Sudden unexpected death in epilepsy (SUDEP) is the major cause of death that affects patients with epilepsy. The risk of SUDEP increases according to the frequency and severity of uncontrolled seizures; therefore, SUDEP risk is higher in patients with refractory epilepsy (RE), in whom most antiepileptic drugs (AEDs) are ineffective for both seizure control and SUDEP prevention. Consequently, RE and SUDEP share a multidrug resistance (MDR) phenotype, which is mainly associated with brain overexpression of ABC-transporters such as P-glycoprotein (P-gp). The activity of P-gp can also contribute to membrane depolarization and affect the normal function of neurons and cardiomyocytes. Other molecular regulators of membrane potential are the inwardly rectifying potassium channels (Kir), whose genetic variants have been related to both epilepsy and heart dysfunctions. Although it has been suggested that dysfunctions of the cardiac, respiratory, and brainstem arousal systems are the causes of SUDEP, the molecular basis for explaining its dysfunctions remain unknown. In rats, repetitive seizures or status epilepticus induced high expression of P-gp and loss Kir expression in the brain and heart, and promoted membrane depolarization, malignant bradycardia, and the high rate of mortality. Here we reviewed clinical and experimental evidences suggesting that abnormal expression of depolarizing/repolarizing factors as P-gp and Kir could favor persistent depolarization of membranes without any rapid functional recovery capacity. This condition induced by convulsive stress could be the molecular mechanism leading to acquired severe bradycardia, as an ineffective heart response generating the appropriate scenario for SUDEP development. This article is part of the Special Issue "NEWroscience 2018".

中文翻译：

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P-糖蛋白（P-gp）和内向整流钾（Kir）通道在癫痫猝死（SUDEP）中的作用

癫痫猝死 (SUDEP) 是影响癫痫患者的主要死亡原因。SUDEP 的风险根据不受控制的癫痫发作的频率和严重程度而增加；因此，难治性癫痫 (RE) 患者的 SUDEP 风险较高，其中大多数抗癫痫药物 (AED) 对控制癫痫发作和预防 SUDEP 均无效。因此，RE 和 SUDEP 具有多药耐药 (MDR) 表型，这主要与 ABC 转运蛋白如 P-糖蛋白 (P-gp) 的脑过度表达有关。P-gp 的活性还可以促进膜去极化并影响神经元和心肌细胞的正常功能。膜电位的其他分子调节剂是内向整流钾通道 (Kir)，其遗传变异与癫痫和心脏功能障碍有关。虽然有人认为心脏、呼吸和脑干唤醒系统的功能障碍是 SUDEP 的原因，但解释其功能障碍的分子基础仍然未知。在大鼠中，重复性癫痫发作或癫痫持续状态诱导大脑和心脏中 P-gp 的高表达和 Kir 表达的丧失，并促进膜去极化、恶性心动过缓和高死亡率。在这里，我们回顾了临床和实验证据，表明去极化/复极化因子如 P-gp 和 Kir 的异常表达可能有利于膜的持续去极化，而没有任何快速功能恢复能力。这种由惊厥应激引起的情况可能是导致获得性严重心动过缓的分子机制，因为无效的心脏反应产生了 SUDEP 发展的适当场景。本文是特刊“NEWroscience 2018”的一部分。