Previous studies have shown that administration of the N-methyl-D-aspartate(NMDA) receptor antagonist 3-(2-carboxypiperazin-4-yl)-1-phosphonic acid (CPP) to newborn piglets prevents the hypoxia-induced modification of the NMDA receptor, but does not prevent the hypoxia-induced decrease in cerebral Na+,K+-ATPase activity. Furthermore, administration of CPP to normoxic piglets decreases Na+,K+-ATPase activity as well. Lipid peroxidation induced by free radical generation may decrease Na+,K+-ATPase activity. The present study tests the hypothesis that CPP administration during normoxia generates free radicals and induces lipid peroxidation. 13 anesthetized, ventilated newborn piglets - 7 treated with 2 mg/kg IV CPP 1 hr prior to biopsy (CPP) and 6 untreated (Nx) - were studied. Cortical biopsies were obtained via cranial windows and homogenized in 100 Mm α-phenyl-N-tertbutyl-nitrone (PBN). The PBN adducts were extracted in a 2:1 mixture of chloroform: methanol and electron spin resonance spectroscopy (ESR) performed. Signal height (intensity) of spectrum divided by tissue weight was expressed as mm/g tissue. Conjugated dienes (CDs) were measured as an index of lipid peroxidation. Free radical intensity was higher in CPP (493±397 mm/g tissue) vs. Nx (51±83 mm/g tissue) animals, p<0.05. CDs were elevated in CPP (57±19 nmol/g brain) vs. Nx(0±0 nmol/g brain) animals, p<0.05. The data demonstrate that administration of CPP generates free radicals and induces lipid peroxidation which may decrease Na+,K+-ATPase activity in newborn piglets. Since CPP is an antagonist of the NMDA receptor and has previously been shown to alter glucose metabolism during cerebral dysfunction, we speculate that CPP generates free radicals through a pathway independent of the NMDA receptor by altering glucose utilization and uncoupling oxidative phosphorylation in brain cell mitochondria during normoxia in newborn piglets. Funded by NIH-HD-20337,MOD #6-FY94-0135,UCPR 506-93.
