Assessment of long-term morphological and behavioral alterations and drug interventions post-hypoxia-ischemia

Periventricular leukomalacia (PVL) occurs in pre-term infants and is often the result of a cerebral hypoxic-ischemic (HI) insult. PVL is characterized by white matter damage, a significantly increased risk of epilepsy, mental retardation, and/or cerebral palsy. A rat pup model of PVL has been used to characterize the susceptibility of the neonatal brain to hypoxia-ischemia-induced brain damage. The experiments conducted in this dissertation tested the hypothesis that HI results in sustained myelin basic protein (MBP) reductions, altered brain morphology, motor deficits and that levetiracetam, zonisamide, and/or lamotrigine may have potential efficacy as neuroprotective agents against HI induced brain damage and associated motor deficits. It remains unclear whether the damage observed at P7 persists into adulthood. Therefore, Specific Aim 1 will characterize Hl-induced effect on MBP and ventricular size at PI 1, P21 and P60. While, specific Aim 2 will characterize long-term motor deficits at P21 and P60. In addition, rats exposed to HI at P7 exhibit contralateral motor deficits at P21. Pharmacological intervention post-HI, using topiramate, is able to normalize both preoligodendrocyte cell loss and the motor deficit. Therefore, Specific aim 3 will assess the protective effects of topiramate, levetiracetam, zonisamide, and lamotrigine on HIinduced MBP lesions at P11 and motor deficits at P21.