Neuroscience Department, US Army Medical Research Institute of Chemical Defense (USAMRICD), Aberdeen Proving Ground, MD, USA.
Department of Neurology, David Geffen School of Medicine at UCLA, Epilepsy Research Laboratory (151), Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, USA.
Neuropharmacology. 2021 Mar 1;185:108444. doi: 10.1016/j.neuropharm.2020.108444. Epub 2021 Jan 5.
The initiation and maintenance of cholinergic-induced status epilepticus (SE) are associated with decreased synaptic gamma-aminobutyric acid A receptors (GABAR) and increased N-methyl-d-aspartate receptors (NMDAR) and amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPAR). We hypothesized that trafficking of synaptic GABAR and glutamate receptors is maladaptive and contributes to the pharmacoresistance to antiseizure drugs; targeting these components should ameliorate the pathophysiological consequences of refractory SE (RSE). We review studies of rodent models of cholinergic-induced SE, in which we used a benzodiazepine allosteric GABAR modulator to correct loss of inhibition, concurrent with the NMDA antagonist ketamine to reduce excitation caused by increased synaptic localization of NMDAR and AMPAR, which are NMDAR-dependent. Models included lithium/pilocarpine-induced SE in rats and soman-induced SE in rats and in Es1-/- mice, which similar to humans lack plasma carboxylesterase, and may better model soman toxicity. These model human soman toxicity and are refractory to benzodiazepines administered at 40 min after seizure onset, when enough synaptic GABAR may not be available to restore inhibition. Ketamine-midazolam combination reduces seizure severity, epileptogenesis, performance deficits and neuropathology following cholinergic-induced SE. Supplementing that treatment with valproate, which targets a non-benzodiazepine site, effectively terminates RSE, providing further benefit against cholinergic-induced SE. The therapeutic index of drug combinations is also reviewed and we show the improved efficacy of simultaneous administration of midazolam, ketamine and valproate compared to sequential drug administration. These data suggest that future clinical trials should treat both the lack of sufficient inhibition and the excess excitation that characterize RSE, and include early combination drug therapies. This article is part of the special issue entitled 'Acetylcholinesterase Inhibitors: From Bench to Bedside to Battlefield'.
从实验室到临床再到战场
胆碱能诱导的癫痫持续状态（SE）的发作和维持与突触γ-氨基丁酸 A 受体（GABAR）减少和 N-甲基-D-天冬氨酸受体（NMDAR）和氨基-3-羟基-5-甲基-4-异恶唑丙酸受体（AMPAR）增加有关。我们假设突触 GABAR 和谷氨酸受体的运输是适应不良的，并导致抗癫痫药物的耐药性；针对这些成分应该可以改善难治性 SE（RSE）的病理生理后果。我们回顾了胆碱能诱导 SE 的啮齿动物模型研究，在这些研究中，我们使用苯二氮䓬类变构 GABAR 调节剂来纠正抑制丧失，同时使用 NMDA 拮抗剂氯胺酮来减少由于 NMDAR 和 AMPAR 的突触定位增加而引起的兴奋，NMDAR 和 AMPAR 的突触定位增加是 NMDA 受体依赖性的。模型包括锂/匹罗卡品诱导的 SE 大鼠和梭曼诱导的 SE 大鼠和 Es1-/- 小鼠，这些小鼠类似于人类缺乏血浆羧酸酯酶，可能更好地模拟梭曼毒性。这些模型模拟人类梭曼毒性，并对 SE 发作后 40 分钟给予的苯二氮䓬类药物耐药，此时可能没有足够的突触 GABAR 可用于恢复抑制。氯胺酮-咪达唑仑联合治疗可降低胆碱能诱导 SE 后的癫痫发作严重程度、癫痫形成、行为缺陷和神经病理学。用丙戊酸补充治疗，丙戊酸针对非苯二氮䓬类药物靶点，可有效终止 RSE，对胆碱能诱导 SE 提供进一步的益处。还回顾了药物联合治疗的治疗指数，我们发现咪达唑仑、氯胺酮和丙戊酸同时给药的疗效优于序贯给药。这些数据表明，未来的临床试验应该治疗 RSE 特征的抑制不足和过度兴奋，包括早期联合药物治疗。本文是题为“乙酰胆碱酯酶抑制剂：从实验室到临床再到战场”的特刊的一部分。
