Nitric Oxide (NO) and Prostaglandins (PG's) are major modulators of cerebral circulation and neuronal homeostasis. To determine the molecular mechanisms by which cerebral PG and NO are regulated during neonatal development, we analysed the expression of mRNA and proteins of major PG-synthases (COX-1 and COX-2) and NO-synthases (b-NOS and ec-NOS) in the brain and cerebral microvessels (MV). Newborn piglets (1 and 4 days) (n=4) and juvenile pigs (6 weeks) (n=3) were anesthetised and the brains perfused and harvested for whole brain tissue and MV. Protein expression for COX-1 and COX-2, ecNOS and bNOS were determined by Western blot analysis. Results showed that there are significant differences in protein levels between age groups with tissue specific expression. The 1 day old newborn brain expressed elevated levels of COX-1 (8 fold), COX-2 (20 fold), bNOS (12-fold) and ecNOS(5-fold) compared to juveniles. These elevated levels at 1 day old are probably due to birth stress as was suggested by the presence of the stress induced cytokine TNFα. TNFα mRNA presence was detected by semi-quantitative rt-PCR only in the brain and microvessels of 1 day old piglet. The 4 day old brains expressed lower levels of COX-1 (2-fold), bNOS(2-fold) and ecNOS (10 fold) than the 6 week old juvenile. Similarly, purified cerebral microvessels of 4 day old piglets showed approximately equal levels of COX-2, and lower levels of COX-1 (2-fold), bNOS (2fold) and ecNOS (4 fold) compared to MV of 6 week old pigs. These protein changes were confirmed by Northern blot and semi-quantitative rt-PCR analysis using total RNA extracted from the brain and MV of the 1 day, 4 day and 6 week old pigs, indicating no existence of posttranscription mechanisms in gene regulation of COX-1, COX-2, bNOS and ecNOS during early postnatal development. To further verify these developmental changes in PG synthases we analyzed PGE2 levels of basal arterial plasma and CSF by radio-immuno assay (RIA). Data show that arterial PGE2 levels were significantly increased in newborn (p=.0003 r=.0957) compared to juvenile while the CSF levels remained comparable. We conclude that dynamic changes in NOS and PG synthases occur in immediate postnatal period with overexpression of COX and NOS isoforms. These data explain the increased circulating PG's at birth in newborn infants.