Perinatal kynurenine pathway metabolism in the normal and asphyctic rat brain

Abstract

The kynurenine pathway of tryptophan degradation contains several metabolites which may influence brain physiology and pathophysiology. The brain content of one of these compounds, kynurenic acid (KYNA), decreases precipitously around the time of birth, possibly to avoid deleterious N-methyl-D-aspartate (NMDA) receptor blockade during the perinatal period. The present study was designed to determine the levels of KYNA, the free radical generator 3-hydroxykynurenine (3-HK), and their common precursor L-kynurenine (L-KYN) between gestational day 16 and adulthood in rat brain and liver. The cerebral activities of the biosynthetic enzymes of KYNA and 3-HK, kynurenine aminotransferases (KATs) I and II and kynurenine 3-hydroxylase, respectively, were measured at the same ages. Additional studies were performed to assess whether and to what extent kynurenines in the immature brain derive from the mother, and to examine the short-term effects of birth asphyxia on brain KYNA and 3-HK levels. The results revealed that 1) the brain and liver content of L-KYN, KYNA and 3-HK is far higher pre-term than postnatally; 2) KAT I and kynurenine 3-hydroxylase activities are quite uniform between E-16 and adulthood, whereas KAT II activity rises sharply after postnatal day 14; 3) during the perinatal period, KYNA, but not L-KYN, may originate in part from the maternal circulation; and 4) oxygen deprivation at birth affects the brain content of both KYNA and 3-HK 1 h but not 24h later.

Characterization of kynurenine aminotransferase III, a novel member of a phylogenetically conserved KAT family

“…KAT I, also known as Glutamine transaminase K (GTK) or cysteine conjugate beta-lyase (CCBL) (Perry et al, 1993(Perry et al, , 1995Carninci and Hayashizaki, 1999), is present in both astrocytes and neurons, and its expression increases after birth, reaching a maximum specific enzyme activity in adult brain of rats (Plant et al, 1997;Ceresoli-Borroni and Schwarcz, 2000). The enzyme activity of KAT I of rat brain was previously shown to have an alkaline pH of optimum (Guidetti et al, 1997).…”

Continuous kynurenine administration during the prenatal period, but not during adolescence, causes learning and memory deficits in adult rats

“…The formation of KYNA takes place preferentially in astrocytes, which release the metabolite into the extracellular milieu where it is ideally positioned to inhibit neuronal NMDA and α7nACh receptors and thus influence cognitive processes (Schwarcz et al 2012). Notably, KYNA concentrations in the mammalian brain are exceptionally high during the prenatal period (Beal et al 1992; Ceresoli-Borroni and Schwarcz 2000). …”

Platform and Poster Session Abstracts

“…The Johns Hopkins University, Baltimore, Md., USA Maintaining cerebral oxygen delivery during a hypoxic event depends upon adequate cerebral vasodilation. Fetal sheep at 0.6-0.7 gestation (term = 145 days) exhibit a smaller increase in cerebral blood flow during hypoxia than at 0.9 gestation, even when normalized for age-differences in cerebral oxygen consumption [1]. This age difference in vascular reactivity is specific for hypoxia because the flow response to hypercapnia [2] and the pial arteriolar dilation to acetylcholine [3] and to adenosine analogues [4] are similar at these ages.…”

“…Several metabolites of the kynurenine pathway of tryptophan degradation may play an important role in brain development. The brain content of one of these metabolites, the neuroprotectant and preferential NMDA receptor antagonist kynurenic acid (KYNA), is remarkably high in the late fetal period and decreases rapidly within hours after birth [1]. KYNA may therefore provide a safety mechanism against possible asphyctic/hypoxic insults during and immediately after delivery.…”