Effect of allopurinol on NMDA receptor modification following recurrent asphyxia in newborn piglets.
The present study tests the hypothesis that repeated episodes of asphyxia will lead to alterations in the characteristics of the N-methyl-d-aspartate (NMDA) receptor in the brain cell membrane of newborn piglets and that pre-treatment with allopurinol, a xanthine oxidase inhibitor, will prevent these modifications. Eighteen newborn piglets were studied. Six untreated and six allopurinol treated animals were subjected to eight asphyxial episodes and compared to six normoxic, normocapneic controls. Brain cell membrane Na+,K+-ATPase activity was determined to assess membrane function. Na+,K+-ATPase activity was decreased from control following asphyxia in both the untreated and treated animals (47.7+/-3.2 vs. 43.0+/-2.2 and 41.0+/-5.3 micromol Pi/mg protein/h, p<0.05, respectively). 3H-MK-801 binding studies were performed to measure NMDA receptor binding characteristics. The receptor density (Bmax) in the untreated asphyxia group was decreased compared to control animals (0.80+/-0.11 vs. 1.13+/-0.33, p<0.05); furthermore, the dissociation constant (Kd) was also decreased (3.8+/-0.7 vs. 9.2+/-2.2, p<0.05), indicating an increase in receptor affinity. In contrast, Bmax in the allopurinol treated asphyxia group was similar to control (1. 06+/-0.37); and Kd was higher (lower affinity) than in the untreated group (6.5+/-1.4, p<0.05). The data indicate that recurrent asphyxial episodes lead to alterations in NMDA receptor characteristics; and that despite cell membrane dysfunction as seen by a decrease in Na+,K+-ATPase activity, allopurinol prevents modification of NMDA receptor-ion channel binding characteristics induced by repeated episodes of asphyxia.
Marro
P J
PJ
Department of Pediatrics, Maine Medical Center, Portland, ME 04102-3134, USA.
Hoffman
D
D
Schneiderman
R
R
Mishra
O P
OP
Delivoria-Papadopoulos
M
M
D000493:Allopurinol / Q000627:therapeutic use*; D000818:Animals; D000831:Animals, Newborn; D001238:Asphyxia Neonatorum / Q000188:drug therapy*; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D016291:Dizocilpine Maleate / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006801:Humans; D007231:Infant, Newborn; D007473:Ion Channels / Q000187:drug effects; D011869:Radioligand Assay; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects*; D012008:Recurrence; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D013552:Swine; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors
D004791:Enzyme Inhibitors; D007473:Ion Channels; D016194:Receptors, N-Methyl-D-Aspartate; D000493:Allopurinol; D016291:Dizocilpine Maleate; D014969:Xanthine Oxidase; D000254:Sodium-Potassium-Exchanging ATPase