Department of Neuroscience, Tufts University School of Medicine, Boston, Massachusetts 02111, USA.
Epilepsia. 2012 Dec;53 Suppl 9(0 9):79-88. doi: 10.1111/epi.12037.
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.
苯二氮䓬类药物已被使用数十年，作为治疗癫痫持续状态（SE）的一线治疗药物。由于其确切机制尚不完全清楚，苯二氮䓬类药物的疗效随癫痫持续时间的延长而降低。这通常迫使临床医生不得不采用更激进的二线和三线治疗方法，但这些方法并不总是有效。苯二氮䓬类药物的抗癫痫作用是通过γ-氨基丁酸 A 型（GABA(A)）受体介导的。几十年来，研究的重点一直是癫痫发作后 GABA 能抑制的失败，这可能是 SE 期间苯二氮䓬类药物耐药性发展的原因。然而，GABA(A)信号转导缺陷的细节仍在很大程度上未知。因此，有必要提高我们对苯二氮䓬类药物耐药性机制的理解，以便制定更有效的治疗策略。在这篇综述中，我们讨论了支持改变 GABA(A)受体功能是导致人类和动物模型中苯二氮䓬类药物耐药性 SE 的主要原因的证据。我们特别讨论了目前的主流假说，该假说基于 GABA(A)受体数量和亚型的改变，以及成熟大脑中氯离子稳态失调的潜在影响。
