Objective To investigate the effect of donepezil hydrochloride on the expression of Calpain Ⅰ-Cdk5/p25 pathway in the hippocampal CA1 area by cerebral ischemia and reperfusion in mice.Methods Mice were divided into model group,sham-operated group and donepezil-treated group.The expression of Calpain Ⅰ in hippocampal CA1 area was measured by immunohistochemistry staining respectively at 4,6 and 8 weeks post cerebral ischemia and reperfusion.Western blot was used to evaluate Cdk5 and p25 protein expression.Results The abilities of learning and memory performance was damaged significantly at 4,6 and 8 weeks after surgery compared to sham-operated group (P＜ 0.05).The expression of Calpain Ⅰ of model group were (0.098 ± 0.009),(0.129 ±0.01),(0.116 ± 0.01),which were higher than that of sham-operated group (0.03 ± 0.003),(0.031 ± 0.003),(0.029 ±0.003) and there was significant difference (P ＜ 0.05).The expression of Cdk5 in model group was (0.54 ± 0.05),(0.73 ± 0.07),(0.7 ± 0.06),which were higher than that of sham-operated group (0.23 ±0.02),(0.31 ± 0.02),(0.33 ± 0.02) and there was significant difference (P ＜ 0.05).The expression of p25 in model group was (0.44 ± 0.04),(0.51 ± 0.04),(0.55 ± 0.06),which were higher than that of sham-operated group(0.19 ± 0.02),(0.24 ± 0.02),(0.2 ± 0.02) and there was significant difference (P ＜ 0.05).The expression of Calpain Ⅰ of donepezil-treated group was (0.041 ± 0.004),(0.054 ± 0.004),(0.046 ± 0.003),which were lower than that of model group.The expression of Cdk5 was (0.28 ± 0.02),(0.33 ± 0.03),(0.38 ± 0.02),and expression of p25 was (0.26 ± 0.02),(0.25 ± 0.03),(0.21 ± 0.02),which were lower than that of model group respectively(P ＜ 0.05).Conclusion Donepezil hydrochloride probably improve the learning and memory abilities by reducing the expression of Calpain Ⅰ and Cdk5/p25.