Neuroscience Department, U.S. Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Maryland (L.A.L., D.A.N., E.O.L., C.R.S., M.F.S.); BioSEaD, LLC, Rockville, Maryland (M.d.A.F.); and Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, California, and Epilepsy Research Laboratory, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California (J.N., C.G.W.)
Neuroscience Department, U.S. Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Maryland (L.A.L., D.A.N., E.O.L., C.R.S., M.F.S.); BioSEaD, LLC, Rockville, Maryland (M.d.A.F.); and Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, California, and Epilepsy Research Laboratory, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California (J.N., C.G.W.).
J Pharmacol Exp Ther. 2024 Jan 17;388(2):347-357. doi: 10.1124/jpet.123.001789.
Benzodiazepine pharmacoresistance develops when treatment of status epilepticus (SE) is delayed. This response may result from gamma-aminobutyric acid A receptors (GABAR) internalization that follows prolonged SE; this receptor trafficking results in fewer GABAR in the synapse to restore inhibition. Increase in synaptic N-methyl-D-aspartate receptors (NMDAR) also occurs in rodent models of SE. Lacosamide, a third-generation antiseizure medication (ASM), acts on the slow inactivation of voltage-gated sodium channels. Another ASM, rufinamide, similarly acts on sodium channels by extending the duration of time spent in the inactivation stage. Combination therapy of the benzodiazepine midazolam, NMDAR antagonist ketamine, and ASMs lacosamide (or rufinamide) was investigated for efficacy against soman (GD)-induced SE and neuropathology. Adult male rats implanted with telemetry transmitters for monitoring electroencephalographic (EEG) activity were exposed to a seizure-inducing dose of GD and treated with an admix of atropine sulfate and HI-6 1 minute later and with midazolam monotherapy or combination therapy 40 minutes after EEG seizure onset. Rats were monitored continuously for seizure activity for two weeks, after which brains were processed for assessment of neurodegeneration, neuronal loss, and neuroinflammatory responses. Simultaneous administration of midazolam, ketamine, and lacosamide (or rufinamide) was more protective against GD-induced SE compared with midazolam monotherapy. In general, lacosamide triple therapy had more positive outcomes on measures of epileptogenesis, EEG power integral, and the number of brain regions protected from neuropathology compared with rats treated with rufinamide triple therapy. Overall, both drugs were well tolerated in these combination models. SIGNIFICANCE STATEMENT: We currently report on improved efficacy of antiseizure medications lacosamide and rufinamide, each administered in combination with ketamine (NMDAR antagonist) and midazolam (benzodiazepine), in combatting soman (GD)-induced seizure, epileptogenesis, and brain pathology over that provided by midazolam monotherapy, or dual therapy of midazolam and lacosamide (or rufinamide) in rats. Administration of lacosamide as adjunct to midazolam and ketamine was particularly effective against GD-induced toxicity. However, protection was incomplete, suggesting the need for further study.
苯二氮䓬类药物耐药性在治疗癫痫持续状态（SE）时发生延迟。这种反应可能是由于 GABA A 受体（GABAR）内陷引起的，该受体内陷是由于 SE 持续时间延长所致；这种受体运输导致突触中 GABA R 减少，以恢复抑制。在 SE 的啮齿动物模型中，突触 NMDA 受体（NMDAR）也会增加。拉科酰胺，第三代抗癫痫药（ASM），作用于电压门控钠离子通道的缓慢失活。另一种 ASM，鲁非酰胺，通过延长失活阶段的时间同样作用于钠离子通道。研究了苯二氮䓬类药物咪达唑仑、NMDA 拮抗剂氯胺酮和 ASM 拉科酰胺（或鲁非酰胺）联合治疗对梭曼（GD）诱导的 SE 和神经病理学的疗效。成年雄性大鼠植入遥测发射器以监测脑电图（EEG）活动，然后暴露于引起癫痫发作的 GD 剂量下，并在 1 分钟后给予硫酸阿托品和 HI-6，然后在 EEG 癫痫发作后 40 分钟给予咪达唑仑单药治疗或联合治疗。大鼠连续监测癫痫发作活动两周，然后对大脑进行处理，以评估神经退行性变、神经元丢失和神经炎症反应。与咪达唑仑单药治疗相比，同时给予咪达唑仑、氯胺酮和拉科酰胺（或鲁非酰胺）对 GD 诱导的 SE 更具保护作用。一般来说，与用鲁非酰胺三联疗法治疗的大鼠相比，拉科酰胺三联疗法在癫痫发生、EEG 功率积分和免受神经病理学影响的脑区数量等方面对癫痫发生的测量有更多的积极结果。总的来说，这两种药物在这些联合模型中都有良好的耐受性。意义：我们目前报告了抗癫痫药物拉科酰胺和鲁非酰胺的疗效提高，这两种药物分别与氯胺酮（NMDA 拮抗剂）和咪达唑仑（苯二氮䓬类药物）联合使用，在对抗梭曼（GD）诱导的癫痫发作、癫痫发生和大脑病理学方面，优于咪达唑仑单药治疗或咪达唑仑和拉科酰胺（或鲁非酰胺）的双重治疗在大鼠中。拉科酰胺作为咪达唑仑和氯胺酮的辅助药物对抗 GD 诱导的毒性特别有效。然而，保护并不完全，这表明需要进一步研究。
