Objective:To investigate the effects of high mobility group box 1(HMGB1) antagonist BoxA on seizure onset and hippocampus injury in a rat epilepsy model. Methods:Male SD rats were divided into the sham operation group,the epilepsy model group,the low,middle and high doses of BoxA pretreated epilepsy groups. The rat epilepsy model was made by micro-injection of kainic acid into the hippocampus. Various doses of BoxA were administered to the epilepsy model by intracerebroventricular injection prior to kainic acid injection. The sham operation group were injected with the same volume of normal saline into the hippocampus and lateral ventricle,respectively. We observed the rats’ behavior during seizure and recorded seizure onset time(SOT) to stage Ⅲ as an indicator to assess epileptic susceptibility. The brain pathological change was observed by HE staining. The injury degree of the hippocampus was estimated by NeuN staining as an indicator to assess the damage of brain tissue. The expression of phosphorylated nuclear factor-κB-p65(p-NFκB-p65) was also detected by immunohistochemical staining. Results:SOT in the low,middle and high doses of BoxA pretreated epilepsy group all significantly prolonged compared to the epilepsy group (P < 0.05). Compared to the epilepsy group,hippocampus injury and neuron loss were obviously reduced in the BoxA pretreated epilepsy group (P < 0.05). Although pretreatment with high dose BoxA also prolonged SOT and decreased the intensity of brain injury compared to the middle and low dose BoxA,there were no statistically significant differences. The expressions of p-NFκB-p65 in the middle and high dose BoxA groups were reduced remarkably compared with the EP group (P < 0.05 ),and there was no statistical difference between the EP group and the low dose BoxA group. Conclusion:Administration of HMGB1 antagonist BoxA to epileptic rats could reduce seizure susceptibility and attenuate the injury of brain by inhibit the activation of NFκB,which showed brain protective effect in epilepsy rats.