title: Melatonin antagonizes Mn-induced oxidative injury through the activation of keap1-Nrf2-ARE signaling pathway in the striatum of mice.
abstract: Excessive manganese (Mn) exposure can lead to oxidative injury. Nuclear factor erythroid 2-related factor 2 (Nrf2) exerts an antioxidant response toward various environmental toxicants in the brain. However, the role of Nrf2 against Mn-induced oxidative injury remains largely unexplored. This study investigated the role of melatonin (MLT), an agent that was recently shown to induce the activation of the Kelch-like ECH-associated protein 1 (Keap1)-Nrf2-antioxidant response elements (ARE) pathway against manganism. Mice were randomly divided into six groups, including control, 12.5, 25, 50 mg/kg MnCl2, MLT control, and MLT + 50 mg/kg MnCl2. The following were determined: behavioral activity; pathological changes; immunofluorescence staining of Neuronal Nuclei and glial fibrillary acidic protein; cell apoptosis; the levels of reactive oxygen species (ROS), malondialdehyde (MDA), and glutathione (GSH); the immunohistochemical expression; and the protein levels of Nrf2, Keap1, and downstream enzymes. Mn-induced motor disorders, pathological damage, neuron degeneration, astrocytes activation, apoptosis, ROS and MDA generation, and GSH depletion. Nrf2, keap1, heme oxygenase-1 and NAD(P)H dehydrogenase, and quinone 1 showed a biphasic expression trend, which was most evidenced in the 12.5 mg/kg MnCl2 group. Changes in γ-glutamylcysteine synthetase, glutathione peroxidase 1, glutathionine S-transferase, glutathione reductase, and superoxide dismutase decreased in a concentration-dependent manner as a result of Mn exposure. MLT antagonized oxidative injury through the activation of the Keap1-Nrf2-ARE signaling pathway. In conclusion, disturbance of the Keap1-Nrf2-ARE signaling pathway partly caused oxidative injury. MLT can activate Nrf2 and its downstream enzymes and reverse Mn-induced oxidative injury.
authors.affiliation: Department of Environmental Health, School of Public Health, China Medical University, Shenyang, 110001, Liaoning, People's Republic of China, dengyu.cmu@163.com.
authors.forename: Yu
authors.initials: Y
authors.lastname: Deng
authors.forename: Jiayu
authors.initials: J
authors.lastname: Zhu
authors.forename: Chao
authors.initials: C
authors.lastname: Mi
authors.forename: Bin
authors.initials: B
authors.lastname: Xu
authors.forename: Congcong
authors.initials: C
authors.lastname: Jiao
authors.forename: Yuehui
authors.initials: Y
authors.lastname: Li
authors.forename: Donghui
authors.initials: D
authors.lastname: Xu
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.forename: Zhaofa
authors.initials: Z
authors.lastname: Xu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D061745:Antioxidant Response Elements; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001835:Body Weight / Q000187:drug effects; D002712:Chlorides / Q000633:toxicity*; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000378:metabolism; D005260:Female; D000072019:Kelch-Like ECH-Associated Protein 1; D008124:Locomotion / Q000187:drug effects; D008297:Male; D017895:Manganese Compounds; D008550:Melatonin / Q000494:pharmacology*; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000975:Antioxidants; D002712:Chlorides; D003598:Cytoskeletal Proteins; C117301:Keap1 protein, mouse; D000072019:Kelch-Like ECH-Associated Protein 1; D017895:Manganese Compounds; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D017382:Reactive Oxygen Species; D008550:Melatonin; C025340:manganese chloride