Multidrug resistance-associated protein I decreases the concentrations of antiepileptic drugs in cortical extracellular fluid in amygdale kindling rats  

作　　者：Ying-hui CHEN Cui-cui WANG Xia XIAO Li WEI Guoxiong XU 

机构地区：[1]Department of Neurology, Jinshan Hospital, Fudan University, Shanghai 201508, China [2]Department of Neurology, Shanghai Medical College, Fudan University, Shanghai 200032, China [3]Center Laboratory, Jinshan Hospital, Fudan University, Shanghai 201508, China

出　　处：《Acta Pharmacologica Sinica》2013年第4期473-479,共7页中国药理学报（英文版）

摘　　要：Aim： To investigate whether multidrug resistance-associated protein 1 （MRP1） was responsible for drug resistence in refractory epi- lepsy in amygdale kindling rats. Methods： Rat amygdale kindling was used as a model of refractory epilepsy. The expression of MRP1 mRNA and protein in the brains was examined using RT-PCR and Western blot. MRPl-positive cells in the cortex and hippocampus were studied with immunohis- tochemical staining. The rats were intraperitoneally injected with phenytoin （50 mg/kg） or carbamazepine （20 mE=v＇kg）, and their con- centrations in the cortical extracellular fluid were measured using microdialysis and HPLC. Probenecid, a MRP1 inhibitor （40 mmoVL, 50 IJL） was administered through an inflow tube into the cortex 30 min before injection of the antiepileptic drugs. Results： The expression of MRP1 mRNA and protein was significantly up-regulated in the cortex and hippocampus in amygdale kindling rats compared with the control group. Furthermore, the number of MRPl-positive cells in the cortex and hippocampus was also sig- nificantly increased in amygdale kindling rats. Microdialysis studies showed that the concentrations of phenytoin and carbamazepine in the cortical extracellular fluid were significantly decreased in amygdale kindling rats. Pre-administration of probenecid could restore the concentrations back to their control levels. Conclusion： Up-regulation of MRP1 is responsible for the resistance of brain cells to antiepileptic drugs in the amygdale kindling rats.Aim： To investigate whether multidrug resistance-associated protein 1 （MRP1） was responsible for drug resistence in refractory epi- lepsy in amygdale kindling rats. Methods： Rat amygdale kindling was used as a model of refractory epilepsy. The expression of MRP1 mRNA and protein in the brains was examined using RT-PCR and Western blot. MRPl-positive cells in the cortex and hippocampus were studied with immunohis- tochemical staining. The rats were intraperitoneally injected with phenytoin （50 mg/kg） or carbamazepine （20 mE=v＇kg）, and their con- centrations in the cortical extracellular fluid were measured using microdialysis and HPLC. Probenecid, a MRP1 inhibitor （40 mmoVL, 50 IJL） was administered through an inflow tube into the cortex 30 min before injection of the antiepileptic drugs. Results： The expression of MRP1 mRNA and protein was significantly up-regulated in the cortex and hippocampus in amygdale kindling rats compared with the control group. Furthermore, the number of MRPl-positive cells in the cortex and hippocampus was also sig- nificantly increased in amygdale kindling rats. Microdialysis studies showed that the concentrations of phenytoin and carbamazepine in the cortical extracellular fluid were significantly decreased in amygdale kindling rats. Pre-administration of probenecid could restore the concentrations back to their control levels. Conclusion： Up-regulation of MRP1 is responsible for the resistance of brain cells to antiepileptic drugs in the amygdale kindling rats.

关 键 词：multidrug resistance-associated protein 1 refractory epilepsy amygdale kindling antiepileptic drug PHENYTOIN carbam-azepine cortex hippocampus MICRODIALYSIS 

分 类 号：Q573[生物学—生物化学] Q51