Manganese (Mn) is an essential element that is required in trace amount for normal growth, development as well maintenance of proper function and regulation of numerous cellular and biochemical reactions. Yet, excessive Mn brain accumulation upon chronic exposure to occupational or environmental sources of this metal may lead to a neurodegenerative disorder known as manganism, which shares similar symptoms with idiopathic Parkinson’s disease (PD). In recent years, Mn exposure has gained public health interest for two primary reasons: continuous increased usage of Mn in various industries, and experimental findings on its toxicity, linking it to a number of neurological disorders. Since the first report on manganism nearly two centuries ago, there have been substantial advances in the understanding of mechanisms associated with Mn-induced neurotoxicity. This review will briefly highlight various aspects of Mn neurotoxicity with a focus on the role of astrocytic glutamate transporters in triggering its pathophysiology.

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• Sex-specific associations of a ferroalloy metal mixture with motor function in Italian adolescents
  Alexa Friedman, Samantha Schildroth, Victoria Fruh, Maxine H. Krengel, Yorghos Tripodis, Donatella Placidi, Roberta F. White, Roberto G. Lucchini, Donald R. Smith, Robert O. Wright, Megan K. Horton, Birgit Claus Henn
  Environmental Epidemiology.2024; 8(4): e321.     CrossRef
• Astrocyte dysregulation as an epileptogenic factor: a systematic review
  Komang Trisna Sumadewi, Bryan Gervais de Liyis, Ni Made Linawati, I Putu Eka Widyadharma, I Nyoman Mantik Astawa
  The Egyptian Journal of Neurology, Psychiatry and Neurosurgery.2024;[Epub]     CrossRef
• Lactational Exposure of Human Infants to Metal (loid)s: A Comparison of Industrial and Urban Inhabitants in North of the Persian Gulf
  Leila Amiri, Atefeh Khalili Doroodzani, Afshin Ostovar, Sina Dobaradaran, Azam Mohammadi, Iraj Nabipour, Alireza Raeisi, Hasan Malekizadeh, Akram Farhadi, Reza Saeedi, Sima Afrashteh, Shahrokh Nazmara, Mozhgan Keshtkar
  Biological Trace Element Research.2024; 202(5): 1829.     CrossRef
• Pathogenesis and management of multiple sclerosis revisited
  Abhi Shah, Viraj Panchal, Kashyap Patel, Zainab Alimohamed, Nirja Kaka, Yashendra Sethi, Neil Patel
  Disease-a-Month.2023; 69(9): 101497.     CrossRef
• Structures and coordination chemistry of transporters involved in manganese and iron homeostasis
  Shamayeeta Ray, Rachelle Gaudet
  Biochemical Society Transactions.2023; 51(3): 897.     CrossRef
• The role of excitatory amino acid transporter 2 (EAAT2) in epilepsy and other neurological disorders
  Sahar Alijanpour, Mohammad Miryounesi, Soudeh Ghafouri-Fard
  Metabolic Brain Disease.2023; 38(1): 1.     CrossRef
• Transcranial direct current stimulation ameliorates motor and cognitive functions by regulating neuronal excitotoxicity in experimental Parkinson’s disease model
  Güven AKÇAY, Serhan TAMERER
  Cukurova Medical Journal.2023; 48(3): 919.     CrossRef
• Effects of Chronic Hydrocodone Exposure and Ceftriaxone on the Expression of Astrocytic Glutamate Transporters in Mesocorticolimbic Brain Regions of C57/BL Mice
  Woonyen Wong, Youssef Sari
  Toxics.2023; 11(10): 870.     CrossRef
• Upregulation of glutamate transporter 1 by mTOR/Akt pathway in astrocyte culture during oxygen–glucose deprivation and reoxygenation
  Mi Li, Jingmei Yu, Huan Deng, Shansha Xie, Qiuling Li, Yuping Zhao, Shubin Yin, Yi-Fei Ji
  Experimental Brain Research.2023; 241(1): 201.     CrossRef
• Munc18-1 Contributes to Hippocampal Injury in Septic Rats Through Regulation of Syntanxin1A and Synaptophysin and Glutamate Levels
  Fajuan Tang, Lin Chen, Hu Gao, Yupeng Lei, Linli Pan, Dongqiong Xiao, Xihong Li
  Neurochemical Research.2023; 48(3): 791.     CrossRef
• Comparative analysis of astrocytes in the prefrontal cortex of primates: Insights into the evolution of human brain energetics
  Emily L. Munger, Melissa K. Edler, William D. Hopkins, Patrick R. Hof, Chet C. Sherwood, Mary Ann Raghanti
  Journal of Comparative Neurology.2022; 530(18): 3106.     CrossRef
• Ultrasmall Fe@Fe3O4 nanoparticles as T1–T2 dual-mode MRI contrast agents for targeted tumor imaging
  Donglin Liu, Jiaojiao Li, Chengbin Wang, Lu An, Jiaomin Lin, Qiwei Tian, Shiping Yang
  Nanomedicine: Nanotechnology, Biology and Medicine.2021; 32: 102335.     CrossRef
• Effects of Pentoxifylline in a Rat Model of Manganism: Evaluation of the Possible Toxicity
  Romina Tanideh, Omid Farshad, Akram Jamshidzadeh, Aida Iraji, Murat Senturk
  Journal of Chemistry.2021; 2021: 1.     CrossRef
• Exercise increases striatal Glu reuptake and improves motor dysfunction in 6-OHDA-induced Parkinson’s disease rats
  Yan Feng, Shifang Zhou, Jian Sun
  Experimental Brain Research.2021; 239(11): 3277.     CrossRef
• Single step nanospray drying preparation technique of gabapentin-loaded nanoparticles-mediated brain delivery for effective treatment of PTZ-induced seizures
  Alaa H. Salama, Abeer A.A. Salama, Mona Elhabak
  International Journal of Pharmaceutics.2021; 602: 120604.     CrossRef
• Micellar buccal film for safe and effective control of seizures: Preparation, in vitro characterization, ex vivo permeation studies and in vivo assessment
  Alaa H. Salama, Mona Basha, Abeer A.A. Salama
  European Journal of Pharmaceutical Sciences.2021; 166: 105978.     CrossRef
• Magnetic Nanoparticles in Cancer Therapy and Diagnosis
  Ali Farzin, Seyed Alireza Etesami, Jacob Quint, Adnan Memic, Ali Tamayol
  Advanced Healthcare Materials.2020;[Epub]     CrossRef
• Associations between manganese exposure and multiple immunological parameters in manganese-exposed workers healthy cohort
  Xiang Chen, Zhenfang Liu, Xiaoting Ge, Xiaoyu Luo, Sifang Huang, Yanting Zhou, Defu Li, Hong Cheng, Longman Li, Lulu Huang, Qingzhi Hou, Gaohui Zan, Yanli Tan, Chaoqun Liu, Yunfeng Zou, Xiaobo Yang
  Journal of Trace Elements in Medicine and Biology.2020; 59: 126454.     CrossRef
• Glutamate Transporters (EAAT-1–3) as a Factor in the Pathogenesis and a Potential Therapeutic Target in Epilepsy
  I. V. Smolensky, S. V. Ovsepian, A. V. Zaitsev
  Neuroscience and Behavioral Physiology.2020; 50(6): 777.     CrossRef
• Sodium Para-aminosalicylic Acid Reverses Changes of Glutamate Turnover in Manganese-Exposed Rats
  Zhao-Cong Li, Fang Wang, Shao-Jun Li, Lin Zhao, Jun-Yan Li, Yue Deng, Xiao-Juan Zhu, Yu-Wen Zhang, Dong-Jie Peng, Yue-Ming Jiang
  Biological Trace Element Research.2020; 197(2): 544.     CrossRef
• 6-OHDA ile Oluşturulan Parkinson Hastalığı Modelinde Astrogliozis ve Glutamat Taşıyıcı Protein GLT1 Ekspresyonu
  Zehra MİNBAY, Bülent GÖREN, Özhan EYİGÖR
  Uludağ Üniversitesi Tıp Fakültesi Dergisi.2020; 46(3): 385.     CrossRef
• Dysregulation of TFEB contributes to manganese-induced autophagic failure and mitochondrial dysfunction in astrocytes
  Ziyan Zhang, Jingqi Yan, Aaron B. Bowman, Miles R. Bryan, Rajat Singh, Michael Aschner
  Autophagy.2020; 16(8): 1506.     CrossRef
• Neurobiology, Functions, and Relevance of Excitatory Amino Acid Transporters (EAATs) to Treatment of Refractory Epilepsy
  Aleksey V. Zaitsev, Ilya V. Smolensky, Pascal Jorratt, Saak V. Ovsepian
  CNS Drugs.2020; 34(11): 1089.     CrossRef
• Dietary Intake and Urinary Excretion of Manganese in Korean Healthy Adults
  Mi-Kyeong Choi, Yun Jung Bae
  Biological Trace Element Research.2020; 196(2): 384.     CrossRef
• Ceftriaxone Treatment Affects EAAT2 Expression and Glutamatergic Neurotransmission and Exerts a Weak Anticonvulsant Effect in Young Rats
  Aleksey V. Zaitsev, Sergey L. Malkin, Tatyana Y. Postnikova, Ilya V. Smolensky, Olga E. Zubareva, Irina V. Romanova, Maria V. Zakharova, Vladimir B. Karyakin, Vladimir Zavyalov
  International Journal of Molecular Sciences.2019; 20(23): 5852.     CrossRef
• Brain mitochondria as potential therapeutic targets for managing hepatic encephalopathy
  Reza Heidari
  Life Sciences.2019; 218: 65.     CrossRef
• Role of Astrocytes in Manganese Neurotoxicity Revisited
  Tao Ke, Marta Sidoryk-Wegrzynowicz, Edward Pajarillo, Asha Rizor, Félix Alexandre Antunes Soares, Eunsook Lee, Michael Aschner
  Neurochemical Research.2019; 44(11): 2449.     CrossRef
• The role of zinc, copper, manganese and iron in neurodegenerative diseases
  Leda Mezzaroba, Daniela Frizon Alfieri, Andrea Name Colado Simão, Edna Maria Vissoci Reiche
  NeuroToxicology.2019; 74: 230.     CrossRef
• The role of astrocytic glutamate transporters GLT-1 and GLAST in neurological disorders: Potential targets for neurotherapeutics
  Edward Pajarillo, Asha Rizor, Jayden Lee, Michael Aschner, Eunsook Lee
  Neuropharmacology.2019; 161: 107559.     CrossRef
• Association of circulating manganese levels with Parkinson’s disease: A meta-analysis
  Ke Du, Ming-Yan Liu, Yan-Zhu Pan, Xin Zhong, Min-Jie Wei
  Neuroscience Letters.2018; 665: 92.     CrossRef
• Synthesis and characterization of [Mn(phen)(H 2 O) 4 ]·SO 4 ·2H 2 O
  Ibanphylla Syiemlieh, Arvind Kumar, Sunshine D. Kurbah, Ram A. Lal
  Journal of Molecular Structure.2018; 1166: 102.     CrossRef
• Manganese exposure induces neuroinflammation by impairing mitochondrial dynamics in astrocytes
  Souvarish Sarkar, Emir Malovic, Dilshan S. Harischandra, Hilary A. Ngwa, Anamitra Ghosh, Colleen Hogan, Dharmin Rokad, Gary Zenitsky, Huajun Jin, Vellareddy Anantharam, Anumantha G. Kanthasamy, Arthi Kanthasamy
  NeuroToxicology.2018; 64: 204.     CrossRef
• The Impact of Environmental Mn Exposure on Insect Biology
  Yehuda Ben-Shahar
  Frontiers in Genetics.2018;[Epub]     CrossRef
• Assessment of gender and age effects on serum and hair trace element levels in children with autism spectrum disorder
  Anatoly V. Skalny, Natalia V. Simashkova, Anastasia A. Skalnaya, Tatiana P. Klyushnik, Geir Bjørklund, Margarita G. Skalnaya, Alexey A. Tinkov
  Metabolic Brain Disease.2017; 32(5): 1675.     CrossRef
• Cellular Fates of Manganese(II) Pentaazamacrocyclic Superoxide Dismutase (SOD) Mimetics: Fluorescently Labeled MnSOD Mimetics, X-ray Absorption Spectroscopy, and X-ray Fluorescence Microscopy Studies
  Claire M. Weekley, Isabell Kenkel, Rainer Lippert, Shengwei Wei, Dominik Lieb, Tiffanny Cranwell, Jason L. Wedding, Annika S. Zillmann, Robin Rohr, Milos R. Filipovic, Ivana Ivanović-Burmazović, Hugh H. Harris
  Inorganic Chemistry.2017; 56(11): 6076.     CrossRef
• Health status of male steel workers at an electric arc furnace (EAF) in Trentino, Italy
  Roberto Cappelletti, Marcello Ceppi, Justina Claudatus, Valerio Gennaro
  Journal of Occupational Medicine and Toxicology.2016;[Epub]     CrossRef
• Biochemical and ecophysiological responses to manganese stress by ectomycorrhizal fungus Pisolithus tinctorius and in association with Eucalyptus grandis
  Gabriela C. Canton, Amanda A. Bertolazi, Antônio J. D. Cogo, Frederico Jacob Eutrópio, Juliana Melo, Sávio Bastos de Souza, Cesar A. Krohling, Eliemar Campostrini, Ary Gomes da Silva, Arnoldo R. Façanha, Nuno Sepúlveda, Cristina Cruz, Alessandro C. Ramos
  Mycorrhiza.2016; 26(5): 475.     CrossRef
• Null allele mutants of trt-1 , the catalytic subunit of telomerase in Caenorhabditis elegans , are less sensitive to Mn-induced toxicity and DAergic degeneration
  Omamuyovwi M. Ijomone, Mahfuzur R. Miah, Tanara V. Peres, Polycarp U. Nwoha, Michael Aschner
  NeuroToxicology.2016; 57: 54.     CrossRef
• Iron Oxide Based Nanoparticles for Multimodal Imaging and Magnetoresponsive Therapy
  Nohyun Lee, Dongwon Yoo, Daishun Ling, Mi Hyeon Cho, Taeghwan Hyeon, Jinwoo Cheon
  Chemical Reviews.2015; 115(19): 10637.     CrossRef
• Changes in Brain Metallome/Metabolome Pattern due to a Single i.v. Injection of Manganese in Rats
  Katharina Neth, Marianna Lucio, Alesia Walker, Julia Zorn, Philippe Schmitt-Kopplin, Bernhard Michalke, Fanis Missirlis
  PLOS ONE.2015; 10(9): e0138270.     CrossRef
• Manganese-induced neurotoxicity: from C. elegans to humans
  Pan Chen, Sudipta Chakraborty, Tanara V. Peres, Aaron B. Bowman, Michael Aschner
  Toxicology Research.2015; 4(2): 191.     CrossRef
• Complex liaisons moving forward the Parkinson’s disease? An appraisal
  Graziella Rubino
  Basal Ganglia.2015; 5(4): 77.     CrossRef
• α-Synuclein Protects Against Manganese Neurotoxic Insult During the Early Stages of Exposure in a Dopaminergic Cell Model of Parkinson’s Disease
  Dilshan S. Harischandra, Huajun Jin, Vellareddy Anantharam, Arthi Kanthasamy, Anumantha G. Kanthasamy
  Toxicological Sciences.2015; 143(2): 454.     CrossRef
• Effects of developmental exposure to manganese and/or low iron diet: Changes to metal transporters, sucrose preference, elevated zero-maze, open-field, and locomotion in response to fenfluramine, amphetamine, and MK-801
  Robyn M. Amos-Kroohs, Colin P. Bloor, Momina A. Qureshi, Charles V. Vorhees, Michael T. Williams
  Toxicology Reports.2015; 2: 1046.     CrossRef
• Is it possible to enhance the organism’s resistance to toxic effects of metallic nanoparticles?
  Boris A. Katsnelson, Larisa I. Privalova, Marina P. Sutunkova, Ilzira A. Minigalieva, Vladimir B. Gurvich, Vladimir Y. Shur, Oleg H. Makeyev, Irina E. Valamina, Ekaterina V. Grigoryeva
  Toxicology.2015; 337: 79.     CrossRef
• Silymarin as a Natural Antioxidant: An Overview of the Current Evidence and Perspectives
  Peter Surai
  Antioxidants.2015; 4(1): 204.     CrossRef
• Attenuation of Combined Nickel(II) Oxide and Manganese(II, III) Oxide Nanoparticles’ Adverse Effects with a Complex of Bioprotectors
  Ilzira Minigalieva, Boris Katsnelson, Larisa Privalova, Marina Sutunkova, Vladimir Gurvich, Vladimir Shur, Ekaterina Shishkina, Irene Valamina, Oleg Makeyev, Vladimir Panov, Anatoly Varaksin, Ekaterina Grigoryeva, Ekaterina Meshtcheryakova
  International Journal of Molecular Sciences.2015; 16(9): 22555.     CrossRef
• Blood Metal Concentrations of Manganese, Lead, and Cadmium in Relation to Serum Ferritin Levels in Ohio Residents
  Yangho Kim, Danelle T. Lobdell, Chris W. Wright, Vihra V. Gocheva, Edward Hudgens, Rosemarie M. Bowler
  Biological Trace Element Research.2015; 165(1): 1.     CrossRef
• Neutron Activation Analysis of Scalp Hair from ALS Patients and Residents in the Kii Peninsula, Japan
  Tameko Kihira, Iori Sakurai, Sohei Yoshida, Ikuro Wakayama, Koichi Takamiya, Ryo Okumura, Yuhto Iinuma, Keiko Iwai, Yoshinori Kajimoto, Yasuhiro Hiwatani, Junko Kohmoto, Kazushi Okamoto, Yasumasa Kokubo, Shigeki Kuzuhara
  Biological Trace Element Research.2015; 164(1): 36.     CrossRef
• Correlation between the biochemical pathways altered by mutated parkinson-related genes and chronic exposure to manganese
  Jerome A. Roth
  NeuroToxicology.2014; 44: 314.     CrossRef
• Iron Deficiency is Not Associated with Increased Blood Cadmium in Infants
  Jung-Hun Park, Sangkyu Park, Yangho Kim
  Annals of Occupational and Environmental Medicine.2014;[Epub]     CrossRef
• Manganese leads to an increase in markers of oxidative stress as well as to a shift in the ratio of Fe(ii)/(iii) in rat brain tissue
  Katharina Fernsebner, Julia Zorn, Basem Kanawati, Alesia Walker, Bernhard Michalke
  Metallomics.2014; 6(4): 921.     CrossRef
• Iron deficiency increases blood concentrations of neurotoxic metals in children
  Yangho Kim, Sangkyu Park
  Korean Journal of Pediatrics.2014; 57(8): 345.     CrossRef
• Sex-specific Profiles of Blood Metal Levels Associated with Metal–Iron Interactions
  Byung-Kook Lee, Yangho Kim
  Safety and Health at Work.2014; 5(3): 113.     CrossRef
• Blood Manganese Concentration is Elevated in Infants with Iron Deficiency
  Sangkyu Park, Chang-Sun Sim, Heun Lee, Yangho Kim
  Biological Trace Element Research.2013; 155(2): 184.     CrossRef