Kynurenine Pathway as a New Target of Cognitive Impairment Induced by Lead Toxicity During the Lactation

Abstract

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 The poison was withdrawn, and tap water was given until 60 PND of the progeny.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...

Cognitive Impairment Induced by Lead Exposure during Lifespan: Mechanisms of Lead Neurotoxicity

“…KYNA is an antagonist of NMDAr and a negative allosteric modulator of α7 nAChRs. This study provided evidence of the involvement of tryptophan catabolism and kynurenine pathway as a new mechanism of Pb toxicity affecting neurotransmission and impairing cognitive performance [ 132 ].…”

“…In animal models, neurobehavioral deficits induced by prenatal, preweaning, and postweaning Pb exposure persist until adulthood. It has been described that Pb exposure alters the locomotor activity [ 133 , 134 ], increases aggressive behavior [ 135 ], and causes motor coordination impairment [ 136 ], response inhibition deficits, deficient task solving capacities [ 137 , 138 ], and learning and memory impairment [ 132 , 139 , 140 , 141 ].…”

Subchronic N-acetylcysteine Treatment Decreases Brain Kynurenic Acid Levels and Improves Cognitive Performance in Mice

“…An investigator who was unaware of the experimental protocol performed all behavioral experiments. BFLT is an adaptation [49] of the model described by Lehmkuhl et al for the evaluation of olfactory dysfunction [50]. Since acute Kyn administration models cognitive impairment (see Introduction), four groups of animals were used: (1) subchronic saline, (2) subchronic NAC, (3) subchronic saline + acute Kyn, and (4) subchronic NAC + acute Kyn.…”

“…Briefly, the motor/kinetic activity was recorded during 5 min after the habituation period, and the cage was cleaned with alcohol between each test. Results are expressed as total distance walked (cm) and ambulatory time (s) recorded in 5 min, as previously reported [49]. After behavioral tests, brain was dissected out for KYNA determination (see above).…”

Evaluation of Analytes Characterized with Potential Protective Action after Rat Exposure to Lead

“…On the other hand, Pb acetate alters the binding affinity of Trp with liver nuclei, which affects protein synthesis in the liver. In addition, recently, the effect of Pb on the kynurenine pathway of Trp metabolism has been shown, which may also contribute to neurocognitive impairment caused by Pb [ 13 ].…”