多药耐药基因在慢性癫癎大鼠中的表达及托吡酯对其表达的影响

目的探讨多药耐药基因（mdr）在慢性大鼠中的表达及托吡酯（TPM）对其表达的影响。方法将生后28d的SD大鼠给予海人酸致,对照组给予相同的方法注射生理盐水。待自发性形成后,将癫痫组分为持续状态并发自发性（简称SE）组、持续状态并发自发性治疗（简称SE＋TPM）组、非癫痫持续状态并发自发性癫痫（简称N—SE）组和非持续状态并发自发性治疗（简称N—SE＋TPM）组;将生理盐水对照组分为正常生理盐水对照组和正常生理盐水对照治疗（对照＋TPM）组。治疗组均给予TPM治疗,治疗6周后,将所有大鼠断头取海马,RT—PCR检测mdr1α和mdr1b mRNA的表达。结果SE组、SE＋TPM组和N—SE＋TPM组的mdr1α和mdr1b mRNA表达均比对照组高（P〈0．001或〈0．05）,SE＋TPM组的mdr1α和mdr1b mRNA表达也比SE组高（P〈0．001）,其他治疗组（N—SE＋TPM,对照＋TPM）mdr1α和mdr1b mRNA表达较相对应的未治疗（N—SE,对照）组相比高,但无统计学意义（P〉0．05）。结论反复癫痫发作,特别是持续状态可使大鼠海马中mdr1α和mdr1b mRNA表达增加,颞叶的耐药可能与mdr1α和mdr1b mRNA高表达有关。TPM可增加大鼠海马中mdr1α和mdr1b mRNA的表达,尤其mdr1α mRNA的表达更明显。mdr1α 和mdr1b mRNA高表达可能与癫痫和TPM均有关。

Expression of multidrug resistance gene and topiramate affect expression of multidrug resistance gene in the hippocampus of spontaneous epileptic rats

Objective Refractory temporal lobe epilepy (TCE) shows a unique type of hippocampal damage, referred to as hippocampal sclerosis. The mechanisms underlying drug-refractoriness in TCE are poorly understood, which may be connected with pharmacoresistance to antiepileptic drugs (AEDs). Some sdudies show that expression of the multidrug resistance gene (mdr1a and mdr1b) and p-glycoprotein encoded by mdr1a and mdr1b are high in the brain, especially in the hippocampus, and the expression may lead to reduction of AEDs concentration in the brain. But most of these studies focused on acute epileptic activity shortly after status epilepticus(SE), spontaneous seizures are seldom studied. The authors used a rat model of kainic acid induced spontaneous seizures to investigate expression of mdr1a and mdr1b mRNA, and explore whether topiramate (TPM) affects expression of mdr1a and mdr1b in the hippocampus. Methods Seizures were induced by intraperitoneal injection of 10 mg/kg kainic acid at postnatal day 28. Control rats were injected with sodium chloride. All rats were divided into 4 groups 1 week after spontaneous seizures developped: status epilepticus complicated with spontaneous seizures (SE, n=8) group, status epilepticus complicated with spontaneous seizures treated with TPM (SE+TPM, n=9) group, spontaneous seizures without status epilepticus (N-SE, n=7) group, spontaneous seizures without status epilepticus treaded with TPM (N-SE+TPM, n=8) group, control (n=7) group and control treated with TPM (control +TPM, n=7) group. The treated rats were given therapeutic dose of TPM (25 mg/kg). All the rats were killed on the 42nd day of administration. The mdr1a and mdr1b mRNAs in the hippocampus were measured by RT-PCR. Results Expression of mdr1a and mdr1b mRNA in the hippocampus increased significantly in the SE+TPM group, SE group and N-SE+TPM group compared with control group (P<0.001or <0.05). The mRNA in SE+TPM group increased significantly compared with the SE group,too (P<0.01). The mdr1a and mdr1b mRNA expression in the hippocampus in control +TPM and N-SE groups did not change. Conclusion Frequent seizures,especially status epilepticus resulted in overexpression of mdr1a and mdr1b mRNAs in the hippocampus. The drug-refractoriness mechanism in TCE may be related to overexpression of mdr1a and mdr1b mRNAs. TPM could enhance the expression of mdr1a and mdr1b mRNAs in the hippocampus. Seizure activity and TPM are likely to be the main determinant in enhancing mdr1a and mdr1b mRNA expression in epilepsy.