Abstracts

IL-1 is a potent pro-inflammatory cytokine with neuromodulatory functions within the central nervous system. IL-1 signal transduction is mediated by the type I receptor (IL-1RI), which is expressed by neurons in the primary cell layers of the hippocampus. Using mice lacking IL-1R1, the hypothesis that endogenous IL-1 contributes to neuroplasticity associated with PTZ-induced kindling, a model of epileptogenesis, was tested herein., Homozygous male C57BL/6 mice (8-10 weeks) lacking a functional IL-1RI gene or wild-type controls were bred at the UCHC and acclimatized to handling stress for one week prior to use. A PTZ dose-response relationship was performed to determine the effect of IL-1RI deletion on acute convulsant activity of PTZ. Kindling was induced by a once daily administration of a subconvulsive dose of PTZ. All mice were monitored for 15 min following PTZ administration and scored for seizure severity using an established seizure severity scale (Stages 0-4). The latency (time to onset) of a generalized convulsive seizure (Stage 3-4) was also measured. Mice were considered kindled after exhibiting [ge] 4 consecutive Stage 3-4 seizures., PTZ induced kindling in wild-type C57BL/6 mice in a dose-dependent manner. After 18 days (i.e., 18 doses of PTZ), 40 and 57% of mice subjected to daily doses of 20 or 24mg/kg PTZ, respectively, had become kindled. In stark contrast, IL-1RI null mice, treated in parallel, did not become sensitized to the convulsant properties of PTZ (0% kindled at either 20 or 24 mg/kg PTZ after 18 days). To determine if the inability of IL-1RI null mice to kindle was due to decreased sensitivity to PTZ, the dose-response relationship to acute PTZ-induced seizures was determined. Compared to controls, IL-1RI null mice were less sensitive to acute PTZ-induced seizures, as indicated by a rightward shift in the acute convulsive response between 20-58 mg/kg PTZ. For example, 36mg/kg PTZ elicited a mean seizure score of 2.9 [plusmn] 0.3 in control mice but only 1.1 [plusmn] 0.1 in the IL-1RI null mice. Further, IL1-R1 null mice showed an increased latency to a seizure elicited by 50mg/kg PTZ, a dose that resulted in generalized convulsions in both mouse strains. Time to onset was 138 [plusmn] 23 and 336 [plusmn] 60 sec for control and IL-1RI null mice, respectively. To determine if kindling could be achieved in IL1-R1 null mutants, these mice were administered once daily doses of 31mg/kg PTZ. This dosing paradigm induced kindling in IL-1RI null mice that resembled kindling induced in control mice with 24mg/kg PTZ., Results from this study indicate that IL-1RI null mice are less prone to PTZ-induced kindling. This is likely due to a reduction in the sensitivity of these mice to PTZ and not to an inability to kindle. These findings suggest that endogenous IL-1 facilitates PTZ-induced kindling by decreasing the PTZ seizure threshold., (Supported by Patterson Trust [amp] Donaghue Medical Research Foundation.)