Kim Annink

154 Chapter 7 Preclinical studies – neonatal administration for HIE The first animal studies investigating the neuroprotective effect of allopurinol in HIE were performed by Palmer and colleagues in 7-day-old rat pups (38-40). In the first studies allopurinol was administrated 30 minutes before inducing hypoxia and this resulted in a reduction of cerebral edema and a lower incidence of infarction (39). Furthermore, ATP increased and the Pi/PCr ratio decreased at 31P-NMR- spectroscopy in rats, which represents a preserved cerebral metabolism (38). In a subsequent study by this group using 7-day-old rat pups, allopurinol was given 15 minutes after inducing hypoxia. This led to reduced atrophy and cerebral edema, as well as less overall brain injury based on a histology scoring system (40). In the studies in which allopurinol was administered before inducing hypoxia core temperature was not measured, so it cannot be excluded that these rats were hypothermic and that this partly has influenced the neuroprotective effect (38,39). In the study of Palmer et al. in 1993, the core body temperature was measured before and after allopurinol administration. In the placebo group the temperature varied 0.16±0.18 degrees of Celsius before and after placebo administration and in the allopurinol 0.09±0.32 degrees of Celsius, so these are only minor variations in temperature (40). Hypothermia is therefore an unlikely explanation for the beneficial effect of allopurinol in these rat pups. The effect of allopurinol in asphyxiated piglets was investigated with phosphorous magnetic resonance spectroscopy, Near Infrared Spectroscopy (NIRS), electroencephalography (EEG) and histology by Peeters-Scholte et al. (41,42). After one hour of hypoxia, allopurinol was administered directly during start of reperfusion and 12 hours after reperfusion. On magnetic resonance spectroscopy, a preservation of the cerebral energy status was found and based on T2-weighted magnetic resonance imaging (MRI) less edema in the cortex, striatum and thalami were found in allopurinol treated animals. However, there was no improvement on NIRS, aEEG or histology (41,42). The authors’ explanation was that the moderately asphyxiated piglets might have experienced a positive effect on outcome, but that treatment with allopurinol had no effect when the brain is too severely damaged. Although the cerebral energy status might have been preserved, severe brain damage might already have occurred and did not improve after allopurinol. However, no sub-analysis was performed to confirm this hypothesis (41, 42). Rectal temperature remained stable in both groups during the study. Only short-term outcomes until 24 hours after birth were measured (41,42).