Epileptogenic Effects of Perinatal Hypoxia

Several major questions regarding the pathophysiology of hypoxia-induced neonatal seizures remain unanswered.  First, it is not clear why the immature brain is so susceptible to the epileptogenic effects of hypoxia, because seizures are much less likely to  complicate the outcome of hypoxia/ischemia in the adult.  Second, seizures complicating hypoxic encephalopathy can be refractory to anticonvulsant therapy that is effective in adult seizure disorders, indicating that the mechanism underlying perinatal hypoxia-induced seizures may be age-dependent.  Third, it is not known how the acute perinatal seizures relate to later epilepsy and whether the two phenomena share a common mechanism.  The overall goal of this research program has been to identify age-specific mechanisms of epileptogenesis that can be uniquely targeted for therapy in the immature brain. We have focused on neonatal seizures associated with hypoxic encephalopathy, as it is clear that refractory neonatal seizures do not respond to conventional antiepileptic drugs (AEDs) that are effective later in life.  We and others have shown that the status of many factors governing neuronal excitability in the immature is strikingly different from that in the older brain. Over the last 15 years of this grant (NS31718), we have 1) developed a rodent model of hypoxic neonatal seizures, 2) shown that the antagonists of the a-amino-3-hydroxy-5-methyl-4-isoxazole propionate subtype of glutamate receptors (AMPARs) are selectively effective in suppressing these seizures and their long term consequences, 3) demonstrated that specific neurotransmitter receptors are overexpressed in cortical and hippocampal neurons at the age of vulnerability to seizures in both the rodent and human neonatal brain, and 4) revealed both immediate early and late seizure induced changes in intrinsic excitatory glutamate and inhibitory γ-amino butyric acid A receptor (GABAAR) expression and function in hippocampal and cortical networks. Hence this model system has provided a reliable platform upon which to base studies related to elucidating potentially preventable and/or reversible steps in the epileptogenic cascade in the neonatal brain. We have shown that systemic administration of AMPAR antagonists for 48 hrs following seizures can prevent the long term consequences, and hence may be disease modifying. The last 2 funding cycles of this grant have made critical contributions that have resulted in two agents (topiramate [TPM ] and bumetanide) being proposed for the first therapeutic trials for neonatal seizures in the last 4+ decades by the Neonatal Seizure Treatment Trials (NESTT) Network). 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. 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.