Liu Xiaodong, Yang Zhihong, Yang Jiansong, Yang Huiwen
Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, PR China.
Neuropharmacology. 2007 Oct;53(5):657-63. doi: 10.1016/j.neuropharm.2007.07.012. Epub 2007 Aug 6.
The purposes of this study were to investigate whether P-glycoprotein (P-GP) is overexpressed in the brain of pentylenetetrazole (PTZ)-kindled rats, and to investigate the effects of P-GP up-regulation on the distribution of phenobarbital (PB) in brain and its antiepileptic effects. Kindled rats were developed using a subconvulsive dose of PTZ (30 mg/kg, once every 2 days, i.p.) for 24 days. P-GP expression and function were measured by Western blot analysis and rhodamine 123 (Rho 123) distribution in brain. Kindled rats received 10 mg/kg of PB alone or co-administration of cyclosporine A (CsA, 5 mg/kg). At 60 min after administration of PB, concentrations of PB in brain and plasma were measured and the tissue-to-plasma concentration ratios of PB were calculated. Anticonvulsive effects of PB (13.2 mg/kg) alone or co-administration of CsA on the kindled rats were observed. The results showed that kindling resulted in 1.7-fold increase of P-GP level in brain, accompanied by significant decrease of tissue-to-plasma concentration ratios of Rho 123 and PB in hippocampus and cortex without affecting their concentrations in plasma. Co-administration of CsA reversed the decrease of PB concentration in brain without affecting PB level in plasma and significantly potentiated the anticonvulsive effects of PB. The present study demonstrated that chronic PTZ-kindling might increase P-GP expression and function in brain of rat, resulting in decrease of Rho 123 and PB levels in brain tissues. Co-administration of CsA increased PB levels in brain and enhanced anticonvulsive effects of PB by inhibiting P-GP function.
本研究的目的是调查戊四氮（PTZ）点燃大鼠的脑中P-糖蛋白（P-GP）是否过表达，并研究P-GP上调对苯巴比妥（PB）在脑中分布及其抗癫痫作用的影响。采用亚惊厥剂量的PTZ（30mg/kg，每2天腹腔注射1次）诱导大鼠点燃24天。通过蛋白质免疫印迹分析和脑中罗丹明123（Rho 123）分布来检测P-GP的表达和功能。点燃大鼠单独接受10mg/kg的PB或联合给予环孢素A（CsA，5mg/kg）。给予PB后60分钟，测量脑中及血浆中PB的浓度，并计算PB的组织-血浆浓度比。观察PB（13.2mg/kg）单独给药或联合CsA给药对点燃大鼠的抗惊厥作用。结果显示，点燃导致脑中P-GP水平增加1.7倍，同时海马和皮层中Rho 123及PB的组织-血浆浓度比显著降低，而不影响它们在血浆中的浓度。联合给予CsA可逆转脑中PB浓度的降低，而不影响血浆中PB水平，并显著增强PB的抗惊厥作用。本研究表明，慢性PTZ点燃可能增加大鼠脑中P-GP的表达和功能，导致脑组织中Rho 123和PB水平降低。联合给予CsA可增加脑中PB水平，并通过抑制P-GP功能增强PB的抗惊厥作用。
