PRODUCTION AND METABOLISM OF PLATELET-ACTIVATING-FACTOR IN THE NORMALAND ISCHEMIC FETAL-RAT BRAIN

Production and metabolism of platelet-activating factor (PAF) in the f etal rat brain under normal and under ischemic stress conditions were examined. Endogenous PAF levels, determined by a bioassay using PAF-st imulated platelet release of [H-3]serotonin, averaged 2.32 +/- 2.14 pg /mg in control brains and was reduced to 1.10 +/- 1.06 pg/mg after 20 min of maternal-fetal blood flow occlusion. [H-3]PAF administered intr acranially into the fetuses in utero was removed in a biphasic, time-d ependent manner: a rapid component with an estimated elimination rate constant of 0.067 min(-1) and t(1/2) of 10 min and a slower component with an elimination rate of 0.017 min(-1) and t(1/2) of 41 min. In fet al brains subjected to ischemia a delayed elimination of [H-3] PAF was noticed in the slow component (t(1/2) = 59 min), indicating a possibl e difference between the clearance of exogenous and endogenous PAF. Th e disappearance of [H-3]PAF was accompanied by an increase in the radi oactivity associated with lyso-PAF that reached a plateau after 2.5 mi n, possibly indicating the degradation of the fast component. A steady increase in the alkyl-acyl-glycerophosphorylcholine radioactivity com menced after 5 min and continued up to 30 min. The endogenous producti on of PAF and the rapid degradation due to maternal-fetal blood flow o cclusion indicate an additional target for therapeutic intervention in the pathology of intrauterine ischemia. Addition of the calcium ionop hore A23187 stimulated in vitro formation of PAF and lyso-PAF from [H- 3]choline-labeled fetal brain phospholipids, suggesting that intracell ular calcium may play a major stimulatory role in PAF production. Degr adation of polyphosphoinositides by a phospholipase C may constitute a major target for PAF generated either by decapitation or after blood flow occlusion, as evident from the protective effect of the in vivo a dministered BN52021 PAF antagonist.