Objective:To investigate the regulation of high－mobility group box－1(HMGB1)on P－glycoprotein(P－gp)expression in the hippocampus of epileptic rats. Methods:Sixty male SD rats were randomly divided into the sham operation group,epilepsy group,low,medium and high doses of HMGB1 pretreated groups with 12 rats in each group. Various doses of recombinant HMGB1 protein were injected intraventricularly 15 min before micro－injection of kainic acid(KA)into the hippocampus. The latency period to the onset of stage Ⅲ first seizure time was observed to assess epileptic susceptibility and all the rats were sacrificed after 24 hours of the operation. The damage of the hippocampal tissue,the expression levels of mdr1 mRNA and P－gp were detected by immunohistochemical method,real－time PCR and Western blot,respectively. Results:Compared with the epilepsy group,the SOT of epileptic seizure latency in the medium and high doses of HMGB1 pretreated groups were lower than that of the epilepsy group(P < 0.05),the damage of the hippocampal tissue and neuron loss in the hippocampus CA3 area were increased(P < 0.05),and the expression levels of mdr1 mRNA and P－gp were up－regulated in the medium and high doses of HMGB1 pretreated groups(P < 0.05),but there was no significant differences between the low－doses HMGB1 pretreated group and epilepsy group(P > 0.05). Conclusion:HMGB1 could increase seizure susceptibility,the damage of hippocampal tissue and the over－expression levels of P－gp in the hippocampus of seizure rats.