The multidrug transporter hypothesis of drug resistance in epilepsy:: Proof-of-principle in a rat model of temporal lobe epilepsy
The multidrug transporter hypothesis of drug resistance in epilepsy:: Proof-of-principle in a rat model of temporal lobe epilepsy
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DOI：
10.1016/j.nbd.2006.06.014
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发表时间：
2006-10-01
影响因子：
6.1
通讯作者：
Loescher, Wolfgang
中科院分区：
文献类型：
--
作者：
Brandt, Claudia;Bethmann, Kerstin;Loescher, Wolfgang
对药物治疗的耐药性是许多疾病治疗中的一个重要障碍，包括癌症、传染病和癫痫等脑部疾病。多药耐药的表型首先被描述为过表达药物外排转运蛋白P-糖蛋白（P-gp）的化疗耐药癌细胞。最近，在药物难治性癫痫患者的致癫痫脑组织毛细血管内皮细胞中发现了P-gp的过度表达。血脑屏障中这种区域限制性P-gp过表达可能会降低癫痫神经元中抗癫痫药物的浓度，这可能是癫痫多药耐药的合理解释。然而，这一假设缺乏明确的原理证明。在本研究中，我们使用了颞叶癫痫大鼠模型，允许选择耐药和药物反应亚组的癫痫大鼠延长治疗的抗癫痫药物苯巴比妥在最大耐受剂量。我们最近已经表明，从这个模型中选择的耐药大鼠表现出显着的过度表达的P-gp在海马和其他边缘脑区。因此，该模型非常适合于证明耐药性的多药转运体假说。为此，我们选择了一组苯巴比妥耐药大鼠，随后通过苯巴比妥与选择性P-gp抑制剂tariquidar的组合进行治疗。同时给予tariquidar（15-20 mg/kg）完全恢复了苯巴比妥的抗惊厥活性，而不改变抗癫痫药物的血浆药代动力学或神经毒性。这些数据表明，抑制P-gp在癫痫大鼠与已证实的耐药性抵消电阻，提供了第一个证明的原则，多药转运假说的医学难治性癫痫。(c)2006年爱思唯尔公司All rights reserved.
Resistance to drug treatment is an important hurdle in the therapy of many diseases, including cancer, infectious diseases and brain disorders such as epilepsy. A phenotype that is referred to as multidrug resistance was first described for chemotherapy-resistant cancer cells that over-expressed the drug efflux transporter P-glycoprotein (P-gp). More recently, overexpression of P-gp has been found in capillary endothelial cells of epileptogenic brain tissue from patients with medically intractable epilepsy. Such regionally restricted P-gp overexpression in the blood-brain barrier is likely to reduce the concentration of antiepileptic drugs at epileptic neurons, which would be a plausible explanation for multidrug resistance in epilepsy. However, a definite proof-of-principle for this hypothesis is lacking. In the present study, we used a rat model of temporal lobe epilepsy that allows selecting drug-resistant and drug-responsive subgroups of epileptic rats by prolonged treatment with the antiepileptic drug phenobarbital at maximum tolerated doses. We have shown recently that drug-resistant rats selected from this model exhibit a marked overexpression of P-gp in the hippocampus and other limbic brain regions. This model is thus ideally suited to prove the multidrug transporter hypothesis of drug resistance. For this purpose, we selected a group of phenobarbital-resistant rats, which was subsequently treated by combinations of phenobarbital with the selective P-gp inhibitor tariquidar. Coadministration of tariquidar (15-20 mg/kg) fully restored the anticonvulsant activity of phenobarbital without altering plasma pharmacokinetics or neurotoxicity of the antiepileptic drug. These data demonstrate that inhibiting P-gp in epileptic rats with proven drug resistance counteracts resistance, providing the first proof-of-principle of the multidrug transporter hypothesis of medically refractory epilepsy. (c) 2006 Elsevier Inc. All rights reserved.