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Title: Melatonin antagonizes Mn-induced oxidative injury through the activation of keap1-Nrf2-ARE signaling pathway in the striatum of mice. Author: Deng Y, Zhu J, Mi C, Xu B, Jiao C, Li Y, Xu D, Liu W, Xu Z. Journal: Neurotox Res; 2015 Feb; 27(2):156-71. PubMed ID: 25288107. 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.[Abstract] [Full Text] [Related] [New Search]