Abstract: Objective:To investigate the effects of butylphthalide on the hippocampal neuron apoptosis and p38 mitogen-activated protein kinase (MAPK) signaling pathway in the rats with ischemic stroke, and to elucidate the mechanism of butylphthalide in ischemic stroke. Methods:A total of 102 male rats were randomly divided into sham operation group, model group and butylphthalide group;there were 34 rats in each group. The rats in model group and butylphthalide group were used to establish the focal cerebral ischemia models with modified Zea-Longa method. The rats in butylphthalide group were treated with butylphthalide (4.5 mg·kg^-1) after modeling.The rats in sham operation group were intraperitoneally injected with the same volume of normal saline at the same time points. The morphology of neurons was observed by HE staining. The apoptosis of hippocampal neurons was observed by in situ terminal transferase labeling (TUNEL) staining. The expression levels of activated caspase-3 (cleaved caspase-3), B lymphocyte tumor-2 (Bcl-2), Bcl-2 related X protein (Bax), p38, phosphorylation-p38 (p-P38) and MAPK proteins in hippocampus tissue of the rats in various groups were determined by Western blotting method. The expression levels of cleaved caspase-3, Bax, Bcl-2, p38, and MAPK mRNA in hippocampus tissue of the rats in various groups were determined by reverse transcription-polymerase chain reaction (RT-PCR). Results:The neurons in the hippocampal CA1 area of the rats in sham operation group were well aligned and the nuclei and cell membrane were normal. In model group, the neurons in the hippocampal CA1 area were disordered, the cells were swollen and burst, and the nuclei had pyknosis. In butylphthalide group, the structure of some neurons in the hippocampal CA1 area returned to normal. Compared with sham operation group, the number of neurons in the hippocampal CA1 area of the rats in model group was significantly reduced (P<0.01), and the apoptotic index of neurons was significantly increased (P<0.01).Compared with model group, the number of neurons in hippocampal CA1 area of the rats in butylphthalide group was significantly increased (P<0.01), and the apoptotic index of neurons was significantly decreased (P<0.01). Compared with sham operation group, the expression levels of cleaved caspase-3, Bax, p-p38 and MAPK proteins in hippocampal tissue of the rats in model group were significantly increased (P<0.01), and the expression level of Bcl-2 protein in hippocampal tissue of the rats in model group was significantly decreased (P<0.01); compared with model group, the expression levels of cleaved caspase-3, Bax, p-p38 and MAPK proteins in hippocampus tissue of the rats in butylphthalide group were significantly decreased (P<0.01),and the expression level of Bcl-2 protein in hippocampus tissue of the rats in butylphthalide group was significantly increased (P<0.01). Compared with sham operation group, the expression levels of cleaved caspase-3, Bax and MAPK mRNA in hippocampus tissue of the rats in model group were significantly increased (P<0.01), and the expression level of Bcl-2 mRNA in hippocampal tissue of the rats in model group was significantly decreased (P<0.01); compared with model group, the expression levels of cleaved caspase-3, Bax and MAPK mRNA in hippocampus tissue of the rats in butylphthalide group were significantly decreased (P<0.01),and the expression level of Bcl-2 mRNA in hippocampus tissue of the rats in butylphthalide group was significantly increased (P<0.01). Conclusion:Butylphthalide can inhibit the apoptosis of hippocampal neurons in the rats with ischemic stroke by inhibiting the p38 MAPK signaling pathway in the hippocampus tissue.

Key words: butylphthalide, ischemic stroke, hippocampus, apoptosis, p38 mitogen-activated protein kinase, SD rats