The role of S100B in acquired epilepsy induced by inflammation in a neonatal hypoxia-induced animal model.

摘要

Neonatal hypoxic-ischemic encephalopathy (HIE) is a major cause of mortality and morbidity in infants and children. One of the most important consequences of neonatal HIE is epilepsy. Epilepsy is a common neurodegenerative disorder characterized by recurrent unprovoked seizures due to hyperexcitability and hypersynchrony of neuronal activity. Recent studies uncovered important molecular and cellular aspects of hypoxic-ischemic brain injury that may provide a therapeutic target for intervening in the epileptogenesis in the developing brain. We developed and characterized a model of neonatal hypoxic brain injury to test hypotheses about the interaction of astrocytes and microglia in hypoxia-induced brain injury and early steps in epileptogenesis. Specifically, we hypothesize that hypoxia-induced neuronal injury activates microglia which then starts a reciprocal activation cycle of astrocytes and microglia. A critical step in the cycle is activation of the receptor for advanced glycation end products (RAGE) on microglia by S100-beta (S100B) secreted by astrocytes. In our experiments, we administered a RAGE antagonist (FPS-ZM1) to protect brain from the effect of HI induced damage and inhibit the apoptotic pathway and downstream products, including IL-6. Most importantly, the specific interaction between S100B and RAGE receptors further implicate a role for this astrocytic protein in the pathogenesis of epilepsy. Our findings may create a potential for therapeutic intervention for hypoxia-induced epilepsy.