Abstracts

Rationale: Infectious encephalitides are characterized by a pronounced brain inflammation in response to a CNS infection. They are most often associated with seizures during the infection period and pose risks for the development of epilepsy at a later time. Although many cases of infectious encephalitides are of unknown etiology, most of clinical studies suggest their viral origin. Children are three times more prone to viral encephalitis than adults. Mechanisms of viral encephalitis-induced epileptogenesis are poorly understood. Virus-induced cell injury, brain inflammation and initial prolonged seizures, all are contemplated as contributing factors. Our aim was to evaluate the contribution of viral encephalitis-associated inflammation in epileptogensis. Using the rapid kindling model of limbic epileptogenesis, we examined effects of preexisting brain viral-like inflammation on hippocampal excitability and epileptogenesis in immature and adult rats. In addition, we examined whether modulation of kindling by brain inflammation can be controlled by minocycline. Effects of both PIC and minocycline were correlated with hippocampal levels of inflammatory cytokines Interleukin-1β (IL-1β) and Tumor Necrosis Factor a (TNFa). Methods: To produce viral-like inflammation, postnatal day 14 (P14) and postnatal day 120 (P120) rats were injected with polyinosinic-polycytidylic acid (PIC, 10mg, an agonist of toll-like receptor 3, which is an intracellular receptor for viral double-stranded RNA) in ventral hippocampus 24h before kindling procedure. Minocycline (50mg/kg) was injected intraperitonealy for three days in a row prior to the kindling procedure. Levels of IL-1β and TNFa in the hippocampus were examined by ELISA. Results: PIC injection facilitated kindling epileptogenesis, which was evident as faster onset of seizures, increased number of full limbic seizures and prolonged retention of the kindling state. Furthermore, PIC administration led to the increase of both IL1b and TNFa levels in the hippocampus. Treatment with minocycline reversed pro-epileptogenic effects of PIC in both P14 and P120 rats. However, antiepileptic effects of minocycline occurred without affecting levels of IL1b and TNFa in the hippocampus. Conclusions: Hippocampal viral-like inflammation mimicked by PIC facilitates rapid kindling epileptogenesis. This effect is reversed by minocycline, independently of its anti-inflammatory action. These results further implicate viral inflammation and particularly IL1b and TNFa in epileptogenesis following encephalitis. Moreover, the data are consistently observed in P14 and adult rats, thus suggesting that both immature and mature brains share common responses to cerebral viral inflammation.