Abstracts

Rationale: Infantile spasms (IS) are characteristic seizures of infantile epileptic encephalopathies with dire developmental consequences that require better therapies. In this project, we used the multiple-hit rat model of IS to test the therapeutic potential of Celastrol (quinone methide triterpene), an antioxidant and anti-inflammatory drug. Specifically, we determined whether a single injection of Celastrol given after spasms onset, acutely suppresses spasms in the multiple-hit model. Methods: On postnatal day 3 (PN3), male Sprague-Dawley rats received right intracerebroventricular injection of doxorubicin and right intracortical injection of lipopolysaccharide, while intraperitoneal injection (i.p.) of p-chlorophenylalanine was given on PN5. Neurodevelopmental studies were done starting from PN3 daily. Video monitoring was done on PN4 (1 hour pre-drug injection and 5 hours post-drug injection) and on PN5 (2 two-hour sessions). Celastrol (1-4mg/kg i.p.) was administered i.p. on PN4, after spasms onset. This is a randomized, blinded, vehicle-controlled, dose-response study. Linear mixed model models were used to analyze raw or normalized log-transformed spasms rates, taking into account the repeated observations on each animal. We studied 10-14 rats per group. Results: Celastrol caused a dose-related reduction of spasms within 3 hours after a single i.p. injection and was well tolerated. Conclusions: We provide proof-of-concept evidence that Celastrol can acutely decrease the frequency of spasms in the multiple-hit rat model of IS. Further studies are needed in order to determine the therapeutic effectiveness of repeat Celastrol administration on spasms. Funded by: Department of Defense, NINDS, CURE, Heffer Family and Siegel Family Foundations.