Seizure-induced up-regulation of P-glycoprotein at the blood-brain barrier through glutamate and cyclooxygenase-2 signaling
Seizure-induced up-regulation of P-glycoprotein at the blood-brain barrier through glutamate and cyclooxygenase-2 signaling
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DOI：
10.1124/mol.107.041210
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发表时间：
2008-05-01
影响因子：
3.6
通讯作者：
Potschka, Heidrun
中科院分区：
文献类型：
--
作者：
Bauer, Bjoern;Hartz, Anika M. S.;Potschka, Heidrun
血脑屏障药物外排转运蛋白表达增加伴随癫痫发作，使抗癫痫药物治疗复杂化。本研究关注的是确定癫痫发作活动与血脑屏障P-糖蛋白表达增加之间的机制联系。在这方面，我们测试了癫痫发作增加脑细胞外谷氨酸的假设，谷氨酸通过脑毛细血管中的N-甲基-D-天冬氨酸（NMDA）受体和环氧合酶-2（考克斯-2）发出信号，以增加血脑屏障P-糖蛋白的表达。与这一假设相一致，暴露分离的大鼠或小鼠脑毛细血管谷氨酸15至30分钟增加P-糖蛋白的表达和运输活性小时后。这些增加被5 H-二苯并[a，d]环庚烯-5，10-亚胺（马来酸地佐环平）（MK-801）（一种NMDA受体拮抗剂）和塞来昔布（一种选择性考克斯-2抑制剂）阻断;在考克斯-2缺失小鼠的脑毛细血管中未观察到谷氨酸诱导的增加。在大鼠脑内微量注射谷氨酸引起局部脑毛细血管P-糖蛋白表达增加。此外，使用匹鲁卡品癫痫持续状态大鼠模型，我们观察到，在毛细血管P-糖蛋白表达的吲哚美辛，一种考克斯抑制剂的管理，衰减的癫痫诱导的增加。我们的研究结果表明，脑摄取的一些抗癫痫药物可以通过考克斯-2抑制增强。此外，它们提供了对癫痫和其他可能的中枢神经系统疾病耐药性的一种机制的深入了解。
Increased expression of drug efflux transporters at the blood-brain barrier accompanies epileptic seizures and complicates therapy with antiepileptic drugs. This study is concerned with identifying mechanistic links that connect seizure activity to increased P-glycoprotein expression at the blood-brain barrier. In this regard, we tested the hypothesis that seizures increase brain extracellular glutamate, which signals through an N-methyl-D-aspartate (NMDA) receptor and cyclooxygenase-2 (COX-2) in brain capillaries to increase blood-brain barrier P-glycoprotein expression. Consistent with this hypothesis, exposing isolated rat or mouse brain capillaries to glutamate for 15 to 30 min increased P-glycoprotein expression and transport activity hours later. These increases were blocked by 5H-dibenzo[a,d] cyclohepten-5,10-imine (dizocilpine maleate) (MK-801), an NMDA receptor antagonist, and by celecoxib, a selective COX-2 inhibitor; no such glutamate-induced increases were seen in brain capillaries from COX-2-null mice. In rats, intracerebral microinjection of glutamate caused locally increased P-glycoprotein expression in brain capillaries. Moreover, using a pilocarpine status epilepticus rat model, we observed seizure-induced increases in capillary P-glycoprotein expression that were attenuated by administration of indomethacin, a COX inhibitor. Our findings suggest that brain uptake of some antiepileptic drugs can be enhanced through COX-2 inhibition. Moreover, they provide insight into one mechanism that underlies drug resistance in epilepsy and possibly other central nervous system disorders.