Abstracts

Rationale: Infantile spasms (IS) are age-specific epileptic seizures of infantile epileptic encephalopathies with poor prognosis which need better therapies. The pathophysiology of IS has been linked to autoimmune or neuroinflammatory disorders. In addition, reduced levels of interleukin-1 receptor antagonist (IL-1ra) have been reported in infants with IS of different etiologies, and these are restored after treatment. Furthermore, IL-1ra, an FDA approved drug, is currently administered for the treatment of other diseases in humans. Herein, we test the efficacy of IL-1ra to suppress spasms in the multiple-hit rat model of IS due to structural etiology. Methods: Sprague Dawley male rats were used. Multiple-hit model induction: postnatal day (PN) 3 rats were stereotactically infused with doxorubicin (right intracerebroventricular) and lipopolysaccharide (right intraparietal) to induce spasms. On PN5, p-chlorophenylalanine intraperitoneal (i.p.) injection was given. Daily monitoring of weights, surface righting time, open field activity, and negative geotaxis (NG) was recorded. On PN4, after the onset of spasms, IL-1ra (10, 100, or 597 mg/kg intraperitoneally [i.p.]) or vehicle was administered (10-15 rats/group). Video-monitoring was recorded from PN4-PN5 in two daily 2hr sessions except on PN4PM, when a 1hr pre-injection and 5hr post-injection session were done. We followed a randomized, blinded, vehicle-controlled, dose and time response study design. Results: IL-1ra was well tolerated and prevented the time-related increase in normalized frequencies ([normalized frequency = (post-injection frequency/pre-injection frequency) × 100]) of spasms following a single dose administration. It also improved negative geotaxis (NG) scores on PN5. Conclusions: Our findings support a potential role for IL-1r signaling in the progression of IS and possibly neurodevelopmental decline. In our model, IL-1ra emerges as a promising adjunctive treatment for IS that could inhibit the progression of spasms. It is however imperative to fully assess the therapeutic potential, efficacy of early treatment initiation and treatment tolerability of prolonged IL-1ra administration. This project was funded by CURE (Infantile Spasms Initiative), NINDS (NS078333), Department of Defense, and the Heffer Family and Siegel Family Foundations.