An examination of the contribution of endogenous IL-1beta to seizures and epileptogenesis

The overall goal of this thesis was to determine the contribution of endogenous interleukin-1β (IL-1β) signaling on seizures and epileptogenesis. First, using transgenic mice harboring targeted deletions in the genes for either IL-1β or its signaling receptor (IL-1RI), it was found that mice lacking endogenous IL-1β signaling (IL-1RI -/- and IL-1β -/- mice) exhibited a greater incidence of convulsions evoked by the GABAA receptor antagonist, pentylenetetrazole (PTZ). However, this increased sensitivity to PTZ-induced convulsions did not confer these mice with an increased susceptibility to PTZ-induced epileptogenesis, modeled by once daily PTZ treatments (PTZ-induced kindling). These results suggest that endogenous IL-1[3 may possess anti-convulsive properties but lack effect on epileptogenesis. ^ Next, to determine whether the pro-convulsive phenotype of IL-1β -/- is model-dependent, seizures were induced using a pharmacologically distinct convulsant, kainic acid (KA). Using a titrating KA dosing protocol, it is shown that after the last dose of KA, the motor seizures of the IL-1β +/+ mice began to resolve while the seizures in the IL-1β -/- remained severe. Furthermore, the incidence of KA-induced status epilepticus (SE) and death was significantly greater in the IL-1β -/- mice. Seizure severity was also measured by electroencephalography (EEG) and IL-1β -/- mice were found to have more KA-induced electrical activity and demonstrated prolonged electrical activity associated with convulsive seizures. These results support the hypothesis that endogenous IL-1β has anti-convulsive properties that is independent upon the mode of seizure generation. ^ Lastly, the mechanism of the convulsion-prone phenotype of IL-1β signaling deficient mice was investigated. Because evidence suggests that COX-2 metabolites contribute to the neuromodulatory properties of IL-1β, efforts focused on COX-2. First, it was shown that the selective COX-2 inhibitor rofecoxib could mimic the pro-convulsive phenotype demonstrated in IL-1β signaling deficient mice when challenged with PTZ. Furthermore, PTZ-induced kindling acquisition and maintenance was not affected in mice treated with rofecoxib an effect similar to that seen in IL-1β signaling deficient mice. Finally, it is demonstrated that lack of IL-1RI signaling completely occluded the pro-convulsive effects of rofecoxib. In toto, these results suggest that endogenous IL-1β possesses anti-convulsant properties which may be mediated by COX-2 metabolites.