Purpose: Ischemic stroke presents multifaceted pathological outcomes with overlapping mechanisms of cerebral injury. High mortality and disability with stroke warrant a novel multi-targeted therapeutic approach. The neuroprotection with progesterone (PG) and noscapine (NOS) on cerebral ischemia-reperfusion (I-R) injury was demonstrated individually, but the outcome of combination treatment to alleviate cerebral damage is still unexplored.Methods: Randomly divided groups of rats (n=6) were

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... perated, I-R, PG (8mg/kg), NOS (10mg/kg), and PG+NOS (8mg/kg+10mg/kg). The rats exposed to bilateral common carotid artery occlusion, except Sham-operated to investigate the therapeutic outcome of PG and NOS alone and in combination on I-R injury. Besides the alterations in cognitive and motor abilities, we estimated infarct area, oxidative stress, blood-brain barrier (BBB) permeability, and histology after treatment. Pharmacokinetic parameters like Cmax, Tmax, half-life, and AUC0-t were estimated in biological samples to substantiate the therapeutic outcomes of the combination treatment.Results: We report PG and NOS prevent loss of motor ability and improved spatial memory after cerebral I-R injury. Combination treatment significantly reduced inflammation and restricted infarction; it attenuated oxidative stress, BBB damage, and improved grip strength. Histopathological analysis demonstrated a significant reduction in leukocyte infiltration with the most profound effect in the combination group. Simultaneous analysis of PG and NOS in plasma revealed enhanced peak drug concentration, improved AUC, and prolonged half-life; the drug levels in the brain have increased significantly for both. Conclusion: We conclude that PG and NOS have beneficial effects against brain damage and, the co-administration further reinforced neuroprotection in the cerebral ischemia-reperfusion injury.