The tryptophan (Trp) metabolite kynurenic acid (KYNA) is an α7-nicotinic and N-methyl-d-aspartate receptor antagonist. Elevated brain KYNA levels are commonly seen in psychiatric disorders and neurodegenerative diseases and may be related to cognitive impairments. Recently, we showed that N-acetylcysteine (NAC) inhibits kynurenine aminotransferase II (KAT II), KYNA’s key biosynthetic enzyme, and reduces KYNA neosynthesis in rats in vivo. In this study, we examined if repeated systemic administration of NAC influences brain KYNA and cognitive performance in mice. Animals received NAC (100 mg/kg, i.p.) daily for 7 days. Redox markers, KYNA levels, and KAT II activity were determined in the brain. We also assessed the effect of repeated NAC treatment on Trp catabolism using brain tissue slices ex vivo. Finally, learning and memory was evaluated with and without an acute challenge with KYNA’s bioprecursor L-kynurenine (Kyn; 100 mg/kg). Subchronic NAC administration protected against an acute pro-oxidant challenge, decreased KYNA levels, and lowered KAT II activity and improved memory both under basal conditions and after acute Kyn treatment. In tissue slices from these mice, KYNA neosynthesis from Trp or Kyn was reduced. Together, our data indicate that prolonged treatment with NAC may enhance memory at least in part by reducing brain KYNA levels.

the immature brain is especially vulnerable to lead (pb 2+ ) toxicity, which is considered an environmental neurotoxin. pb 2+ exposure during development compromises the cognitive and behavioral attributes which persist even later in adulthood, but the mechanisms involved in this effect are still unknown. On the other hand, the kynurenine pathway metabolites are modulators of different receptors and neurotransmitters related to cognition; specifically, high kynurenic acid levels has been involved with cognitive impairment, including deficits in spatial working memory and attention process. the aim of this study was to evaluate the relationship between the neurocognitive impairment induced by pb 2+ toxicity and the kynurenine pathway. The dams were divided in control group and pb 2+ group, which were given tap water or 500 ppm of lead acetate in drinking water ad libitum, respectively, from 0 to 23 postnatal day (PND). The poison was withdrawn, and tap water was given until 60 PND of the progeny. The locomotor activity in open field, redox environment, cellular function, kynurenic acid (KYNA) and 3-hydroxykynurenine (3-HK) levels as well as kynurenine aminotransferase (KAT) and kynurenine monooxygenase (KMO) activities were evaluated at both 23 and 60 PND. Additionally, learning and memory through buried food location test and expression of KAT and KMO, and cellular damage were evaluated at 60 PND. Pb 2+ group showed redox environment alterations, cellular dysfunction and KYNA and 3-HK levels increased. No changes were observed in KAT activity. KMO activity increased at 23 PND and decreased at 60 pnD. no changes in KAt and KMo expression in control and pb 2+ group were observed, however the number of positive cells expressing KMo and KAt increased in relation to control, which correlated with the loss of neuronal population. cognitive impairment was observed in pb 2+ group which was correlated with KYNA levels. These results suggest that the increase in KYNA levels could be a mechanism by which pb 2+ induces cognitive impairment in adult mice, hence the modulation of kynurenine pathway represents a potential target to improve behavioural alterations produced by this environmental toxin.Lead (Pb 2+ ) is one of the main environmental neurotoxins that represents a health problem due to its multiple industrial, domestic, medical and technological applications 1 . Because its wide distribution, Pb 2+ exposure can occur via eating, drinking or inhalation. This metal can cross placental and blood brain barrier (BBB) and also it is accumulated in several tissues, such as the lungs, liver, kidneys, spleen, brain and bones 2 . It has been reported that the central nervous system (CNS) is a target of lead exposure 3-5 . The developing brain is especially vulnerable to Pb 2+ neurotoxicity since this heavy metal crosses through the placenta during pregnancy and also is able to pass into milk during the lactation period, reaching the developing brain impacting its functionality and morphology 6,7 . There are reports showing tha...