Effect of allopurinol on hypoxia-induced modification of the NMDA receptor in newborn piglets.
The present study tests the hypothesis that pretreatment with allopurinol, a xanthine oxidase inhibitor, will prevent modification of the NMDA receptor during cerebral hypoxia in newborn piglets. Eighteen newborn piglets were studied. Six normoxic control animals were compared to six untreated hypoxic and six allopurinol (20 mg/kg i.v.) pretreated hypoxic piglets. Cerebral hypoxia was induced by lowering the FiO2 to 0.05-0.07 for 1 hour and tissue hypoxia was confirmed biochemically by the measurement of ATP and phosphocreatine. Brain cell membrane Na+,K+-ATPase activity was determined to assess 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 micromol Pi/mg protein/hr, respectively, p < 0.05). [3H]MK-801 binding was determined as an index of NMDA receptor modification. The receptor density (Bmax) in the untreated hypoxic group was decreased compared 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 untreated group (10.0+/-2.0 vs 4.9+/-1.4 nM, p < 0.01), indicating an increase in receptor affinity. However, in the allopurinol treated hypoxic group, the Bmax (1.27+/-0.09 pmol/mg protein) was similar to normoxic control and the Kd (8.1+/-1.2 nM, p < 0.05) was significantly higher than in the untreated hypoxic group. The data show that the administration of allopurinol prior to hypoxia prevents hypoxia-induced modification of the NMDA receptor-ion channel binding characteristics, despite neuronal membrane dysfunction. By preventing NMDA receptor-ion channel modification, allopurinol may produce a neuromodulatory effect during hypoxia and attenuate NMDA receptor mediated excitotoxicity.
Marro
P J
PJ
Department of Pediatrics, Maine Medical Center, Portland 04102-3134, USA.
Andersen
C B
CB
Mishra
O P
OP
Delivoria-Papadopoulos
M
M
D000255:Adenosine Triphosphate / Q000378:metabolism; D000493:Allopurinol / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000201:enzymology / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000378:metabolism; D002534:Hypoxia, Brain / Q000378:metabolism*; D010725:Phosphocreatine / Q000378:metabolism; D011869:Radioligand Assay; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects* / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D013552:Swine
D016194:Receptors, N-Methyl-D-Aspartate; D010725:Phosphocreatine; D000493:Allopurinol; D016291:Dizocilpine Maleate; D000255:Adenosine Triphosphate; D000254:Sodium-Potassium-Exchanging ATPase