EFFECT OF ALLOPURINOL ON NMDA RECEPTOR MODIFICATION FOLLOWING RECURRENT ASPHYXIA IN NEWBORN PIGLETS

The present study tests the hypothesis that repeated episodes of asphy xia will lead to alterations in the characteristics of the N-methyl-D- aspartate (NMDA) receptor in the brain cell membrane of newborn piglet s and that pre-treatment with allopurinol, a xanthine oxidase inhibito r, will prevent these modifications. Eighteen newborn piglets were stu died. Six untreated and six allopurinol treated animals were subjected to eight asphyxial episodes and compared to six normoxic, normocapnei c 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 mu mol Pi/mg protein/h , p<0.05, respectively). H-3-MK-801 binding studies were performed to measure NMDA receptor binding characteristics. The receptor density (B -max) in the untreated asphyxia group was decreased compared to contro l animals (0.80 +/- 0.11 vs. 1.13 +/- 0.33, p<0.05); furthermore, the dissociation constant (K-d) was also decreased (3.8+/-0.7 vs. 9.2+/-2. 2, p<0.05), indicating an increase in receptor affinity. In contrast, B-max in the allopurinol treated asphyxia group was similar to control (1.06 +/- 0.37); and K-d was higher (lower affinity) than in the untr eated group (6.5 +/- 1.4, p<0.05). The data indicate that recurrent as phyxial episodes lead to alterations in NMDA receptor characteristics; and that despite cell membrane dysfunction as seen by a decrease in N a+,K+-ATPase activity, allopurinol prevents modification of NMDA recep tor-ion channel binding characteristics induced by repeated episodes o f asphyxia. (C) 1998 Elsevier Science B.V.