EFFECT OF ALLOPURINOL ON FREE RADICAL FORMATION DURING CEREBRAL HYPOXIA IN NEWBORN PIGLETS. ▴ 247

Abstract

Previous studies have shown that free radical production is increased during cerebral hypoxia in newborn piglets. The present study tests the hypothesis that the xanthine oxidase pathway is a significant source of free radical production during cerebral hypoxia in newborn piglets. Studies were performed in 15 anesthetized, ventilated piglets divided into 2 groups - 7 saline pretreated (Hx) and 8 pretreated with 20 mg/kg IV allopurinol, a xanthine oxidase inhibitor (All-Hx). Piglets were exposed to an FiO2 of 5-7% for 1 hr to achieve a PaO2 of 18-20 mmHg. Cortical biopsies were obtained via cranial windows and homogenized in 100 mMα-phenyl-N-tert-butyl-nitrone (PBN). PBN adducts were extracted in a 2:1 mixture of chloroform:methanol and electron spin resonance spectroscopy performed. Signal height (intensity) of spectrum divided by tissue weight was expressed as mm/g tissue. Brain tissue ATP and phosphocreatine (PCr) concentrations were determined to document cellular energy `metabolism. Conjugated dienes (CD) were determined as an index of lipid peroxidation. Free radical intensity (mm/g brain) was lower in the All-Hx (161±71, mean±S.E.) than the Hx group (387±16) p<0.05. ATP concentrations were higher in the All-Hx than the Hx group (2.2±0.6 vs. 1.1±0.3 μmol/g brain) p<0.05 as were PCr concentrations(0.55±0.14 vs. 0.19±0.03 μmol/g brain) p<0.05. There was no difference in CD levels between the two groups (0.19±0.09 All-Hx vs. 0.19±0.09 nmol/g brain Hx). Results demonstrate that administration of allopurinol prior to hypoxia significantly decreases free radical production and preserves high energy phosphates in the newborn piglet brain during hypoxia. We speculate that the xanthine oxidase pathway is a significant source of free radical generation in the newborn brain during hypoxia and that allopurinol may attenuate free radical production and neuronal injury.(NIH-HD20337, MOD 6-FY94-0135, UCPR 506-93).