Neuroprotective effects of topiramate after hypoxia-ischemia in newborn piglets

Background: Perinatal hypoxia-ischemia (HI) is associated with delayed cerebral damage, which involves receptor-mediated excitotoxicity. Until now, successful interventions to reduce excitotoxicity early after HI in experimental settings failed to transform into clinical applications owing to negative side effects. A promising new approach using the anticonvulsant Topiramate (TPM) has shown to be effective to reduce brain damage after early HI in a rodent model of combined TPM-hypothermia. Here, we used TPM solely administered 1 h after HI in a neonatal piglet model in order to verify possible neuroprotection. Methods: Newborn piglets were subjected to HI by transient occlusion of carotid arteries and hypotension (62-65% of baseline). Fifteen minutes later, an additional reduction of the inspired oxygen fraction to 0.06 was performed for 13 min. One cohort (VEHICLE, n = 8) received saline solution i.v. 1 h after HI and then twice a day. Two further cohorts were treated at same times with TPM (HI-TPM10, n = 8, loading dose 20 mg/kg; maintenance dose 10 mg/kg/day; HI-TPM20, n = 8, loading dose 50 mg/kg; maintenance dose 20 mg/kg/day). Untreated animals (CONTROL, n = 8) received all experimental procedures except HI. Animals were monitored 3 days after HI concerning occurrence of seizures as well as neurological and behavioral functions. After 72 h, the brains were perfused and processed to assess neuronal loss and DNA-fragments (TUNEL staining). Results: There was a significant reduction of neuronal cell loss in HI-TPM20 animals. However, apoptosis was increased in the frontal white matter of HI-TPM20 animals. Conclusions: Exclusive TPM treatment shows neuroprotection in newborn piglets after HI.