Effect of allopurinol on hypoxia-induced modification of the NMDA receptorin newborn piglets

The present study tests the hypothesis that pretreatment with allopurinol, a xanthine oxidase inhibitor, will prevent modification of the NMDA recepto r during cerebral hypoxia in newborn piglets. Eighteen newborn piglets were studied. Six normoxic control animals were compared to six untreated hypox ic and six allopurinol (20 mg/kg i.v.) pretreated hypoxic piglets. Cerebral hypoxia was induced by lowering the FiO(2), to 0.05-0.07 for 1 hour and ti ssue hypoxia was confirmed biochemically by the measurement of ATP and phos phocreatine. Brain cell membrane Na+,K+-ATPase activity was determined to a ssess membrane function. Na+,K+-ATPase activity was decreased from control in both the untreated and treated hypoxic animals (46.0 +/- 1.0 vs 37.9 +/- 2.5 and 37.3 +/- 1.4 mu mol Pi/mg protein/hr, respectively, p < 0.05). [H- 3]MK-801 binding was determined as an index of NMDA receptor modification. The receptor density (Bmax) in the untreated hypoxic group was decreased co mpared to normoxic control (1.09 +/- 0.17 vs 0.68 +/- 0.22 pmol/mg protein, p < 0.01). The dissociation constant (Kd) was also decreased in the untrea ted group (10.0 +/- 2.0 vs 4.9 +/- 1.4 nM, p < 0.01), indicating an increas e in receptor affinity. However, in the allopurinol treated hypoxic group, the Bmax (1.27 +/- 0.09 pmol/mg protein) was similar to normoxic control an d the Kd (8.1 +/-. 1.2 nM, p < 0.05) was significantly higher than in the u ntreated hypoxic group. The data show that the administration of allopurino l prior to hypoxia prevents hypoxia-induced modification of the NMDA recept or-ion channel binding characteristics, despite neuronal membrane dysfuncti on. By preventing NMDA receptor-ion channel modification, allopurinol may p roduce a neuromodulatory effect during hypoxia and attenuate NMDA receptor mediated excitotoxicity.