Abstracts

Rationale: Interleukin-1beta (IL-1β) is a pleotropic cytokine that functions as a pyrogen, acute-phase protein, and immune and inflammatory mediator. In the central nervous system, IL-1β has been implicated in a number of pathophysiological states, including temporal lobe epilepsy. Pertinent to the present study, previous results from experimental studies showed that kainic acid (KA)-induced status epilepticus (SE) was more severe in mice lacking IL-1β ligand, suggesting that endogenous IL-1β signaling might be a homeostatic control mechanism in the brain that functions to maintain an elevated seizure threshold. This possibility was tested further herein using mice that lacked the IL-1 obligate ligand binding and signaling receptor (IL1R1).Methods: C57BL/6 IL1R1 wild-type (+/+) and homozygous mutant (-/-) mice were subjected to SE using a modified dose titration paradigm. All mice received a loading dose of 10mg/kg KA via intraperitoneal injection to initiate the paradigm. This was followed by 2.5mg/kg booster doses administered every 30 minutes until SE was established or until 5 boosters were delivered. Maximum seizure behavior responses were recorded every 10 minutes during the paradigm and SE was defined as 2 or more consecutive 10 minute intervals of rearing and forelimb clonus with episodes of generalized convulsions. Diazepam (5mg/kg, ip) was administered after 90 minutes of SE or upon completion of the full paradigm at 240 minutes to terminate all seizure activity. Comparisons were made between IL1R1 -/- and +/+ littermates treated in parallel.Results: The KA treatment paradigm was developed to minimize mortality and maximize the incidence and severity of SE in wild-type C57BL/6 mice. Thus, 96% (25/26) of IL1R1 +/+ mice survived the SE paradigm. Of these, 72% (18/25) reached SE and 48% (12/25) maintained SE for 90 minutes. By comparison, 72% (13/18) of IL1R1 -/- littermate mice survived the SE paradigm, exposing a relative risk for mortality that was 7 times greater than the IL1-RI +/+ group (two-sided Fisher’s exact, p < 0.0001, 95% CI 2.548–19.23). Additionally, all surviving IL1R1 -/- mice (13/13) reached and maintaining SE for 90 minutes. As a group, IL1R1 mutant mice received a significantly lower total KA dose in the treatment paradigm compared to their wild-type littermate (two-tailed Mann Whitney, p < 0.01) such that only 15% (2/13) of IL1R1 -/- mice received the maximum KA dose (22.5mg/kg, loading dose plus all 5 booster doses), whereas 64% (16/25) of +/+ controls received this dose.Conclusions: In summary, IL1R1 mutant mice were hypersensitive to KA-induced SE, exhibiting a more severe response at a lower dose of KA compared to wild-type IL1R1 mice. These results corroborate results from previous studies with mice lacking IL-1β ligand and are constituent with other evidence supporting the notion that IL-1β signaling is an endogenous modulatory mechanism that suppresses temporal lobe seizures. Funding: NIH/NINDS R01NS051445 (JH and SH), R01NS051445-05A1S1 (RL), and Syracuse University