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目的:研究氟桂利嗪对苯妥英钠耐药癫(drug resistant epilepsy)小鼠癫发作的逆转作用,初步探讨其作用机制。方法:采用戊四氮制作小鼠癫模型,灌胃给予苯妥英钠40mg/(kg·d),共14d,制作耐药癫小鼠模型。造模成功的耐药癫小鼠30只,按随机数字表法分为3组,分别为模型组、维拉帕米组和氟桂利嗪组。在给予苯妥英钠后30min,分别腹腔注射生理盐水、维拉帕米20mg/(kg·d)和氟桂利嗪8mg/(kg·d),连续给药4d,在第4天(d 4)观察给药后30min内小鼠癫发作的严重程度。然后处死小鼠,取脑。采用蛋白质印迹法(Western blot)检测P-糖蛋白(P-gp)表达情况;用免疫组化法测定半胱氨酸蛋白酶-3(caspase-3)的表达情况。结果:给药d 4,氟桂利嗪组小鼠癫发作严重程度较模型组显著减轻(P<0.01)。维拉帕米组和氟桂利嗪组小鼠脑内P-gp的表达量显著减少(P<0.01),且氟桂利嗪的效果优于维拉帕米(P<0.05);维拉帕米组和氟桂利嗪组小鼠皮层和海马半胱氨酸蛋白酶-3表达量也显著减少(P<0.01),氟桂利嗪的作用优于维拉帕米(P<0.05)。结论:氟桂利嗪能够有效降低苯妥英钠耐药小鼠的癫发作严重程度,其主要机制可能与降低小鼠脑组织P-gp的表达有关,同时氟桂利嗪也能降低耐药小鼠脑内半胱氨酸蛋白酶-3的表达,对脑组织可能有保护作用。
Objective: To investigate the reversal effect of flunarizine on the onset of epilepsy in phenytoin resistant drug-resistant epilepsy mice and to explore its possible mechanism. Methods: Pentylenetetrazole was used to make the mouse epilepsy model. The rats were given gavage sodium 40mg / (kg · d) for 14 days to make the drug-resistant epilepsy mouse model. Thirty mice with successful drug-resistant epilepsy were divided into 3 groups according to random number table: model group, verapamil group and flunarizine group. 30 min after the administration of phenytoin, normal saline, verapamil 20mg / (kg · d), and flunarizine 8mg / (kg · d) were injected intraperitoneally for 4 days. On the fourth day (d 4) The severity of the onset of epilepsy in mice was observed within 30 min after administration. Then sacrificed mice, brain. The expression of P-glycoprotein (P-gp) was detected by Western blot. The expression of caspase-3 was detected by immunohistochemistry. Results: Compared with the model group, the severity of epilepsy in flunarizine group was significantly reduced (P <0.01). The expression of P-gp in the verapamil and flunarizine groups was significantly decreased (P <0.01), and flunarizine was better than verapamil (P <0.05) Pamidronate and flunarizine group mice cortex and hippocampal caspase-3 expression was significantly reduced (P <0.01), flunarizine better than verapamil (P <0.05). Conclusion: Flunarizine can effectively reduce the severity of epilepsy in phenytoin-resistant mice. The main mechanism may be related to the decrease of P-gp expression in mouse brain, and flunarizine can also reduce the drug resistance The expression of caspase-3 in rat brain may have a protective effect on brain tissue.