Kim Annink

155 Allopurinol: old drug, new indication in neonates? Several animal studies have been performed to investigate the neuroprotective mechanisms of allopurinol in HIE. Marro et al. showed that uric acid levels were reduced in allopurinol treated piglets with HIE (43). This implicated that the xanthine- oxidase pathway was indeed inhibited after allopurinol administration in piglets, since uric acid is the final product in this cascade. The same group also showed that the Na-K-ATPase pump, that often fails in HIE, was more active in newborn animals suffering HIE following allopurinol administration compared to controls (43,44). As discussed earlier, failure of the Na-K-ATPase pump leads to a calcium influx into the cells which results in cell damage and (pro)radical formation. A decreased failure of the Na-K-ATPase pump might result in less neuronal cell damage. More recently, Marro et al. showed that adenosine and inosine levels were higher in allopurinol treated piglets than in controls (45). This suggested that allopurinol also reduced the conversion of adenosine and inosine into hypoxanthine. Lower hypoxanthine levels might result in less superoxide formation. A high adenosine concentration is also thought to be neuroprotective itself, because adenosine can inhibit the production of excitatory neurotransmitters such as glutamate and increases cerebral blood flow during hypoxia (45). Additionally, high levels of allopurinol and oxypurinol also seem to be direct NPBI chelators and hydroxyl radical scavengers (6,7). NPBI levels in cortical tissues were decreased in allopurinol treated lambs with HIE compared to placebo, but plasma NPBI levels did not differ (7). This suggested that allopurinol and oxypurinol were able to cross the blood brain barrier. However, allopurinol in the dose of 20mg/kg did only partly chelate NPBI levels in lambs (7). Both allopurinol and oxypurinol have a hydroxyl radical scavenging effect. The scavenging effect of oxypurinol was stronger than of allopurinol (6). Whether the possible neuroprotective effect of allopurinol is mainly caused by xanthine-oxidase inhibition or free radical scavenging has not yet been elucidated. All above mentioned preclinical studies only measured short-term outcome. The measurement of long-term outcomes such as long-term neurobehavioral studies are essential to establish a possible effect of allopurinol in HIE. Further, the effect of postnatal allopurinol has not been investigated as an addition to hypothermia treatment in preclinical research. 7