Objective To observe the changes of expression of P-glycoprotein (PGP) in the brain of pentylenetetrazole (PTZ)-kindled epileptic mice after 2-chloride adenosine (2-CAdo) stimulation. Methods The C57BL/6 mice (n=40) were randomly divided into three groups: control group (n=8), PTZ group (n=16) and 2-CAdo group (n=16). The epileptic model was established by intraperitoneal injection of PTZ [30 mg/(kg.d)]. The control group were given the same amount of normal saline. The seizures were observed during PTZ kindling (kindling rate, latency time, start time and durations of seizures). After kindled, the 2-CAdo group was continuously injected with 2-CAdo [0.6 mg/(kg.d)] for 2 weeks. The other two groups were injected with normal saline instead. Then, all the mice of these three groups were sacrificed. HE staining was adopted to observe the histopathological changes of cerebral cortex and hippocampus of the mice, and the expression of PGP was detected by immunohistochemistry and Western blotting. Results At the time of seizures, the mice showed whole body tremor, hair erection, apathy, loss of appetite, cage offense and other abnormalities. HE staining showed that the damage of cerebral cortex and hippocampus of the 2-CAdo group was less than that of the PTZ group. Immunohistochemistry and Western blotting showed that the expression of PGP in the cerebral cortex of the 2-CAdo group was significantly lower than that in the control and PTZ groups. In the hippocampus, the expression of PGP in the 2-CAdo and PTZ groups was significantly higher than that in the control group, especially highest in the 2-CAdo group. Conclusion The 2-CAdo can reduce the damage of brain tissue, upregulate the expression of PGP in the hippocampus, and downregulate the expression of PGP in the cerebral cortex.