P-gp Protein Expression and Transport Activity in Rodent Seizure Models and Human Epilepsy.
P-gp Protein Expression and Transport Activity in Rodent Seizure Models and Human Epilepsy.
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DOI：
10.1021/acs.molpharmaceut.6b00770
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发表时间：
2017-04-03
影响因子：
4.9
通讯作者：
Bauer B
中科院分区：
文献类型：
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作者：
Hartz AM;Pekcec A;Soldner EL;Zhong Y;Schlichtiger J;Bauer B
癫痫的治愈目前还不可用，并且癫痫发作发生、癫痫发作复发和对抗癫痫发作药物的耐药性仍然是严重的临床问题。研究表明，癫痫动物模型和癫痫患者的血脑屏障发生了改变。在这方面，癫痫发作增加了血脑屏障外排转运蛋白（如P-糖蛋白（P-gp））的表达，这被认为减少了抗癫痫药物的脑摄取，因此有助于抗癫痫药物耐药性。本研究的目的是评估从癫痫发作和癫痫动物模型以及癫痫患者分离的脑毛细血管的体内和离体制剂相结合的可行性，以研究血脑屏障上的P-gp。暴露孤立的大鼠脑毛细血管谷氨酸离体上调P-gp的表达水平相似的毛细血管中分离的大鼠癫痫持续状态或慢性癫痫。此外，与年龄匹配的对照个体相比，在动物模型中观察到的P-gp蛋白表达的倍数增加与从癫痫患者分离的人脑毛细血管中观察到的P-gp的倍数增加一致。总体而言，在体内/离体的方法，这里允许详细分析的机制，潜在的姜黄素诱导的P-gp的表达和运输活动的变化在血脑屏障。这种方法可以扩展到其他可能导致耐药性癫痫或其他CNS疾病的血脑屏障蛋白。
A cure for epilepsy is currently not available, and seizure genesis, seizure recurrence, and resistance to antiseizure drugs remain serious clinical problems. Studies show that the blood–brain barrier is altered in animal models of epilepsy and in epileptic patients. In this regard, seizures increase expression of blood–brain barrier efflux transporters such as P-glycoprotein (P-gp), which is thought to reduce brain uptake of antiseizure drugs, and thus, contribute to antiseizure drug resistance. The goal of the current study was to assess the viability of combining in vivo and ex vivo preparations of isolated brain capillaries from animal models of seizures and epilepsy as well as from patients with epilepsy to study P-gp at the blood–brain barrier. Exposing isolated rat brain capillaries to glutamate ex vivo upregulated P-gp expression to levels that were similar to those in capillaries isolated from rats that had status epilepticus or chronic epilepsy. Moreover, the fold-increase in P-gp protein expression seen in animal models is consistent with the fold-increase in P-gp observed in human brain capillaries isolated from patients with epilepsy compared to age-matched control individuals. Overall, the in vivo/ex vivo approach presented here allows detailed analysis of the mechanisms underlying seizure-induced changes of P-gp expression and transport activity at the blood–brain barrier. This approach can be extended to other blood–brain barrier proteins that might contribute to drug-resistant epilepsy or other CNS disorders as well.