Glutamate is critically involved in seizure-induced overexpression of P-glycoprotein in the brain
Glutamate is critically involved in seizure-induced overexpression of P-glycoprotein in the brain
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DOI：
10.1016/j.neuropharm.2008.02.008
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发表时间：
2008-05-01
影响因子：
4.7
通讯作者：
Loescher, W.
中科院分区：
文献类型：
--
作者：
Bankstahl, Jens P.;Hoffmann, Katrin;Loescher, W.
大约 30% 的癫痫患者对药物治疗没有充分反应，这使得耐药性成为治疗这种常见脑部疾病的主要问题。难治性的机制尚不清楚，但可能包括通过血脑屏障处药物外流转运蛋白 P-糖蛋白 (Pgp) 的过度表达来限制抗癫痫药物进入癫痫病灶。在顽固性癫痫患者的致癫痫脑组织和颞叶癫痫啮齿动物模型（包括毛果芸香碱模型）中均发现 Pgp 表达增加。癫痫发作后 Pgp 增加的机制尚不清楚。我们最近提出，癫痫发作时过度释放的兴奋性神经递质谷氨酸参与了癫痫发作引起的大脑中 Pgp 的过度表达。本研究在大鼠毛果芸香碱模型中对这一假设进行了评估。癫痫持续状态 (SE) 90 分钟后，给予地西泮，然后给予媒介物或谷氨酸受体拮抗剂 MK-801（地佐西平）。对媒介物处理的大鼠进行 SE 治疗后，海马中脑毛细血管内皮细胞中的 Pgp 表达增加了约两倍，而 MK-801 完全阻止了这种情况。此外，谷氨酸拮抗剂还减少了海马和海马旁区域发生的神经变性。相比之下，Pgp 抑制剂 tariquidar 不会影响 SE 诱导的 Pgp 过度表达或大多数检查区域的神经变性。数据表明，癫痫发作诱导的谷氨酸释放参与 Pgp 表达的调节，而 MK-801 可以阻断这种表达。 MK-801 在 SE 后给药时可以抵消 Pgp 过度表达和神经元损伤，这一发现可能为难治性 SE 患者提供临床上有用的治疗选择。 (C) 2008 Elsevier Ltd. 保留所有权利。
About 30% of patients with epilepsy do not respond adequately to drug therapy, making pharmacoresistance a major problem in the treatment of this common brain disorder. Mechanisms of intractability are not well understood, but may include limitation of antiepileptic drug access to the seizure focus by overexpression of the drug efflux transporter P-glycoprotein (Pgp) at the blood-brain barrier. Increased expression of Pgp has been determined both in epileptogenic brain tissue of patients with intractable epilepsy and in rodent models of temporal lobe epilepsy, including the pilocarpine model. The mechanisms underlying the increase of Pgp after seizures are unclear. We have recently suggested that the excitatory neurotransmitter glutamate, which is excessively released by seizures, is involved in the seizure-induced overexpression of Pgp in the brain. This hypothesis was evaluated in the present study in the pilocarpine model in rats. After 90 min of status epilepticus (SE), diazepam was administered, followed by either vehicle or the glutamate receptor antagonist MK-801 (dizocilpine). Following SE in vehicle treated rats, Pgp expression in brain capillary endothelial cells increased about twofold in the hippocampus, which was completely prevented by MK-801. Furthermore, neurodegeneration developing in the hippocampus and parahlippocampal regions was reduced by the glutamate antagonist. In contrast, the Pgp inhibitor tariquidar did not affect the SE-induced overexpression of Pgp or neurodegeneration in most regions examined. The data indicate that seizure-induced glutamate release is involved in the regulation of Pgp expression, which can be blocked by MK-801. The finding that MK-801 counteracts both Pgp overexpression and neuronal damage when administered after SE may offer a clinically useful therapeutic option in patients with refractory SE. (C) 2008 Elsevier Ltd. All rights reserved.