Authors :
Presenting Author: Anjik Ghosh, MS – Georgetown University
Patrick Forcelli, PhD – Associate Professor, Pharmacology & Physiology, Georgetown University; Sean Quinlan, PhD – Post-Doctoral Fellow, Pharmacology & Physiology, Georgetown University
Rationale:
Many anti-seizure medications (ASMs) trigger neuronal cell death when administered during a confined period of early life (centered on postnatal day seven) in rodents. Prototypical ASMs used to treat early-life seizures such as phenobarbital and phenytoin induce this effect, whereas levetiracetam does not. However, most prior studies have examined the effect of ASMs in naïve animals, and the degree to which underlying brain injury interacts with these drugs to modify cell death is poorly studied. Moreover, the degree to which drug-induced neuronal cell death differs as a function of sex is unknown.Methods:
We treated postnatal day seven Sprague Dawley rat pups with vehicle, phenobarbital (75 mg/kg), or levetiracetam (200 mg/kg). Separate groups of pups were pre-exposed to either normoxia or graded global hypoxia. Separate groups of males and females were used. 24 hours after drug treatment, brains were collected and processed for markers of cell death. Results:
Consistent with prior studies, phenobarbital, but not levetiracetam, increased cell death in cortical regions, basal ganglia, hippocampus, septum, and lateral thalamus. Sex differences in cell death were observed in the cingulate cortex, somatosensory cortex, and the CA1 and CA3 hippocampus, Hypoxia status did not affect cell death among treatment groups. Conclusions:
We found that a history of graded global hypoxia does not alter the neurotoxic profile of phenobarbital. Levetiracetam, which does not induce cell death in normal developing animals, maintained a benign profile on the background of neonatal hypoxia. We found a sex-based difference, as female animals showed elevated levels of cell death across all treatment conditions. Together, these data address several long-standing gaps in our understanding of the neurotoxic profile of antiseizure medications during early postnatal development. Funding: This project was funded through NIH grant 5R01HD091994-02, entitled, "Structural and functional sequelae of neonatal anticonvulsant exposure: drug-seizure interactions," awarded to Dr. Patrick Forcelli at Georgetown University.