Lanthanum chloride induces autophagy in rat hippocampus through ROS-mediated JNK and AKT/mTOR signaling pathways

• Published in: Metallomics Vol. 11; no. 2; pp. 439 - 453
• Main Authors: Gao, Xiang, Yang, Jinghua, Li, Yingqi, Yu, Miao, Liu, Shiyu, Han, Yarao, Lu, Xiaobo, Jin, Cuihong, Wu, Shengwen, Cai, Yuan
• Format: Journal Article
• Language: English
• Published: England Royal Society of Chemistry 20-02-2019
• Subjects: AKT protein; Animals; Apoptosis; Autophagy; Autophagy - drug effects; Avoidance learning; c-Jun protein; Cell death; Central nervous system; Chlorides; Drinking water; Embryos; FOXO1 protein; FOXO3 protein; Hippocampus; Hippocampus - drug effects; Hippocampus - metabolism; Impairment; Lanthanum; Lanthanum - pharmacology; Lanthanum chlorides; Learning; Macromolecules; Male; Neurons; Organelles; Organic chemistry; Oxidative stress; Oxidative Stress - drug effects; Phagocytosis; Phagosomes; Proto-Oncogene Proteins c-akt - metabolism; Rats; Rats, Wistar; Reactive oxygen species; Reactive Oxygen Species - metabolism; Signal transduction; Signal Transduction - drug effects; Signaling; Spatial discrimination learning; Spatial memory; TOR protein; TOR Serine-Threonine Kinases - metabolism; Transcription factors; Weaning
• ISSN: 1756-5901; 1756-591X
• DOI: 10.1039/c8mt00295a

Lanthanum (La) can cause central nervous system damage in rats and lead to learning and memory impairment, but the relevant mechanisms have not been fully elucidated. Autophagy is the self-balancing and self-renewal process of cells that degrades damaged macromolecules and organelles through the lysosomal pathway. It is an important mechanism to resist harmful stress, but excessive autophagy leads to type II programmed cell death. A variety of chemicals can induce oxidative stress, and a large number of reactive oxygen species (ROS) can regulate the level of autophagy through multiple signaling pathways. Our previous studies showed that La could cause oxidative stress, inhibit Nrf2/ARE signaling pathway and impair learning and memory, but it is unclear whether the mechanism is related to autophagic disorders of neurons. In this study, Wistar rats were exposed to 0% (w/v), 0.25%, 0.5% and 1.0% lanthanum chloride (LaCl
3
) through their mother and drinking water from the embryonic phase to 1 month after weaning, and then the subsequent experiments were performed. The results showed that LaCl
3
impaired spatial learning and memory and avoidance conditioning in rats and induced an increase in ROS levels in hippocampal nerve cells, which up-regulated p-JNK, p-c-Jun, p-FoxO1, p-FoxO3a, Beclin1 and LC3B-II expression and down-regulated p-AKT, p-mTOR and p62 expression. Meanwhile, the number of autophagosomes in hippocampal neurons in the 1.0% LaCl
3
-treated group was significantly increased. These results indicate that La can activate the JNK/c-Jun and JNK/FoxOs signaling pathways, inhibit the AKT/mTOR signaling pathway by inducing oxidative stress, and enhance autophagy in the hippocampus. This study suggests that the mechanism of learning and memory impairment induced by LaCl
3
may be related to excessive autophagy.
Lanthanum (La) can cause central nervous system damage in rats and lead to learning and memory impairment, but the relevant mechanisms have not been fully elucidated.