Overexpression of multidrug resistance-associated protein 2 in the brain of pentylenetetrazole-kindled rats.
Clinical studies and animal models have shown that pharmacoresistant epilepsy is partly due to the overexpression of ATP-binding cassette transporters at the brain. The purposes of the study were to investigate the function and expression of multidrug resistance-associated protein 2 (Mrp2) in the brain of pentylenetetrazole (PTZ)-kindled rats, and the effect of the altered Mrp2 function and expression on phenytoin (PHT) distribution in the brain. Kindled rats were developed by sub-convulsive dose of PTZ (33 mg/kg, every day, intraperitoneal (i.p.)) for 28 days. Mrp2 expression and function were measured by western blot and bromosulfophthalein (BSP) distribution in the brain. PHT concentrations in the brain of PTZ-kindled rats were measured alone or with co-administration of probenecid (50mg/kg). Further experiment was designed to investigate whether PHT treatment prevented the up-regulated brain Mrp2 expression and function induced by PTZ-kindling. The results showed that PTZ-kindling resulted in an increase of Mrp2 level in the hippocampus and cortex of rats, accompanied by significant decreases in the brain-to-plasma concentration ratio of BSP. PTZ-kindling also decreased PHT levels in the hippocampus and cortex without altering PHT concentrations in plasma, resulting in a lower brain-to-plasma concentration ratio of PHT. Co-administration of probenecid increased the brain-to-plasma ratio of BSP and PHT in the brain of both normal and PTZ-kindled rats. A 14-day PHT treatment prevented the up-regulation of Mrp2 expression and function induced by PTZ-kindling, accompanied by increases of PHT concentrations in the brain and good anticonvulsive effects. The present study demonstrated that chronic PTZ-kindling increased Mrp2 expression and function in the rat brain, and the up-regulation partly came from epileptic seizure.
Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.
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D000704:Analysis of Variance; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects*; D002853:Chromatography, Liquid; D004396:Coloring Agents / Q000378:metabolism / Q000494:pharmacology; D003292:Convulsants / Q000633:toxicity; D004195:Disease Models, Animal; D004347:Drug Interactions; D004827:Epilepsy / Q000139:chemically induced* / Q000188:drug therapy / Q000473:pathology*; D007696:Kindling, Neurologic / Q000187:drug effects; D008297:Male; D013058:Mass Spectrometry; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism*; D010433:Pentylenetetrazole / Q000633:toxicity; D010672:Phenytoin / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D013448:Sulfobromophthalein / Q000378:metabolism; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects*
D000927:Anticonvulsants; D004396:Coloring Agents; D003292:Convulsants; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D010433:Pentylenetetrazole; D010672:Phenytoin; D013448:Sulfobromophthalein