Department of Pharmacology Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
Drug Discovery and Development Sage Therapeutics, Cambridge, MA, USA.
Sci Rep. 2017 Nov 10;7(1):15327. doi: 10.1038/s41598-017-15609-w.
Dravet syndrome is an infant-onset epileptic encephalopathy with multiple seizure types that are often refractory to conventional therapies. Treatment with standard benzodiazepines like clobazam, in combination with valproate and stiripentol, provides only modest seizure control. While benzodiazepines are a first-line therapy for Dravet syndrome, they are limited by their ability to only modulate synaptic receptors. Unlike benzodiazepines, neuroactive steroids potentiate a wider-range of GABA receptors. The synthetic neuroactive steroid SGE-516 is a potent positive allosteric modulator of both synaptic and extrasynaptic GABA receptors. Prior work demonstrated anticonvulsant activity of SGE-516 in acute seizure assays in rodents. In this study, we evaluated activity of SGE-516 on epilepsy phenotypes in the Scn1a mouse model that recapitulates many features of Dravet syndrome, including spontaneous seizures, premature death and seizures triggered by hyperthermia. To evaluate SGE-516 in Scn1a mice, we determined the effect of treatment on hyperthermia-induced seizures, spontaneous seizure frequency and survival. SGE-516 treatment protected against hyperthermia-induced seizures, reduced spontaneous seizure frequency and prolonged survival in the Scn1a mice. This provides the first evidence of SGE-516 activity in a mouse model of Dravet syndrome, and supports further investigation of neuroactive steroids as potential anticonvulsant compounds for refractory epilepsies.
德拉维特综合征是一种婴儿期起病的癫痫性脑病，有多种发作类型，通常对常规治疗无效。使用标准苯二氮䓬类药物（如氯巴占）联合丙戊酸钠和司来吉兰治疗，仅能适度控制发作。虽然苯二氮䓬类药物是治疗德拉维特综合征的一线药物，但它们只能调节突触受体，作用有限。与苯二氮䓬类药物不同，神经活性甾体增强了更广泛范围的 GABA 受体作用。合成神经活性甾体 SGE-516 是突触和 extrasynaptic GABA 受体的有效正变构调节剂。先前的工作表明 SGE-516 在啮齿动物急性惊厥试验中具有抗惊厥活性。在这项研究中，我们评估了 SGE-516 在 Scn1a 小鼠模型中的癫痫表型中的活性，该模型再现了德拉维特综合征的许多特征，包括自发性发作、过早死亡和发热引发的发作。为了评估 SGE-516 在 Scn1a 小鼠中的作用，我们确定了治疗对发热诱导的发作、自发性发作频率和存活的影响。SGE-516 治疗可预防发热诱导的发作，降低 Scn1a 小鼠的自发性发作频率并延长其存活时间。这首次提供了 SGE-516 在德拉维特综合征小鼠模型中的活性证据，并支持进一步研究神经活性甾体作为潜在的难治性癫痫的抗惊厥化合物。
