Abstracts

Rationale: There is increasing evidence that infection, and the accompanying neuroinflammatory response, contribute to the detrimental effects of seizures. LPS, an endotoxin known to activate microglia and to elicit robust pro-inflammatory cytokine release, potentiates susceptibility to chemoconvulsant-induced seizures and the severity of seizure-induced cell death in animal models. We have previously shown that kainic acid (KA)-induced status epilepticus results in marked postictal deficits in exploratory behavior in young rats, and that intra-hippocampal injection of activated microglia mimics these effects. Here, we used LPS and the pro-inflammatory cytokine suppressor Minozac (Mnz) to investigate the effect of peripheral infection on behavior and seizure susceptibility. Methods: On P25, CX3cr1GFP/+ were injected with LPS (2.5 mg/kg, i.p.) in order to prime an immune response. Five minutes later, a subgroup of mice was injected with KA (20 mg/kg, i.p.), and seizure latency was recorded. Three hours after seizures, a subgroup was administered Mzc (5 mg/kg, i.p.). Exploratory behavior was then quantified in an open field at 24h intervals for three days. The experiment was repeated with MCP-1:RFP/+;CCR2:GFP/+ transgenic mice in order to visualize activation of microglia and peripheral leukocytes within the CNS. Results: LPS increased susceptibility to seizures; LPS-KA mice (n=18) exhibited significantly decreased latency to seizure onset compared to KA-only mice (n=17, p<0.01). LPS injection alone (n=4) caused transient and reversible deficits in exploratory behavior one day after injection (p<0.05). Mice that experienced KA seizures (n=7) exhibited more severe deficits in exploratory behavior that persisted until 48 hours after seizures (p<0.001 at 24 & 48 h). However, in KA-treated animals, priming with LPS (n=9) conferred no additional exploration deficit. While Mnz had no significant therapeutic effect on KA-only mice and a limited effect on LPS-only mice, Mnz attenuated exploratory deficits in LPS-KA mice (n=8) such that LPS-KA-Mnz group were not significantly different from controls on any day. We detected activation of both RFP+ microglia and GFP+ leukocytes in a LPS primed KA treated mouse while no peripheral leukocytes infiltration was observed in any LPS-only or KA-only mice. Conclusions: We show that LPS potentiates seizure susceptibility and the seizure-induced infiltration of peripheral leukocytes into the CNS. Although “sickness behavior” induced by LPS mimicked seizure-induced exploratory deficits, LPS infection did not worsen the postictal behavioral deficits. Our results suggest that potentiation of seizures and seizure-induced changes by concurrent infection may be mediated by involvement of both innate and acquired immunity and that anti-inflammatory therapy such as Mnz may be particularly helpful for acute exacerbation of seizures by infection or for febrile status epilepticus.