Objective To explore the regulation of berberine on the expressions of CDK4 and cyclin D1 in the neurons after the focal cerebral ischemia/reperfusion and the potential protective mechanism of berberine to neurons. Methods Fifty male Wistar rats were randomly divided into berberine-treated group (n=15), normal control group (n=5), sham-operated group (n=15) and vehicle-treated group (n=15). The model of focal cerebral ischemia was constructed using middle cerebral artery occlusion (MCAO) method. At 1, 3, 5 d after 1 hour ofischemia, the expressions and distributions of Bcl-2, cyclin D1 and CDK4 in each group were detected by immunohistochemistry, and morphological changes of brain were observed by HE staining. Results HE staining showed that in the berberine-treated group, the number of neurons was decreased less than that in vehicle-treated group at reperfusion 3 and 5 d. For the result of immunohistochemistry for Bcl-2 positive neurons, there was no obvious difference between berberine-treated group and vehicle-treated group at reperfusion 1 d (P>0.05),however, the number of the Bcl-2 positive cells in berberine-treated group at reperfusion 3 and 5 was significantly increased (P<0.01), and the numbers of cyclin D 1 and CDK4 positive cells were decreased as compared with those in the vehicle-treated group. Conclusions In the rat focal ischemia model,berberine can inhibit the neural expressions of cyclin D1 and CDK4 in the penumbra, that indicates berberine may have the potential of neural protection. The possible mechanism is that berberine can decrease the neural expression ofcyclin D1 and prevent it from entering the nucleus, thereby blocking the cascade reaction and suppressing the apoptosis mediated by cyclin D1.