Levetiracetam increases neonatal hypoxic-ischemic brain injury under normothermic, but not hypothermic conditions

• In the undamaged developing rodent brain levetiracetam does not exert a neurotoxic effect.
• Levetiracetam aggravates neonatal hypoxic-ischemic brain injury under normothermic but not under hypothermic conditions.
• In newborn infants with pre-existing brain injury levetiracetam should be used with caution.

BackgroundHypoxic-ischemic encephalopathy (HIE) resulting from perinatal asphyxia often leads to severe neurologic impairment or even death. There is a need to advance therapy for infants with HIE, for example to combine hypothermia with pharmacological treatment strategies. Levetiracetam (LEV) is approved for clinical administration to infants older than 4 weeks of age and is also used off-label in neonates. Furthermore, LEV was shown to be neuroprotective in adult animal models of brain injury.Aim of the studyThe aim of this study was to evaluate the neuroprotective potential of LEV in vitro using primary hippocampal neurons, and in vivo using an established model of neonatal hypoxic-ischemic brain injury.ResultsLEV treatment per se did not induce neurotoxicity in the developing rodent brain. Following oxygen glucose deprivation, we observed some, although not a significant, increase in cell death after LEV treatment. In vivo, LEV was administered under normothermic and hypothermic conditions following hypoxic-ischemic brain damage. LEV administration significantly increased brain injury under normothermic conditions. Compared to the normothermia-treated group, in the hypothermia group LEV administration did not increase hypoxic-ischemic brain injury.DiscussionThis study demonstrates that LEV treatment increases neonatal hypoxic-ischemic brain injury. Administration of LEV in the acute phase of the injury might interfere with the balanced activation and inactivation of excitatory and inhibitory receptors in the developing brain. The neurotoxic effect of LEV in the injured newborn brain might further suggest an agonistic effect of LEV on the GABAergic system. Hypothermia treatment attenuates glutamate release following hypoxic-ischemic brain injury and might therefore limit the potentially deleterious effects of LEV. As a consequence, our findings do not necessarily rule out a potentially beneficial effect, but argue for cautious use of LEV in newborn infants with pre-existing brain injury.