Adenosine A1 receptor-mediated suppression of carbamazepine-resistant seizure-like events in human neocortical slices
Adenosine A1 receptor-mediated suppression of carbamazepine-resistant seizure-like events in human neocortical slices
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DOI：
10.1111/epi.13360
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发表时间：
2016-05-01
期刊：
影响因子：
5.6
通讯作者：
Heinemann, Uwe
中科院分区：
文献类型：
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作者：
Klaft, Zin-Juan;Hollnagel, Jan-Oliver;Heinemann, Uwe
目的：对于约30%的癫痫患者，目前的治疗方法不能使其癫痫发作得到满意的控制，因此迫切需要替代的药物治疗策略。在颞叶癫痫（TLE）中，甚至高达80%的患者是药物抗性的，并且仅对少数TLE患者可能进行发作组织的手术切除。在这项研究中，我们研究了人类颞叶皮层脑片中药物耐药的类癫痫事件（SLEs）的嘌呤能调节。方法：记录了来自17名药物耐药患者的77个新皮层脑片的V/VI层场电位，以监测应用8 mM[K+]和50 mM荷包牡丹碱诱导的SLEs。用特异性激动剂激活A（1）受体，可以完全抑制73%的人类颞叶皮层切片中的SLE。在其余切片中，SLE的发生率显著降低。由于部分切片可能具有药物敏感性，我们在对高剂量卡马西平（50 μ M）不敏感的切片中测试了A（1）激动剂的作用。在这些情况下，A（1）激动剂同样有效。此外，ATP和腺苷阻断或调制SLE，一种不是由P2受体而是由腺苷A（1）受体介导的效应。意义：A（1）受体的选择性激活介导了一个强大的抗惊厥作用，在人类新皮层切片从抗药性患者。我们建议，我们的人类切片模型的神经元样活动是一个可行的选择，为未来的研究调查新的抗癫痫药物（AED）的候选人。
Objective: The need for alternative pharmacologic strategies in treatment of epilepsies is pressing for about 30% of patients with epilepsy who do not experience satisfactory seizure control with present treatments. In temporal lobe epilepsy (TLE) even up to 80% of patients are pharmacoresistant, and surgical resection of the ictogenic tissue is only possible for a minority of TLE patients. In this study we investigate purinergic modulation of drug-resistant seizure-like events (SLEs) in human temporal cortex slices.Methods: Layer V/VI field potentials from a total of 77 neocortical slices from 17 pharmacoresistant patients were recorded to monitor SLEs induced by application of 8 mM[K+] and 50 lM bicuculline.Results: Activating A(1) receptors with a specific agonist completely suppressed SLEs in 73% of human temporal cortex slices. In the remaining slices, incidence of SLEs was markedly reduced. Because a subportion of slices can be pharmacosensitive, we tested effects of an A(1) agonist, in slices insensitive to a high dose of carbamazepine (50 lM). Also in these cases the A(1) agonist was equally efficient. Moreover, ATP and adenosine blocked or modulated SLEs, an effect mediated not by P2 receptors but rather by adenosine A(1) receptors.Significance: Selective activation of A(1) receptors mediates a strong anticonvulsant action in human neocortical slices from pharmacoresistant patients. We propose that our human slice model of seizure-like activity is a feasible option for future studies investigating new antiepileptic drug (AED) candidates.