Effect of allopurinol on uric acid levels and brain cell membrane Na +,K +-ATPase activity during hypoxia in newborn piglets

Abstract

Oxygen-free radicals generated by xanthine oxidase during hypoxia-ischemia may result in cellular injury through harmful effects on membrane phospholipids. The present study investigated the effect of administration of allopurinol, an inhibitor of xanthine oxidase, on free-radical generation and brain cell membrane injury during hypoxia by inhibiting the breakdown of hypoxanthine to uric acid. Brain cell membrane Na +,K +-ATPase activity and lipid peroxidation products (conjugated dienes and fluorescent compounds) were determined as indices of brain membrane function and structure. Cerebral oxygenation was continuously monitored during hypoxia by 31P-NMR spectroscopy. Plasma and brain tissue levels of uric acid were measured to evaluate xanthine oxidase activity and purine degradation. Na +,K +-ATPase activity decreased significantly in both hypoxic groups; however, the allopurinol-treated hypoxic group showed a smaller decrease than the untreated hypoxic group (47.3 ± 4.9vs. 42.0 ± 2.7 μmol P i/mg protein/h, P < 0.05), respectively. Conjugated dienes increased significantly in the untreated hypoxic compared to control animals (0.070 ± 0.045vs. 0.004 ± 0.006 μmol/g brain, P < 0.05), with the allopurinol-treated animals having intermediate values (0.053 ± 0.039 μmol/g brain). Fluorescent compounds were lower in the allopurinol-treated hypoxic group compared to the untreated hypoxic group (0.79 ± 0.19vs. 1.06 ± 0.60 μg/quinine sulfate/g brain, P < 0.05). Measurements of serum and brain tissue uric acid were significantly lower during hypoxia in the allopurinol-treated compared to the untreatedgroup (30.3 ± 15.6vs. 45.7 ± 10.6 μM( P < 0.05)and1.69 ± 0.97vs. 4.27 ± 2.37nmol/g( P < 0.05), respectively. Allopurinol is an effective inhibitor of xanthine oxidase and reduces the formation of uric acid in brain tissue under hypoxic conditions. In addition, the present data suggest that allopurinol reduces lipid peroxidation during cerebral hypoxia in newborn piglets. Allopurinol, while unable to offer complete protection from the effects of hypoxia, can attenuate hypoxic brain cell membrane injury.