Background: Epilepsy is a common disorder of brain that is not well controlled via drugs available for it. Gephyrin, a well-known inhibitory synaptic regulator, has a role in epilepsy. Additionally, significant development of oxidative stresses tends to be involved in epileptic seizure pathophysiology that giving rise to neuronal cell death. Zizyphus spina christi is a vastly available Iraqi tree and its leaves have several beneficial effects on central nervous system level. Objective: To investigate the possible neuroprotective effect of crude Zizyphus spina christi extract in kindling model induced. Methods: The removed brains of forty albino male mice from four separate groups were exposed to immunohistochemical test for gephyrin, glutathione, and NeuN expressions. Results: The data found that pretreatment with Zizyphus spina christi crude extract shows highly significant difference (P value <0.001) in immunohistochemical scores for all studied parameters as compared with those being of pentylenetetrazole-kindled group. Conclusion: These findings suggest that crude Zizyphus spina christi extract of leaves is effective in protection against kindling that induced via pentylenetetrazole when applied orally for male mice. Keywords: Gephyrin; glutathione; kindling; NeuN; pentylenetetrazole; Zizyphus spina christi Citation: Al-Humaidhi AM, Abd AH, Ghazi HF. Zizyphus spina christi effect on pentylenetetrazole-induced kindling. Iraqi JMS. 2021; 19(1): 49-55. doi: 10.22578/IJMS.19.1.7