A potential effect of ganaxolone in an animal model of infantile spasms

Rationale: Infantile spasms (IS), a devastating epileptic encephalopathy of infancy, involve various etiologies associated with an unknown underlying common pathophysiology. The efficacy of adrenocorticotropic hormone (ACTH) as an IS therapy suggests a role for steroid hormones in treating IS. This study used an animal model of IS to test the efficacy of ganaxolone, a synthetic neurosteroid, promoting tonic GABA(A) inhibition. Methods: The model of cryptogenic IS used in this study involved prenatal priming of rats with betamethasone (0.4 mg/kg i.p. at 08:30 and 18:30) on gestational day 15. To test the acute effects of ganaxolone, rats were pretreated with ganaxolone (10, 25, or 50 mg/kg i.p.) or vehicle (beta-cyclodextrin, i.p.) 30 min prior to N-methyl-D-aspartate (NMDA)-induced spasms at postnatal day 15 (P15). To mimic human conditions, another group of rats was randomly divided and repeatedly treated with ganaxolone (20 mg/kg at 9:00 and 18:00 from P13-15) or vehicle after experiencing NMDA-triggered spasms at P12. Additional spasms were triggered on P13 and P15. We determined latency to the onset of spasms and the total number of spasms per 90-min observation period after the trigger at P15. On P19 and P21, behavioral tests were performed in rats with randomized repeated treatments. Results: The 25 mg/kg and 50 mg/kg doses of ganaxolone significantly delayed the onset of spasms compared with the controls, and significantly decreased the number of spasms or suppressed their incidence. Ganaxolone had significant side effects in terms of sedation: all animals with the 50 mg/kg dose were sleeping during the test. Randomized ganaxolone treatment for 3 days also significantly delayed the onset and decreased the number of spasms triggered by NMDA on P15, and decreased exploratory behavior after multiple NMDA triggered spasms. Conclusion: Ganaxolone significantly suppresses the development of spasms in the rat model of cryptogenic IS. This synthetic neurosteroid active in an animal model of IS might contribute to the current armamentarium to treat human IS. (C) 2014 Elsevier B.V. All rights reserved.