PGs exert gastric cytoprotection. PG levels in neural tissue (brain and retina) are high in the newborn (NB); but the role of these PG is not known. Since strong uterine contractions at the end of labor cause relative fetal hypoxia, we postulated that high PG levels may confer neuroprotection. We used a model of NB asphyxia (Ax) to first test the effects of acute (45 min) inhibition of PG G/H synthase (PGHS) with flurbiprofen (10 mg/kg iv [decreased PGs], n=6) or saline (n=6), on the electroretinogram (ERG, stable signal) of anesthetized (α-chloralose) and paralyzed (pancuronium) ventilated NB pigs (2-3 days old) before and 1 h after a 5 min period of asphyxia(interruption of ventilation). In separate piglets peroxidation products, malondialdehyde (MDA) and hydroperoxides (PX), were also measured in retina at the same times. Flurbiprofen prevented the post-Ax decrease (26-31%) in photopic and scotopic b-wave (Müller and bipolar cells) amplitude, as well as the rise in MDA and PX of saline-treated pigs; results suggested that PGHS contributed significantly to the post-Ax deterioration in neuro-retinal function. We then assessed if these effects of acute inhibition of PGHS could be reproduced after prolonged inhibition. NB pigs (1 day old) were treated for 24 h with flurbiprofen (10 mg/kg/12 h iv, n=4), diclofenac (2.5 mg/kg/12 h iv[decreased PGs], n=10), or a combination of diclofenac and stable analogs of PG, PGE2, PGI2 and PGF (16,16 dimethyl PGE2, 6 μg/kg/12 h iv; iloprost, 20 μg/kg/12 h iv; fenprostalene, 10 μg/kg/24 h im; n=4), or saline (n=6). ERG was recorded before and 24 h after treatments, and repeated 1 h after Ax; MDA and PX were also measured. Diclofenac for 24 h caused a small (13-19%) decrease in b-wave amplitude which was further markedly reduced by 52-66% 1 h after Ax. Addition of PG analogs totally prevented pre- and post-Ax ERG deterioration. Levels of MDA and PX were low in all animals drug-treated for 24 h. Data indicate that PGHS is a significant source of reactive oxygen species in neonatal neural tissue, and PG confer neuroprotection to the NB apparently via a mechanism independent of effects on oxidant potential.