Abstracts

Rationale: Seizures in early-life produce increased susceptibility to seizures and greater neurologic injury with a second neurologic insult in adulthood. The mechanisms by which this occurs are not known. We previously showed (Somera-Molina et al., Epilepsia 2007 48, 1785-1800) that rats administered kainic acid (KA) on postnatal day (P)15 and treated with a small molecule, Minozac (Mzc), that attenuates brain proinflammatory cytokine upregulation exhibit reduced long-term glial activation and neurobehavioral impairment. Here, we tested the hypothesis that glial activation induced by early-life seizures results in enhanced glial activation and increased susceptibility to seizures and neurologic injury following a ‘second hit’ of seizures in adulthood Methods: P15 rats were administered KA (early-life seizures) or saline (Sal). On P45, animals received either a ‘second hit’ of KA, first exposure to KA (adult seizures) or Sal. Levels of proinflammatory cytokines, chemokines (IL-1β, TNF-α, CXCL1, and CCL2), a chemokine receptor (CX3CR1), and the astrocyte glutamate transporter, GLT-1, were measured together with histological examination of glial and microglial activation. Seizure susceptibility was measured by latency to seizure onset. Hippocampal neuronal injury was measured using the fluorescent marker Fluoro-Jade B. To suppress the increase in pro-inflammatory cytokines after early-life seizures, rats were treated with the small molecule Mzc at 3 and 9 hours after KA exposure on P15. Results: The ‘two-hit’ group had higher levels of cytokines, chemokines, and CX3CR1, as well as greater histological microglial activation compared to the 'adult seizures' group. In addition, the ‘two-hit’ group showed increased susceptibility to seizures and neurologic injury compared to the adult seizures group. Importantly, suppression of cytokine up-regulation after KA-induced seizures on P15 attenuated the enhanced microglial and cytokine response and the increase in seizure susceptibility and neuronal injury in the ‘two-hit’ group. Conclusions: These results implicate astrocyte and microglial activation after early-life seizures in the mechanisms leading to the increase in susceptibility to seizures and neuronal injury with a second neurologic insult in adulthood.