Top

Published in:

01-02-2015 | Original Article

Melatonin Antagonizes Mn-Induced Oxidative Injury Through the Activation of Keap1–Nrf2–ARE Signaling Pathway in the Striatum of Mice

Authors: Yu Deng, Jiayu Zhu, Chao Mi, Bin Xu, Congcong Jiao, Yuehui Li, Donghui Xu, Wei Liu, Zhaofa Xu

Published in: Neurotoxicity Research | Issue 2/2015

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.

Agency for Toxic Substances and Disease Registry (ATSDR) (2012) Toxicological profile for manganese. U.S. Department of Health and Human Services Public Health Service. http://www.atsdr.cdc.gov/toxprofiles/tp151.pdf. Accessed Sept 2012

Ateşşahin A, Karahan I, Yilmaz S et al (2003) The effect of manganese chloride on gentamicin-induced nephrotoxicity in rats. Pharmacol Res 48(6):637–642PubMedCrossRef

Barhoumi R, Faske J, Liu X, et al. (2004) Manganese potentiates lipopolysaccharide-induced expression of NOS2 in C6 glioma cells through mitochondrial-dependent activation of nuclear factor kappaB. Brain Res Mol Brain Res 122(2):167–179PubMedCrossRef

Bowman AB, Kwakye GF, Hernández H et al (2011) Role of manganese in neurodegenerative diseases. J Trace Elem Med Biol 25(4):191–203PubMedCentralPubMedCrossRef

Cordova FM, Aguiar AS Jr, Peres TV et al (2013) Manganese-exposed developing rats display motor deficits and striatal oxidative stress that are reversed by Trolox. Arch Toxicol 87(7):1231–1244PubMedCrossRef

Deng Y, Xu Z, Xu B et al (2009) The protective effect of riluzole on manganese caused disruption of glutamate-glutamine cycle in rats. Brain Res 1289:106–117PubMedCrossRef

Farina M, Avila DS, da Rocha JB et al (2013) Metals, oxidative stress and neurodegeneration: a focus on iron, manganese and mercury. Neurochem Int 62(5):575–594PubMedCentralPubMedCrossRef

Finkelstein MM, Jerrett M (2007) A study of the relationships between Parkinson’s disease and markers of traffic-derived and environmental manganese air pollution in two Canadian cities. Environ Res 104(3):420–432PubMedCrossRef

Food and Drug Administration (2005) Guidance for industry: estimating the maximum safe starting dose in initial clinical trials for therapeutics in adult healthy volunteers. Center for Drug Evaluation and Research (CDER), Rockville

Fu J, Woods CG, Yehuda-Shnaidman E et al (2010) Low-level arsenic impairs glucose-stimulated insulin secretion in pancreatic beta cells: involvement of cellular adaptive response to oxidative stress. Environ Health Perspect 118(6):864–870PubMedCentralPubMedCrossRef

Gorell JM, Johnson CC, Rybicki BA et al (1998) Occupational exposure to manganese, copper, lead, iron, mercury and zinc and the risk of Parkinson’s disease. Neurotoxicology 20(2–3):239–247

Gunter TE, Gavin CE, Aschner M et al (2006) Speciation of manganese in cells and mitochondria: a search for the proximal cause of manganese neurotoxicity. Neurotoxicology 27(5):765–776PubMedCrossRef

Jiang JK, Ma X, Wu QY et al (2014) Upregulation of mitochondrial protease HtrA2/Omi contributes to manganese-induced neuronal apoptosis in rat brain striatum. Neuroscience 268:169–179PubMedCrossRef

Jung KH, Hong SW, Zheng HM et al (2009) Melatonin downregulates nuclear erythroid 2-related factor 2 and nuclear factor-kappaB during prevention of oxidative liver injury in a dimethylnitrosamine model. J Pineal Res 47(2):173–183PubMedCrossRef

Jung KH, Hong SW, Zheng HM et al (2010) Melatonin ameliorates cerulein-induced pancreatitis by the modulation of nuclear erythroid 2-related factor 2 and nuclear factor-kappaB in rats. J Pineal Res 48(23):239–250PubMedCrossRef

Kern CH, Smith DR (2011) Preweaning Mn exposure leads to prolonged astrocyte activation and lasting effects on the dopaminergic system in adult male rats. Synapse 65(6):532–544PubMedCentralPubMedCrossRef

Kern CH, Smith DR. (2011) Preweaning Mn exposure leads to prolonged astrocyte activation and lasting effects on the dopaminergic system in adult male rats. Synapse 65(6): 532-544.Kilic U, Kilic E, Tuzcu Z et al (2013) Melatonin suppresses cisplatin-induced nephrotoxicity via activation of Nrf-2/HO-1 pathway. Nutr Metab (Lond) 10(1):7PubMedCentralCrossRef

Lee ES, Yin Z, Milatovic D et al (2009) Estrogen and tamoxifen protect against Mn-induced toxicity in rat cortical primary cultures of neurons and astrocytes. Toxicol Sci 110(1):156–167PubMedCentralPubMedCrossRef

Lin CH, Huang JY, Ching CH, et al (2008) Melatonin reduces the neuronal loss, downregulation of dopamine transporter, and upregulation of D2 receptor in rotenone-induced parkinsonian rats. J Pineal Res 44(2): 205-213

Liu Y, Zhang L, Zhang H et al (2012) Exogenous melatonin modulates apoptosis in the mouse brain induced by high-LET carbon ion irradiation. J Pineal Res 52(1):47–56PubMedCrossRef

Lowry OH, Rosebrough NJ, Farr AL et al (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193(1):265–275PubMed

Magesh S, Chen Y, Hu L (2012) Small molecule modulators of Keap1–Nrf2–ARE pathway as potential preventive and therapeutic agents. Med Res Rev 32(4):687–726PubMedCentralPubMedCrossRef

Milatovic D, Gupta RC, Yu Y (2011) Protective effects of antioxidants and anti-inflammatory agents against manganese-induced oxidative damage and neuronal injury. Toxicol Appl Pharmacol 256(3):219–226PubMedCentralPubMedCrossRef

Negi G, Kumar A, Sharma SS (2011) Melatonin modulates neuroinflammation and oxidative stress in experimental diabetic neuropathy: effects on NF-kappaB and Nrf2 cascades. J Pineal Res 50(2):124–131PubMed

Nguyen T, Nioi P, Pickett CB (2009) The Nrf2–antioxidant response element signaling pathway and its activation by oxidative stress. J Biol Chem 284(20):13291–13295PubMedCentralPubMedCrossRef

Normandin L, Hazell AS (2002) Manganese neurotoxicity: an update of pathophysiologic mechanisms. Metab Brain Dis 17(4):375–387PubMedCrossRef

Oszlánczi G, Vezér T, Sárközi L et al (2010) Functional neurotoxicity of Mn-containing nanoparticles in rats. Ecotoxicol Environ Saf 73(8):2004–2009PubMedCrossRef

Prabhakaran K, Ghosh D, Chapman GD et al (2008) Molecular mechanism of manganese exposure-induced dopaminergic toxicity. Brain Res Bull 76(4):361–367PubMedCrossRef

Reagan-Shaw S, Nihal M, Ahmad N (2008) Dose translation from animal to human studies revisited. Faseb J 22(3):659–661PubMedCrossRef

Reiter RJ (2000) Melatonin: lowering the high price of free radicals. News Physiol Sci 15:246–250PubMed

Settivari R, VanDuyn N, LeVora J (2013) The Nrf2/SKN-1-dependent glutathione S-transferase pi homologue GST-1 inhibits dopamine neuron degeneration in a Caenorhabditis elegans model of manganism. Neurotoxicology 38:51–60PubMedCentralPubMedCrossRef

Villalba M, Martínez-Serrano A, Börner C et al (1992) NMDA-induced increase in [Ca²⁺]_i and 45Ca²⁺ uptake in acutely dissociated brain cells derived from adult rats. Brain Res 570(1–2):347–353PubMedCrossRef

Wang Z, Ma C, Meng CJ et al (2012) Melatonin activates the Nrf2–ARE pathway when it protects against early brain injury in a subarachnoid hemorrhage model. J Pineal Res 53(2):129–137PubMedCrossRef

Woods CG, Fu J, Xue P, et al. (2009) Dose-dependent transitions in Nrf2-mediated adaptive response and related stress responses to hypochlorous acid in mouse macrophages. Toxicol Appl Pharmacol 238(1):27-36

Xu B, Wu SW, Lu CW et al (2013) Oxidative stress involvement in manganese-induced alpha-synuclein oligomerization in organotypic brain slice cultures. Toxicology 305:71–78PubMedCrossRef

Zhang F, Xu Z, Gao J et al (2008) In vitro effect of manganese chloride exposure on energy metabolism and oxidative damage of mitochondria isolated from rat brain. Environ Toxicol Pharmacol 26(2):232–236PubMedCrossRef

Zhao S, Zhang L, Xu Z et al (2013) Neurotoxic effects of iron overload under high glucose concentration. Neural Regen Res 8(36):3423PubMedCentralPubMed

Title: Melatonin Antagonizes Mn-Induced Oxidative Injury Through the Activation of Keap1–Nrf2–ARE Signaling Pathway in the Striatum of Mice
Authors: Yu Deng
Jiayu Zhu
Chao Mi
Bin Xu
Congcong Jiao
Yuehui Li
Donghui Xu
Wei Liu
Zhaofa Xu
Publication date: 01-02-2015
Publisher: Springer US
Published in: Neurotoxicity Research / Issue 2/2015
Print ISSN: 1029-8428
Electronic ISSN: 1476-3524
DOI: https://doi.org/10.1007/s12640-014-9489-5

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Melatonin Antagonizes Mn-Induced Oxidative Injury Through the Activation of Keap1–Nrf2–ARE Signaling Pathway in the Striatum of Mice

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 2/2015

A Comprehensive View of the Epigenetic Landscape. Part II: Histone Post-translational Modification, Nucleosome Level, and Chromatin Regulation by ncRNAs

Enhanced Aggressive Behaviour in a Mouse Model of Depression

N-Methyl-d-aspartate Preconditioning Prevents Quinolinic Acid-Induced Deregulation of Glutamate and Calcium Homeostasis in Mice Hippocampus

3,4-Dihydroxyphenylethanol Attenuates Spatio-Cognitive Deficits in an Alzheimer’s Disease Mouse Model: Modulation of the Molecular Signals in Neuronal Survival-Apoptotic Programs

Correlation Between Attenuation of Protein Disulfide Isomerase Activity Through S-Mercuration and Neurotoxicity Induced by Methylmercury

Evaluation of Levodopa and Carbidopa Antioxidant Activity in Normal Human Lymphocytes In Vitro: Implication for Oxidative Stress in Parkinson’s Disease