OBJECTIVE:To investigate the efficacy of adminis-tration of tanshinone Ⅱ A(TSA)combined with mesenchymal stem cells(MSCs)for the treatment of learning and memory impairment caused by vas-cular dementia(VaD)and to determine the underly-ing mechanism.METHODS:Modified four-vessel occlusion was used to establish a VaD model in rats,and their spa-tial learning and memory capacity was assessed by the Morris water maze.The rats were randomized into MSCs,TSA,MSCs combined with TSA,vehicle and sham groups.Histological changes were deter-mined by hematoxylin and eosin staining,and the hippocampal neuron apoptosis ratio was assessed by flow cytometry.Western blotting was performed to detect Bcl-2 and Bax expression.The reactive oxi-dative species(ROS)levels and the activity of total superoxide dismutase(T-SOD),an antioxidant en-zyme in the rat hippocampus,were determined.RESULTS:TSA combined with MSCs treatment ad-ministered by intravenous injection in the tail sig-nificantly attenuated cognitive deficits in the VaD model compared with the vehicle group(P＜0.01),and its protective effect on cognitive function was greater than that obtained by treatment with MSCs or TSA alone.Furthermore,TSA combined with MSCs treatment achieved synergistic effects in sup-pressing neuronal apoptosis in the rat hippocam-pus caused by global brain ischemia via up-regulat-ing the expression of Bcl-2,an anti-apoptosis pro-tein,and decreasing the expression of Bax,a pro-apoptotic protein.In addition,TSA combined with MSCs treatment attenuated ROS production and enhanced T-SOD activity in the rat hippocam-pus,and the antioxidant effect was greater than that of treatment with MSCs or TSA alone.CONCLUSION:TSA combined with MSCs treat-ment improved the spatial learning and memory capacity in a VaD model via suppressing neuronal apoptosis and antioxidant activity in the hippocam-pus,and this improvement was greater with com-bined treatment than with treatment with MSCs or TSA alone.