Abstract
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.
Highlights
Dravet syndrome is a severe infant-onset epileptic encephalopathy most often caused by de novo mutation of SCN1A resulting in heterozygous loss-of-function of the Nav1.1 voltage-gated sodium channel[1]
We evaluated the ability of SGE-516 to improve epilepsy phenotypes in the Scn1a+/− mouse model of Dravet syndrome
Using a series of optimized phenotyping assays, we recently demonstrated that the response profile of Scn1a+/− mice to standard anticonvulsant therapies is similar to reported drug responses of children with Dravet syndrome[14]
Summary
Dravet syndrome is a severe infant-onset epileptic encephalopathy most often caused by de novo mutation of SCN1A resulting in heterozygous loss-of-function of the Nav1.1 voltage-gated sodium channel[1]. The neurosteroids alphaxalone and allopregnanolone have demonstrated protective effects in animal models against seizures or status epilepticus induced by pentylenetetrazol (PTZ), kaniate, bicuculline, pilocarpine and in the 6 Hz psychomotor test[7,8,9,10]. We evaluated the ability of SGE-516 to improve epilepsy phenotypes in the Scn1a+/− mouse model of Dravet syndrome. Using a series of optimized phenotyping assays, we recently demonstrated that the response profile of Scn1a+/− mice to standard anticonvulsant therapies is similar to reported drug responses of children with Dravet syndrome[14]. We evaluated SGE-516 in the Scn1a+/− Dravet mouse model and studied the effect of SGE-516 treatment on hyperthermia-induced seizures, spontaneous generalized tonic-clonic seizure (GTCS) frequency and survival. We found that treatment of Scn1a+/− mice with SGE-516 resulted in significant phenotype improvement, including reduced seizure burden and improved survival
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