Kynurenic acid in brain and cerebrospinal fluid of fetal, newborn, and adult sheep and effects of placental embolization

Concentrations of the endogenous glutamate receptor antagonist kynurenic ac id (KA) were measured in various brain regions and in cisternal cerebrospin al fluid of fetal, newborn, and adult sheep. KA concentrations were signifi cantly higher in the fetal brain and cerebrospinal fluid at 90 and 140 d ge station compared with postnatal ages. In fetuses of 132-139 d gestation, KA concentrations in cerebrospinal fluid collected by drainage from an indwel ling cisternal catheter increased significantly after infusion of the organ ic acid transport inhibitor probenecid (100 or 200 mg/kg, i.v.) indicating active transport of KA out of the fetal brain. In fetuses in which the umbi lical circulation had been chronically restricted from 120 to 140 d gestati on by partial embolization of the placenta, plasma concentrations of the KA precursor kynurenine were significantly lower than in control fetuses, and KA concentrations in the hypothalamus and hippocampus were significantly r educed; other brain regions were not affected. These results indicate that the production of KA is higher in the fetal brain compared with the newborn and adult brain. Because KA diminishes the risk of excitotoxic neuronal da mage under hypoxic-ischemic conditions, the high levels of KA in the brain before birth may have a neuroprotective function. The decrease of KA concen trations in the hypothalamus and hippocampus after umbilical embolization s uggests that, after chronic hypoxia in utero, these regions of the brain ma y become more vulnerable to subsequent episodes of acute hypoxia or ischemi a encountered in late gestation or during parturition.