Abstracts

Rationale: Infantile spasms (IS), a devastating epileptic encephalopathy of infancy, have various etiologies associated with an unknown underlying common pathophysiology. In the USA, adrenocorticotropic hormone (ACTH) is a drug of choice, followed by vigabatrin for relatively successful treatment of IS. The pharmacodynamic mechanisms of ACTH action are still obscure, however ACTH efficacy (as well as of corticosteroids) suggests a role of steroid hormones in the IS. This study was designed to test whether ganaxolone, a synthetic neurosteroid which targets tonic inhibitory conductance mediated by extrasynaptic GABAA receptor containing the delta subunit, is effective in an animal model of IS. Methods: An established and validated model of cryptogenic infatile spasms was used: Rats were prenatally primed with betamethasone (0.4 mg/kg i.p. at 08:30 and 18:30) on gestational day 15. On postnatal day 15, rats were pretreated with ganaxolone (10, 25, or 50 mg/kg i.p.) or vehicle ( -cyclodextrin, i.p.) 30 min prior to spasms. Subsequently, we triggered spasms with i.p. injection of 15 mg/kg of NMDA and determined latency to onset of spasm and the total number of spasms per 75-minute observation period after the NMDA injection.Results: The 10 mg/kg dose of ganaxolone has no significant effect on the development of NMDA-triggered spasms. The 25 mg/kg (n=5) and 50 mg/kg (n=6) dose of ganaxolone significantly delayed onset of spasms (Mantel-Cox log rank test, p<0.001) compared to vehicle controls (n=6). Also, 50 mg/kg of ganaxolone significantly decreased incidence of spasms (Mann-Whitney U test, p=0.002). The significant side effect of ganaxolone was sedation, all of the animals with 50 mg/kg ganaxolone were sleeping during the test.Conclusions: Ganaxolone significantly suppressed development of spasms in this model of cryptogenic IS. This efficacy of neurosteroid active on tonic GABAAR in animal model of IS suggests another approach to the development of additional armamentarium for treatment of human IS.