PGE(2), via EP3 receptors, regulates brain nitric oxide synthase in the perinatal period

We tested the hypothesis that high prostaglandin levels during the perinata l period might regulate brain nitric oxide synthase (nNOS) expression. nNOS and cyclooxygenase (COX)-2 mRNAs mere higher in brain cortex and the periv entricular area of newborn rats and pigs compared with adult brain. Nitric oxide synthase activity was also 2.5- to 4-fold higher in newborn than in a dult brain. Administration of nonselective COX inhibitor ibuprofen or COX-2 inhibitor nimesulide every 8 h for 24 h to newborn rats and pigs reduced p rostaglandin levels and caused comparable reductions in nNOS mRNA, protein, and activity to levels of adults; COX inhibitor-induced changes were preve nted by cotreatment with PGE(2) analog, 16,16-dimethyl-PGE(2), and agonist for the EP3 receptor of PGE(2), sulprostone, but not by PGI(2) analog carba prostacyclin, PGD(2), EP1 receptor agonist 17-phenyl trinor-PGE(2), and EP2 agonist butaprost. Concordant observations were made in vitro and revealed that nNOS expression (detected by NADPH diaphorase reactivity) mostly pres ent in neurons of the deeper cortical layers was reduced by COX inhibitor, and this effect was prevented by EP3 agonist. In conclusion, high levels of PGE(2) in neonatal brain contribute to the increased expression of nNOS by acting on EP3 receptors; this positive interaction between PGE(2) and nNOS might be required physiologically for normal brain development.