Structural and functional sequelae of neonatal anticonvulsant exposure: drug-seizure interactions

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Project Summary Pharmacotherapy during critical periods of brain development can adversely affect nervous system function. This poses a challenge for the treatment of neurological disorders, where the underlying illness and the treatment both may have adverse effects. One example of this is balancing the choice of medication for the treatment of seizures, one of the most common neurological disorders of infancy. Seizures in neonates are a common occurrence after hypoxia (or hypoxia-ischemia); these seizures are typically aggressively treated with anticonvulsant drugs. Hypoxia-induced seizures are associated with a profound increase in risk for later-in-life seizures, as well as significant developmental delays and intellectual disabilities. However, the outcomes due to the seizures and the outcomes due to the drug therapy are confounded. In this application, we propose to evaluate: (1) the effect of hypoxia-induced seizures, (2) the effect of the three most common anti-seizure drugs used in babies (phenobarbital, phenytoin, levetiracetam), and (3) the efficacy of a neuroprotective intervention (melatonin). We will determine the degree to which seizures and drugs influence brain development at the level of biochemistry (assessment of programmed cell death, oxidative stress), neurophysiology (patch-clamp recordings from neurons in hippocampal CA1 subfield), and behavior (tests of learning and memory in adult animals exposed to drugs and/or seizures as babies). We will also evaluate biomarkers of drug safety through peripheral measurement of oxidative stress and high-resolution magnetic resonance imaging of animals exposed to these early life insults. Finally, we will determine if our neuroprotective intervention ameliorates some, or all, of the adverse outcomes associated with seizures and/or drug treatment.