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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Scientist Development Award - Research (K02)
Project #
5K02NS048237-04
Application #
7628025
Study Section
NST-2 Subcommittee (NST)
Program Officer
Fureman, Brandy E
Project Start
2006-09-01
Project End
2010-05-31
Budget Start
2009-06-01
Budget End
2010-05-31
Support Year
4
Fiscal Year
2009
Total Cost
$136,868
Indirect Cost
Name
Children's Memorial Hospital (Chicago)
Department
Type
DUNS #
074438755
City
Chicago
State
IL
Country
United States
Zip Code
60611
Kazl, Cassandra; Foote, L Tracy; Kim, Min-Jung et al. (2009) Early-life experience alters response of developing brain to seizures. Brain Res 1285:174-81
Millichap, John J; Koh, Sookyong; Laux, Linda C et al. (2009) Child Neurology: Dravet syndrome: when to suspect the diagnosis. Neurology 73:e59-62
Choi, Jieun; Nordli Jr, Douglas R; Alden, Tord D et al. (2009) Cellular injury and neuroinflammation in children with chronic intractable epilepsy. J Neuroinflammation 6:38
Choi, Jieun; Koh, Sookyong (2008) Role of brain inflammation in epileptogenesis. Yonsei Med J 49:1-18
Koh, Sookyong; Magid, Rhamy; Chung, Hyokwon et al. (2007) Depressive behavior and selective down-regulation of serotonin receptor expression after early-life seizures: reversal by environmental enrichment. Epilepsy Behav 10:26-31