Neurochlore, Fundamental Research Department, Ben-Ari Institute of Neuroarcheology, Marseille, France.
Department of Anesthesiology, Vanderbilt University Medical School, Nashville, Tennessee, USA.
Epilepsia. 2021 Apr;62(4):935-940. doi: 10.1111/epi.16830. Epub 2021 Feb 3.
Kaila, Löscher, and colleagues report that phenobarbital (PHB) and midazolam (MDZ) attenuate neonatal seizures following birth asphyxia, but the former only when applied before asphyxia and the latter before or after the triggering insult. In contrast, the NKCC1 chloride importer antagonist bumetanide (BUM) had no effect whether applied alone or with PHB. The observations are compelling and in accord with earlier studies. However, there are several general issues that deserve discussion. What is the clinical relevance of these data and the validity of animal models of encephalopathic seizures? Why is it that although they act on similar targets, these agents have different efficacy? Are both PHB and MDZ actions restricted to γ-aminobutyric acidergic (GABAergic) mechanisms? Why is BUM inefficient in attenuating seizures but capable of reducing the severity of other brain disorders? We suggest that the relative failure of antiepileptic drugs (AEDs) to treat this severe life-threatening condition is in part explicable by the recurrent seizures that shift the polarity of GABA, thereby counteracting their effects on their target. AEDs might be efficient after a few seizures but not recurrent ones. In addition, PHB and MDZ actions are not limited to GABA signals. BUM efficiently attenuates autism symptomatology notably in patients with tuberous sclerosis but does not reduce the recurrent seizures, illustrating the uniqueness of epilepsies. Therefore, the efficacy of AEDs to treat babies with encephalopathic seizures will depend on the history and severity of the seizures prior to their administration, challenging a universal common underlying mechanism.
凯拉、勒舍尔和同事报告称，苯巴比妥（PHB）和咪达唑仑（MDZ）可减轻新生儿窒息后癫痫发作，但前者仅在窒息前应用，后者在触发损伤前或后应用。相比之下，NKCC1 氯离子转运体抑制剂布美他尼（BUM）无论是单独应用还是与 PHB 联合应用都没有效果。这些观察结果令人信服，与早期研究一致。然而，有几个一般性问题值得讨论。这些数据的临床意义以及脑性癫痫发作的动物模型的有效性如何？为什么尽管它们作用于相似的靶点，但这些药物的疗效却不同？PHB 和 MDZ 的作用是否都仅限于γ-氨基丁酸能（GABAergic）机制？为什么 BUM 不能有效减轻癫痫发作，但能够减轻其他脑疾病的严重程度？我们认为，抗癫痫药物（AEDs）治疗这种严重危及生命的疾病的相对失败部分可以解释为反复癫痫发作改变了 GABA 的极性，从而抵消了它们对目标的作用。AEDs 在几次癫痫发作后可能会有效，但在反复癫痫发作后则不然。此外，PHB 和 MDZ 的作用不仅限于 GABA 信号。BUM 可有效减轻自闭症症状，特别是在结节性硬化症患者中，但不能减少反复癫痫发作，说明了癫痫的独特性。因此，AEDs 治疗患有脑病性癫痫发作的婴儿的疗效将取决于其给药前癫痫发作的病史和严重程度，这对普遍存在的共同潜在机制提出了挑战。
