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The synthetic neuroactive steroid SGE-516 reduces seizure burden and improves survival in a Dravet syndrome mouse model

机译:合成的神经活性类固醇SGE-516减少了癫痫发作负担,改善了Dravet综合征小鼠模型的存活

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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 GABAA receptors. The synthetic neuroactive steroid SGE-516 is a potent positive allosteric modulator of both synaptic and extrasynaptic GABAA 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.
机译:Dravet综合征是一种婴儿发作癫痫患者,其具有多种癫痫发作类型,通常对常规疗法难以难以忍受。用标准苯二氮氧基己胺处理,如氯罗巴唑,与丙戊酸甲酸乙酯组合,仅提供适度的癫痫发作控制。虽然苯二氮卓类是针对Dravet综合征的一线治疗,但它们仅受其仅调节突触受体的能力的限制。与苯并二氮杂卓,神经活性类固醇强调更广泛的GABAA受体。合成的神经活性类固醇SGE-516是突触和促进突触突触GABAA受体的有效的正颠型调节剂。在啮齿动物中,现有工作证明了SGE-516的抗惊厥活性在啮齿动物中急性癫痫发作测定。在这项研究中,我们评估了SCN1A + /癫痫表型对癫痫表型的SGE-516的活性。鼠标模型重新承认Dravet综合征的许多特征,包括热疗引发的自发癫痫发作,过早死亡和癫痫发作。在SCN1A + /中评估SGE-516 /?小鼠,我们确定了治疗对高温诱导的癫痫发作,自发癫痫发作和存活的影响。 SGE-516治疗保护免疫诱导的癫痫发作,降低自发癫痫发作频率,在SCN1A + /中延长存活率老鼠。这提供了Dravet综合征小鼠模型中SGE-516活性的第一种证据,并支持进一步调查神经活性类固醇作为难治性癫痫的潜在抗惊厥化合物。

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