Neuroscience Department, U.S. Army Medical Research Institute of Chemical Defense (USAMRICD), Aberdeen Proving Ground, Maryland, USA.
Military Psychiatry and Neuroscience Department, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA.
Epilepsia Open. 2021 Dec;6(4):757-769. doi: 10.1002/epi4.12552. Epub 2021 Oct 23.
Cholinergic-induced status epilepticus (SE) is associated with a loss of synaptic gamma-aminobutyric acid A receptors (GABA R) and an increase in N-methyl-D-aspartate receptors (NMDAR) and amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPAR) that may contribute to pharmacoresistance when treatment with benzodiazepine antiseizure medication is delayed. The barbiturate phenobarbital enhances inhibitory neurotransmission by binding to a specific site in the GABA R to increase the open state of the channel, decrease neuronal excitability, and reduce glutamate-induced currents through AMPA/kainate receptors. We hypothesized that phenobarbital as an adjunct to midazolam would augment the amelioration of soman-induced SE and associated neuropathological changes and that further protection would be provided by the addition of an NMDAR antagonist.
We investigated the efficacy of combining antiseizure medications to include a benzodiazepine and a barbiturate allosteric GABA R modulator (midazolam and phenobarbital, respectively) to correct loss of inhibition, and ketamine to reduce excitation caused by increased synaptic localization of NMDAR and AMPAR, which are NMDA-dependent. Rats implanted with transmitters to record electroencephalographic (EEG) activity were exposed to soman and treated with atropine sulfate and HI-6 one min after exposure and with antiseizure medication(s) 40 minutes after seizure onset.
The triple therapy combination of phenobarbital, midazolam, and ketamine administered at 40 minutes after seizure onset effectively prevented soman-induced epileptogenesis and reduced neurodegeneration. In addition, dual therapy with phenobarbital and midazolam or ketamine was more effective than monotherapy (midazolam or phenobarbital) in reducing cholinergic-induced toxicity.
Benzodiazepine efficacy is drastically reduced with time after seizure onset and inversely related to seizure duration. To overcome pharmacoresistance in severe benzodiazepine-refractory cholinergic-induced SE, simultaneous drug combination to include drugs that target both the loss of inhibition (eg, midazolam, phenobarbital) and the increased excitatory response (eg, ketamine) is more effective than benzodiazepine or barbiturate monotherapy.
胆碱能诱导的癫痫持续状态（SE）与突触γ-氨基丁酸 A 受体（GABA R）的丧失以及 N-甲基-D-天冬氨酸受体（NMDAR）和氨基酸-3-羟基-5-甲基-4-异恶唑丙酸受体（AMPAR）的增加有关，如果在使用苯二氮䓬类抗惊厥药物治疗时延迟，可能会导致药物抵抗。巴比妥类药物苯巴比妥通过与 GABA R 的特定结合位点结合来增强抑制性神经传递，从而增加通道的开放状态，降低神经元兴奋性，并减少谷氨酸诱导的 AMPA/KA 受体电流。我们假设，苯巴比妥作为咪达唑仑的辅助药物，将增强对梭曼诱导的 SE 及相关神经病理学变化的改善作用，而添加 NMDAR 拮抗剂将提供进一步的保护。
我们研究了联合使用抗惊厥药物的疗效，包括苯二氮䓬类和巴比妥类别构 GABA R 调节剂（分别为咪达唑仑和苯巴比妥）以纠正抑制丧失，以及氯胺酮以减少由于 NMDA 依赖性突触定位增加而引起的兴奋，即 NMDAR 和 AMPAR。将用于记录脑电图（EEG）活动的发射器植入大鼠体内，在暴露后 1 分钟给予硫酸阿托品和 HI-6，并在发作后 40 分钟给予抗惊厥药物。
在发作后 40 分钟给予苯巴比妥、咪达唑仑和氯胺酮的三联治疗组合有效地预防了梭曼诱导的癫痫发生，并减少了神经退行性变。此外，与咪达唑仑或苯巴比妥单药治疗相比，苯巴比妥和咪达唑仑或氯胺酮的双药治疗在减轻胆碱能诱导的毒性方面更有效。
苯二氮䓬类药物的疗效随着发作后时间的推移而急剧降低，与发作持续时间成反比。为了克服严重的苯二氮䓬类难治性胆碱能诱导的 SE 中的药物抵抗，同时使用药物联合治疗，包括针对抑制丧失（例如，咪达唑仑、苯巴比妥）和兴奋性反应增加（例如，氯胺酮）的药物，比苯二氮䓬类或巴比妥类单药治疗更有效。
