Brain Inflammation in Childhood Epilepsy

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DESCRIPTION (provided by applicant): Chronic epilepsy often starts with an isolated, prolonged convulsion in early life followed by a period of remission; seizures then re-emerge and may become intractable. This period of remission following an initial seizure provides a window of opportunity for intervention prior to the onset of epilepsy and irreversible brain damage. The specific focus of this proposal is to investigate the role of brain inflammation in childhood epilepsy and to determine whether anti-inflammatory therapy can reverse the epileptogenic effect of early- life seizures. We have developed a "two-hit" seizure model demonstrating that an early life seizure, without causing overt cellular injury, increases susceptibility to seizures and to seizure-induced neuronal injury in adulthood. To elucidate the mechanisms linking seizures in the developing brain to later-onset epilepsy, we have used high-density oligonucleotide gene arrays and characterized the molecular cascades occurring after early life seizures that may underlie later increased seizure susceptibility. Our preliminary results indicate that activation of microglia and subsequent increases in cytokines and complements may be the key initiating events for seizure-induced inflammatory responses. Using two seizure models in parallel, perinatal hypoxia and early-life kainic acid (KA), we propose to test the following hypothesis: the inflammatory reaction provoked by early life seizures primes the developing brain so that microglia are modified, leading to rapid reactivation by a second seizure in adulthood. Aim 1 will establish whether microglial activation and proliferation after KA-induced status epilepticus in adulthood is increased in rats with prior experience of early-life seizures. Aim 2 will determine if this long- term sensitizing effect of early-life seizures can be blocked by post-treatment with anti-inflammatory drugs. Aim 3 will identify specific inflammatory pathways involved in the priming effect of early-life seizures using oligonucleotide gene arrays. Aim 4 will evaluate the long-term effect of early life seizures on subsequent KA seizure-induced activation and proliferation of microglia using transgenic mice with GFP-tagged microglia. We will test the human relevance of our data by examining inflammatory genes in human epilepsy surgery specimen. Together these Aims are designed to test the central hypothesis that the epileptogenic effect of early life seizures is mediated by brain inflammation.