The Epileptogenic Effect of Perinatal Hypoxia

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Neonatal seizures associated with hypoxic encephalopathy are refractory to conventional AED therapy, and are associated with long term neurodevelopmental delay, cognitive impairment and epilepsy. The newborn brain is fundamentally different from the adult brain, and is uniquely susceptible to epileptic stimuli as a function of physiological hyperexcitability required for activity dependent synaptogenesis and cortical development. In the prior 15 years, this research program has generated a reliable rodent model of neonatal hypoxic seizures, identified specific age-dependent mechanisms, validated the age specific expression of these targets in human neonatal cortical tissue, and executed therapeutic trials in the rat targeted towards these mechanisms, using clinically available drugs. In our rodent models of neonatal seizures, we have shown that systemic administration of glutamate receptor antagonists for 48 hrs following seizures can prevent the long term consequences, and hence may be disease modifying. The present proposal will focus on this immediate and early post seizure window to identify rapid post-translational modifications of existing protein and regulatory mechanisms governing the translation of protein from of pre-existing mRNA that may be preventable and/or reversible. Aim 1. To determine the time course of seizure-induced changes in ionotropic glutamate receptor function, and whether they are associated with post-translational modification of receptor subunits. Aim 2. To establish whether post-translational modifications in AMPARs and NMDARs are merely correlated or mechanistically related to in hypoxic seizure-induced epileptogenesis in vivo and in vitro. Aim 3. To determine whether the mammalian target of rapamycin (mTOR) signaling pathway represents a therapeutic target for prevention of hypoxic-seizure induced hyperexcitability. Aim 4. To continue our human tissue study of maturational patterns of glutamate receptor expression and investigate whether mTOR pathway activation can be detected in postmortem human brain tissue from hypoxic term infants. Our preliminary results reveal that many of these early seizure induced changes in proteins are strikingly similar to those observed in models of synaptic plasticity. The overall hypothesis of this proposal is that these early changes represent intervention points for antiepileptogenesis, even after the seizures have been induced. A major focus for this funding period is to identify these molecular targets in this 48 hr window and intervene with available off-the-shelf drugs that are known to have modulatory activity at these targets. Project narrative and health relevance Neonatal seizures associated with hypoxic encephalopathy are refractory to conventional AED therapy, and are associated with long term neurodevelopmental delay, cognitive impairment and epilepsy. The newborn brain is fundamentally different from the adult brain, and is uniquely susceptible to epileptic stimuli as a function of physiological hyperexcitability required for activity dependent synaptogenesis and cortical development. In the prior 15 years, this research program (NS31718) has generated a reliable model of neonatal hypoxic seizures, identified specific age-dependent mechanisms, validated the age specific expression of these targets in human neonatal cortical tissue, and executed therapeutic trials in the rat targeted towards these mechanisms, using clinically available drugs. Through direct and collaborative efforts, this research program has been critical to proposing the only 2 agents being considered for the first therapeutic trials by the Neonatal Seizure Treatment Trial Network (NESTT) for neonatal seizures in the last 4+ decades. The 2 agents are topiramate (TPM), which we have shown targets the AMPARs that are overexpressed in the immature brain, and bumetanide, a blocker of a specific Cl- transporter NKCC1 that we have shown to be overexpressed in the newborn brain and which contributes to the lack of efficacy of GABA agonists (barbiturates, benzodiazepines) in this population. Notably AMPAR antagonists, including TPM, are effective at preventing long term consequences when administered after the initial seizures, and hence this may be the first FDA-approved agent to inhibit epileptogenesis in neonates. The present proposal aims to refine our understanding of this novel antiepileptogenic effect, and potentially elucidate other targets that can be used for therapeutic intervention in this unique population.