Althaus Alison L, McCarren Hilary S, Alqazzaz Aymen, Jackson Cecelia, McDonough John H, Smith Carl D, Hoffman Ethan, Hammond Rebecca S, Robichaud Albert J, Doherty James J
Drug Discovery, Sage Therapeutics, Inc., Cambridge, MA, USA.
United States Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, MD, USA.
Epilepsy Behav. 2017 Mar;68:22-30. doi: 10.1016/j.yebeh.2016.12.024. Epub 2017 Jan 18.
Organophosphorus nerve agents (OPNAs) are irreversible inhibitors of acetylcholinesterase that pose a serious threat to public health because of their use as chemical weapons. Exposure to high doses of OPNAs can dramatically potentiate cholinergic synaptic activity and cause status epilepticus (SE). Current standard of care for OPNA exposure involves treatment with cholinergic antagonists, oxime cholinesterase reactivators, and benzodiazepines. However, data from pre-clinical models suggest that OPNA-induced SE rapidly becomes refractory to benzodiazepines. Neuroactive steroids (NAS), such as allopregnanolone, retain anticonvulsant activity in rodent models of benzodiazepine-resistant SE, perhaps because they modulate a broader variety of GABA receptor subtypes. SGE-516 is a novel, next generation NAS and a potent and selective GABA receptor positive allosteric modulator (PAM). The present study first established that SGE-516 reduced electrographic seizures in the rat lithium-pilocarpine model of pharmacoresistant SE. Then the anticonvulsant activity of SGE-516 was investigated in the soman-intoxication model of OPNA-induced SE. SGE-516 (5.6, 7.5, and 10mg/kg, IP) significantly reduced electrographic seizure activity compared to control when administered 20min after SE onset. When 10mg/kg SGE-516 was administered 40min after SE onset, seizure activity was still significantly reduced compared to control. In addition, all cohorts of rats treated with SGE-516 exhibited significantly reduced neuronal cell death as measured by FluoroJade B immunohistochemistry. These data suggest synthetic NASs that positively modulate both synaptic and extrasynaptic GABA receptors may be candidates for further study in the treatment of OPNA-induced SE.
有机磷神经毒剂（OPNAs）是乙酰胆碱酯酶的不可逆抑制剂，因其被用作化学武器而对公众健康构成严重威胁。高剂量接触OPNAs可显著增强胆碱能突触活性并导致癫痫持续状态（SE）。目前针对OPNA暴露的标准治疗方法包括使用胆碱能拮抗剂、肟类胆碱酯酶复活剂和苯二氮䓬类药物。然而，临床前模型的数据表明，OPNA诱导的SE会迅速对苯二氮䓬类药物产生耐药性。神经活性甾体（NAS），如别孕烯醇酮，在苯二氮䓬类药物耐药性SE的啮齿动物模型中保留抗惊厥活性，这可能是因为它们能调节更多种类的GABA受体亚型。SGE-516是一种新型的、新一代NAS，也是一种强效且选择性的GABA受体正性变构调节剂（PAM）。本研究首先证实，SGE-516在药物抵抗性SE的大鼠锂-匹罗卡品模型中可减少脑电图癫痫发作。然后在OPNA诱导的SE的梭曼中毒模型中研究了SGE-516的抗惊厥活性。在SE发作后20分钟给予SGE-516（5.6、7.5和10mg/kg，腹腔注射），与对照组相比，脑电图癫痫发作活动显著降低。当在SE发作后40分钟给予10mg/kg SGE-516时，与对照组相比，癫痫发作活动仍显著降低。此外，通过FluoroJade B免疫组织化学检测，所有接受SGE-516治疗的大鼠队列的神经元细胞死亡均显著减少。这些数据表明，能正向调节突触和突触外GABA受体的合成NASs可能是进一步研究治疗OPNA诱导的SE的候选药物。
