Combination treatment with progesterone and rehabilitation training further promotes behavioral recovery after acute ischemic stroke in mice

Abstract

Purpose: The present study was aimed to investigate whether combination treatment with progesterone and rehabilitation training would be more effective than monotherapy after cerebral ischemia. Methods: C57BL/6 mice were subjected to focal ischemia by photothrombosis and were treated with progesterone (2 mg/kg), rehabilitation training or their combination. 2,3,5-triphenyltetrazolium chloride (TTC) staining and Nissl staining were used to measure infarct size at day 3 and day 7 after surgery, and rotarod test and grip strength test were conducted to evaluate behavioral outcomes. Results: TTC staining indicated that progesterone, rehabilitation training and their combination produced a different degree of reduction in infarct volume compared with vehicle control at day 3 after ischemia (progesterone: 16.70 ± 0.93 mm³, p < 0.01, rehabilitation training: 22.19 ± 0.93 mm³, p < 0.05, progesterone + rehabilitation training: 14.76 ± 0.92 mm³, p < 0.01, vehicle control: 28.73 ± 1.05 mm³). Nissl staining revealed that prolonged treatment of progesterone, rehabilitation training and their combination led to a significant decrease in infarct volume at day 7 after ischemia (progesterone: 18.64 ± 1.83 mm³, p < 0.01, rehabilitation training: 25.07 ± 1.70 mm³, p < 0.05, progesterone + rehabilitation training: 17.09 ± 0.92 mm³, p < 0.01, vehicle control: 30.31 ± 1.36 mm³). No accumulative effect in the reduction of infarct volume was observed in combination therapy at both day 3 and day 7 after ischemia. However, combination therapy significantly improved behavioral performances in the first week after photothrombosis. Combination treatment significantly enhanced rotarod performance and forelimb grip strength at all time points within 7 days after ischemia compared with rehabilitation alone, and significantly improved rotarod performance and forelimb grip strength from day 2 after ischemia compared with progesterone alone. Conclusion: Our results suggested that combination treatment with progesterone and rehabilitation training had no additive effect in reducing infarct volume, but combination therapy exhibited enhanced efficacy in promoting functional recovery after ischemic stroke, suggesting progesterone and rehabilitation training may exert their effects via different mechanisms.