1 and GluR2 subunit of AMPA receptors found to be significantly (p<0.05) enhanced in perampanel and aniracetam treated group.

The results exhibited that sequential treatment of perampanel and aniracetam improved neurobehavioral outcome and infarct damage via anti-inflammatory and anti-apoptotic effect in ischemic reperfusion injury.