Benzodiazepines have been used for decades as first-line treatment for status epilepticus (SE). For reasons that are not fully understood, the efficacy of benzodiazepines decreases with increasing duration of seizure activity. This often forces clinicians to resort to more drastic second- and third-line treatments that are not always successful. The antiseizure properties of benzodiazepines are mediated by γ-aminobutyric acid type A (GABA(A) ) receptors. Decades of research have focused on the failure of GABAergic inhibition after seizure onset as the likely cause of the development benzodiazepine resistance during SE. However, the details of the deficits in GABA(A) signaling are still largely unknown. Therefore, it is necessary to improve our understanding of the mechanisms of benzodiazepine resistance so that more effective strategies can be formulated. In this review we discuss evidence supporting the role of altered GABA(A) receptor function as the major underlying cause of benzodiazepine-resistant SE in both humans and animal models. We specifically address the prevailing hypothesis, which is based on changes in the number and subtypes of GABA(A) receptors, as well as the potential influence of perturbed chloride homeostasis in the mature brain.

译文

:苯二氮卓类药物已被用作癫痫持续状态(SE)的一线治疗。由于尚未完全理解的原因,苯二氮卓类药物的功效会随着癫痫发作持续时间的增加而降低。这通常迫使临床医生诉诸于并非总是成功的更激烈的二线和三线治疗。苯二氮卓类药物的抗癫痫作用是由γ-氨基丁酸A型(GABA(A))受体介导的。数十年的研究集中在癫痫发作后GABA能抑制的失败,这可能是SE期间对苯二氮卓类药物产生耐药性的可能原因。但是,GABA(A)信号转导的赤字的细节仍然很大程度上未知。因此,有必要增进我们对苯二氮卓类药物耐药性机制的了解,以便制定更有效的策略。在这篇综述中,我们讨论了在人和动物模型中支持改变的GABA(A)受体功能作为苯二氮卓类抗药性SE的主要原因的作用的证据。我们专门针对流行的假说,该假说基于GABA(A)受体的数量和亚型的变化,以及成熟脑中摄动氯稳态的潜在影响。

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