Background: Hypoxic-ischemic encephalopathy (HIE) is an important cause of neonatal mortality and
neurological morbidity, even despite hypothermia treatment. Neuronal damage in these infants is partly caused by
the production of superoxides via the xanthine-oxidase pathway and concomitant free radical formation. Allopurinol
is a xanthine-oxidase inhibitor and can potentially reduce the formation of these superoxides that lead to
brain damage in HIE.
Methods: The aim of this review is to provide an overview of the animal and clinical data about the neuroprotective
effect of allopurinol in HIE and the relevant mechanisms leading to brain injury in HIE.
Results: A possible neuroprotective effect of allopurinol has been suggested based on several preclinical studies
in rats, piglets and sheep. Allopurinol seemed to inhibit the formation of superoxide and to scavenge free radicals
directly, but the effect on brain damage was inconclusive in these preclinical trials. The neuroprotective effect
was also investigated in neonates with HIE. In three small studies, in which, allopurinol was administered postnatally
and a pilot and one multi-center study, in which, allopurinol was administered antenatally, a possible beneficial
effect was found. After combining the data of 2 postnatal allopurinol studies, long-term follow-up was only
beneficial in infants with moderate HIE, therefore, large-scale studies are needed. Additionally, safety, pharmacokinetics
and the neuroprotective effect of allopurinol in other neonatal populations are discussed in this review.
Conclusion: The available literature is not conclusive whether allopurinol is a neuroprotective add-on therapy in
infants with HIE. More research is needed to establish the neuroprotective effect of allopurinol especially in combination