Abstracts

Rationale: Infantile Spasms (IS) are typical epileptic seizures of the West syndrome. IS may be followed by neurodevelopmental deficits and early mortality, while many infants with IS may develop intractable epilepsies. Early cessation of spasms may improve outcome. The multiple-hit rat model of chronic refractory IS is a model of IS due to structural lesions, which has been used extensively for the identification of new therapies. To identify treatments with rapid onset of effect on spasms, we used the multiple-hit rat model of IS to assess the potency and tolerability of anti-inflammatory and/or anti-oxidant drugs to suppress spasms, when treatments are given after spasms onset. Here, we tested the effects of tripterene celastrol (inhibits lipid peroxidation, NF-kB activation and cytokine release) and edaravone (free radical scavenger and antioxidant, inhibits NF-kB activation).Methods: Male Sprague-Dawley rats received right intracerebral injections of doxorubicin and lipopolysaccharide on postnatal day (PN) 3 and intraperitoneal (i.p.) injection of p-chlorophenylalanine on PN5. The outcomes were evaluated daily using a battery of neurodevelopmental tests. Animals were video-monitored on PN4 (1 hour pre-drug injection and 5 hours post-drug injection) and on PN5 (2 two-hour sessions). Celastrol (1, 2, or 4mg/kg), edaravone (1, 10, or 30 mg/kg) or their respective vehicles were administered as single i.p. injections using randomized, blinded, dose- and time-response study design. Different cohorts were perfused on PN4, and brain sections were studied using immunofluorescence for inflammatory markers. A linear mixed model analysis of raw or normalized log-transformed spasm frequencies, considering the repeated observations, was used. 10-17 rats per group were studied.Results: Rats induced according to the multiple-hit protocol showed overactivation of NF-kB signaling pathway in the cerebral cortex of PN4 rats. A single i.p. injection of Celastrol resulted in acute, dose-dependent spasm reduction for 3 consequent hours after injection, while edaravone had no impact on spasms.Conclusions: The acute reduction of spasms by celastrol suggests a role of anti-inflammatory and/or anti-oxidant pathways in the pathogenesis and treatment of IS strikethrough. The distinct effects of celastrol and edaravone may be due to different target mechanisms. The efficacy of celastrol on both behavioral and electroclinical spasms is being currently analyzed using video-EEG studies. Funded by the Department of Defense W81XWH-13-1-0180 grant, CURE (Infantile Spasms Initiative), NINDS, the Heffer family and Segal family foundations, and the Abbe Goldstein/Joshua Lurie and Laurie Marsh/ Dan Levitz families.