Abstracts

Rationale: Various factors contribute to the occurrence of Febrile Seizures (FS): increase in body temperature, inflammatory response to viral or bacterial infection, genetic predisposition and cerebral immaturity. Clinical and experimental studies have pointed out the involvement of brain inflammation both in FS ictogenesis and epileptogenesis. Our aim was to evaluate the impact of systemic inflammation triggered by viral infection on ictogenesis, epileptogenesis, and associated inflammatory responses. Methods: Systemic viral-like response was induced in male Wistar rats by intraperitoneal (i.p.) injection of polyinosinic: polycytidylic acid (PIC), a toll-like receptor 3 (TLR3) agonist. Immature (13-days old) and adult (75 days old) rats were injected with 5 mg/kg PIC or saline 24 hours before the onset of hippocampal rapid kindling. Hippocampal afterdischarge duration (ADD) and afterdischarge threshold (ADT) were measured before and after rapid kindling. The number of stimulations needed to develop the first full limbic (stage 4) seizure, total number of stage 4 seizures, and mean seizure score were recorded. Further, we measured serum and brain levels of cytokines Interleukin-1β (IL1β), Interleukin-6 (IL6), Interleukin-10 (IL10), and tumor necrosis factor α (TNFα) 2, 6 and 24 hours after PIC injection. Using immunostaining, we evaluated microglial (using Iba1 antibodiy) and astrocytic (using GFAP antibody) activation 24 hours after PIC injection. Results: In pups, PIC treatment led to a significant increase of ADD at the retest (p=0.01), total number of stage 4 seizures (p=0.01), and of mean seizure score at ADT (p= 0.02; all comparisons vs. saline) and to the decrease of number of stimulations needed to exhibit the first stage 4 seizure (p=0.02). In adult rats, no difference was observed between the PIC and saline groups. We found significant rise in IL1β serum level 2 hours (p= 0.01) and 6 hours (p= 0.02) after PIC injection and the increase of IL1β brain level 6 hours (p=0.007) after PIC injection in pups, but not in adult rats. In pups, we observed more Iba1 positive cells in dentate gyrus (p=0.04) and CA1 (p=0.02) areas in PIC group compared to the controls, while no differences were found for the GFAP signal. In adult rats, neither Iba1, nor GFAP signal differed between PIC and saline groups. Conclusions: A viral-like induced inflammation triggered by a TLR3 agonist enhances the rapid kindling epileptogenesis only of the rat pups. IL1β appears to determine the specific confinement of effects of PIC to the immature age. Inflammation produced by a TLR3 agonist is also characterized by microglial proliferation in dentate gyrus and CA1 in pups.