【摘要】 目的考察拉莫三嗪对慢性癫痫大鼠海马P糖蛋白(P-glycoprotein protein,PGP)和主穹隆蛋白(major vault protein,MVP)的表达及氨基酸含量的影响。方法 SPF级雄性SD大鼠采用戊四氮制备慢性癫痫大鼠并随机分为模型组、拉莫三嗪低剂量(5 mg/kg)组和拉莫三嗪高剂量(10 mg/kg)组,取健康大鼠为对照组,每组15只,所有组别灌胃给药,模型组和对照组灌胃给予生理盐水,给药体积均为1 mL/100 g。记录所有大鼠治疗前及治疗后的行为学特征及体质量,记录治疗后的癫痫发作时间和脑电波,免疫组化法及Western blot法检测海马中的PGP和MVP表达,由HPLC检测海马中天冬氨酸(aspartate,Asp)、谷氨酸(glutamate,Glu)和甘氨酸(glycine,Gly)含量。结果对照组大鼠活动正常。慢性癫痫模型组大鼠表现为活动减少、咀嚼、节律性点头,头颈上仰、前肢阵挛发作,少数大鼠竖尾或尾拍地面。拉莫三嗪组大鼠由早期的头颈上仰、前肢阵挛发作逐渐过渡到竖毛及嘴和面部肌肉抽搐,少见竖尾或尾拍地的情况。治疗前,与对照组比,模型组及拉莫三嗪组的体质量均明显降低(P<0.05),治疗后,与对照组比,模型组体质量、脑电图频率、海马的Gly明显降低(P<0.05),癫痫发作时间、脑电图波幅、海马的Asp、Glu、PGP和MVP增高(P<0.05),与模型组比,拉莫三嗪组的体质量、脑电图频率、海马的Gly明显升高(P<0.05),癫痫发作时间、脑电图波幅、海马的Asp、Glu、PGP和MVP降低(P<0.05),且呈拉莫三嗪剂量依赖性趋势。结论拉莫三嗪治疗慢性癫痫与降低海马PGP、MVP蛋白及改善海马氨基酸相关。更多还原

【Abstract】 Objective To investigate the effects of lamotrigine on P-glycoprotein(PGP) and major vault protein(MVP) expression, and amino acid contents in the hippocampus of rats with chronic epilepsy. Methods Specific pathogen-free male Sprague-Dawley rats were used as model, low-dose lamotrigine(5 mg/kg), and high-dose lamotrigine(10 mg/kg) groups. In addition, healthy rats(n=15) were used as a control group. All groups were intragastrically administered the drug for 25 days. Rats in the model and control groups were administered normal saline at a dose of 1 mL/100 g. Behavioral characteristics and body mass of all rats before and after treatment were recorded. Seizure duration and brain waves after treatment were also recorded. PGP and MVP were detected in the hippocampi by immunohistochemistry and western blot. Aspartate(Asp), glutamate(Glu), and glycine(Gly) contents in hippocampi were detected by high-performance liquid chromatography. Results Rats in the control group showed normal behaviors, while chronic epilepsy model group rats exhibited reduced activity, chewing, rhythmic nodding, upward motions of the head and neck, and forelimb clonic seizures; moreover, a few rats exhibited a vertical tail or tail shot. Rats in the two lamotrigine-treated groups gradually transitioned from early upward motions of the head and neck, and forelimb clonic seizures to piloerection of the hair and mouth and facial muscles, with rare vertical tails or tail shots. Before treatment, body weights of the model group and two lamotrigine-treated groups were significantly decreased compared with the control group(P< 0.05). After treatment, body mass, electroencephalogram frequency, and Gly contents in the hippocampus were significantly decreased(P< 0.05) in the lamotrigine-treated groups compared with the control group; whereas seizure duration, electroencephalogram amplitude, and hippocampal contents of Asp, Glu, PGP, and MVP were increased(P< 0.05). Compared with the model group, body mass, electroencephalogram frequency, and Gly contents in the hippocampus were significantly increased(P< 0.05); whereas seizure duration, electroencephalogram amplitude, and hippocampal contents of Asp, Glu, PGP, and MVP were significantly decreased(P< 0.05) in the two lamotrigine-treated groups in a dose-dependent manner. Conclusions Lamotrigine can be used to treat chronic epilepsy by reducing PGP and MVP, and improving amino acid levels in the hippocampus.更多还原