Skip to main content

Effect of Microglia Activation on Dopaminergic Neuronal Injury Induced by Manganese, and Its Possible Mechanism

Abstract

Manganese (Mn) is an essential trace element. It is known to have various functions, such as participating in enzymatic synthesis, and promoting hematopoiesis. On the other hand, it can cause toxic injury upon excess intake. However, toxic effects and its mechanism on glial cells are unclear. In the present study, we demonstrated that MnCl2 can activate microglia, and that this can cause dopaminergic neuronal injury. Investigation of the underlying mechanisms showed that inducible nitric oxide synthase (iNOS), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) was induced and highly expressed following Mn treatment. Moreover, pretreatment with S-methylisothiourea (SMT. iNOS inhibitor), Mn-induced iNOS expression and dopaminergic neuronal injury were partly reverse. Pretreatment with minocycline (microglia activation inhibitor), Mn-induced activation of microglia and dopaminergic neuronal injury was partly reverse. Taken together, our results showed that Mn can cause microglia activation, which can up-regulate the level of IL-1β, TNF-α and iNOS, and these inflammatory factors can cause dopaminergic neuronal injury. SMT and minocycline prevent Mn-induced dopaminergic neuronal injury.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Abbreviations

Mn:

Manganese

PD:

Parkinson’s disease

CNS:

Central nervous system

NO:

Nitric oxide

TNF-α:

Tumor necrosis factor-α

IL-1β:

Interleukin-1β

GM-CSF:

Granulocyte-macrophage colony-stimulating factor

SD-rats:

Sprague-Dawley rats

SMT:

S-methylisothiourea

TH:

Tyrosine hydroxylase

DMEM/F12:

Dulbecco’s modified eagle medium:Nutrient mixture F-12(Ham)(1:1)

FBS:

Fetal bovine serum

BSA:

Bovine serum albumin

iNOS:

Inducible nitric oxide synthase

IFN-γ:

Interferon gamma

SN:

Substantia nigra

References

  • Ambrosini E, Aloisi F (2004) Chemokines and glial cells: a complex network in the central nervous system. Neurochem Res 29:1017–1038

    PubMed  Article  CAS  Google Scholar 

  • Anantharam V, Kitazawa M, Wagner J, Kaul S, Kanthasamy AG (2002) Caspase-3-dependent proteolytic cleavage of protein kinase Cdelta is essential for oxidative stress-mediated dopaminergic cell death after exposure to methylcyclopentadienyl manganese tricarbonyl. J Neurosci 22:1738–1751

    PubMed  CAS  Google Scholar 

  • Anantharam V, Kitazawa M, Latchoumycandane C, Kanthasamy A, Kanthasamy AG (2004) Blockade of PKCdelta proteolytic activation by loss of function mutants rescues mesencephalic dopaminergic neurons from methylcyclopentadienyl manganese tricarbonyl (MMT)-induced apoptotic cell death. Ann N Y Acad Sci 1035:271–289

    PubMed  Article  CAS  Google Scholar 

  • Arvin KL, Han BH, Du Y, Lin SZ, Paul SM, Holtzman DM (2002) Minocycline markedly protects the neonatal brain against hypoxic-ischemic injury. Ann Neurol 52:54–61

    PubMed  Article  CAS  Google Scholar 

  • Braak H, Ghebremedhin E, Rub U, Bratzke H, Del Tredici K (2004) Stages in the development of Parkinson’s disease-related pathology. Cell Tissue Res 318:121–134

    PubMed  Article  Google Scholar 

  • Cai T, Yao T, Li Y, Chen Y, Du K, Chen J, Luo W (2007) Proteasome inhibition is associated with manganese-induced oxidative injury in PC12 cells. Brain Res 1185:359–365

    PubMed  Article  CAS  Google Scholar 

  • Frigo DE, Vigh KA, Struckhoff AP, Elliott S, Beckman BS, Burow ME, McLachlan JA (2005) Xenobiotic-induced TNF-alpha expression and apoptosis through the p38 MAPK signaling pathway. Toxicol Lett 155:227–238

    PubMed  Article  CAS  Google Scholar 

  • Hirata Y, Suzuno H, Tsuruta T, Oh-Hashi K, Kiuchi K (2008) The role of dopamine transporter in selective toxicity of manganese and rotenone. Toxicology 244:249–256

    PubMed  Article  CAS  Google Scholar 

  • Hunter CL, Bachman D, Granholm AC (2004) Minocycline prevents cholinergic loss in a mouse model of Down’s syndrome. Ann Neurol 56:675–688

    PubMed  Article  CAS  Google Scholar 

  • Iravani MM, Kashefi K, Mander P, Rose S, Jenner P (2002) Involvement of inducible nitric oxide synthase in inflammation-induced dopaminergic neurodegeneration. Neuroscience 110:49–58

    PubMed  Article  CAS  Google Scholar 

  • Kato S, Sugimura N, Nakashima K, Nishihara T, Kowashi Y (2005) Actinobacillus actinomycetemcomitans induces apoptosis in human monocytic THP-1 cells. J Med Microbiol 54:293–298

    PubMed  Article  CAS  Google Scholar 

  • Kitazawa M, Wagner JR, Kirby ML, Anantharam V, Kanthasamy AG (2002) Oxidative stress and mitochondrial-mediated apoptosis in dopaminergic cells exposed to methylcyclopentadienyl manganese tricarbonyl. J Pharmacol Exp Ther 302:26–35

    PubMed  Article  CAS  Google Scholar 

  • Lee YB, Nagai A, Kim SU (2002) Cytokines, chemokines, and cytokine receptors in human microglia. J Neurosci Res 69:94–103

    PubMed  Article  CAS  Google Scholar 

  • Li GJ, Zhao Q, Zheng W (2005) Alteration at translational but not transcriptional level of transferrin receptor expression following manganese exposure at the blood-CSF barrier in vitro. Toxicol Appl Pharmacol 205:188–200

    PubMed  Article  CAS  Google Scholar 

  • Liberatore GT, Jackson-Lewis V, Vukosavic S, Mandir AS, Vila M, McAuliffe WG, Dawson VL, Dawson TM, Przedborski S (1999) Inducible nitric oxide synthase stimulates dopaminergic neurodegeneration in the MPTP model of Parkinson disease. Nat Med 5:1403–1409

    PubMed  Article  CAS  Google Scholar 

  • Malthankar GV, White BK, Bhushan A, Daniels CK, Rodnick KJ, Lai JC (2004) Differential lowering by manganese treatment of activities of glycolytic and tricarboxylic acid (TCA) cycle enzymes investigated in neuroblastoma and astrocytoma cells is associated with manganese-induced cell death. Neurochem Res 29:709–717

    PubMed  Article  CAS  Google Scholar 

  • Ryu JK, Franciosi S, Sattayaprasert P, Kim SU, McLarnon JG (2004) Minocycline inhibits neuronal death and glial activation induced by beta-amyloid peptide in rat hippocampus. Glia 48:85–90

    PubMed  Article  Google Scholar 

  • Sagoo P, Chan G, Larkin DF, George AJ (2004) Inflammatory cytokines induce apoptosis of corneal endothelium through nitric oxide. Invest Ophthalmol Vis Sci 45:3964–3973

    PubMed  Article  Google Scholar 

  • Suk K (2004) Minocycline suppresses hypoxic activation of rodent microglia in culture. Neurosci Lett 366:167–171

    PubMed  Article  CAS  Google Scholar 

  • Tieu K, Ischiropoulos H, Przedborski S (2003) Nitric oxide and reactive oxygen species in Parkinson’s disease. IUBMB Life 55:329–335

    PubMed  Article  CAS  Google Scholar 

  • Tomas-Camardiel M, Rite I, Herrera AJ, de Pablos RM, Cano J, Machado A, Venero JL (2004) Minocycline reduces the lipopolysaccharide-induced inflammatory reaction, peroxynitrite-mediated nitration of proteins, disruption of the blood-brain barrier, and damage in the nigral dopaminergic system. Neurobiol Dis 16:190–201

    PubMed  Article  CAS  Google Scholar 

  • van Rossum D, Hanisch UK (2004) Microglia. Metab Brain Dis 19:393–411

    PubMed  Article  Google Scholar 

  • Vilhardt F (2005) Microglia: phagocyte and glia cell. Int J Biochem Cell Biol 37:17–21

    PubMed  Article  CAS  Google Scholar 

  • Wada O, Yanagisawa H (1996) Trace elements and their physiological roles. Nippon Rinsho 54:5–11

    PubMed  CAS  Google Scholar 

  • Wang X, Zhu S, Drozda M, Zhang W, Stavrovskaya IG, Cattaneo E, Ferrante RJ, Kristal BS, Friedlander RM (2003) Minocycline inhibits caspase-independent and -dependent mitochondrial cell death pathways in models of Huntington’s disease. Proc Natl Acad Sci USA 100:10483–10487

    PubMed  Article  CAS  Google Scholar 

  • Wu DC, Jackson-Lewis V, Vila M, Tieu K, Teismann P, Vadseth C, Choi DK, Ischiropoulos H, Przedborski S (2002) Blockade of microglial activation is neuroprotective in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson disease. J Neurosci 22:1763–1771

    PubMed  CAS  Google Scholar 

  • Yrjanheikki J, Keinanen R, Pellikka M, Hokfelt T, Koistinaho J (1998) Tetracyclines inhibit microglial activation and are neuroprotective in global brain ischemia. Proc Natl Acad Sci USA 95:15769–15774

    PubMed  Article  CAS  Google Scholar 

  • Yrjanheikki J, Tikka T, Keinanen R, Goldsteins G, Chan PH, Koistinaho J (1999) A tetracycline derivative, minocycline, reduces inflammation and protects against focal cerebral ischemia with a wide therapeutic window. Proc Natl Acad Sci USA 96:13496–13500

    PubMed  Article  CAS  Google Scholar 

  • Zeevalk GD, Bernard LP (2005) Energy status, ubiquitin proteasomal function, and oxidative stress during chronic and acute complex I inhibition with rotenone in mesencephalic cultures. Antioxid Redox Signal 7:662–672

    PubMed  Article  CAS  Google Scholar 

  • Zeevalk GD, Bernard LP, Nicklas WJ (1998) Role of oxidative stress and the glutathione system in loss of dopamine neurons due to impairment of energy metabolism. J Neurochem 70:1421–1430

    PubMed  CAS  Article  Google Scholar 

  • Zhang J, Fitsanakis VA, Gu G, Jing D, Ao M, Amarnath V, Montine TJ (2003) Manganese ethylene-bis-dithiocarbamate and selective dopaminergic neurodegeneration in rat: a link through mitochondrial dysfunction. J Neurochem 84:336–346

    PubMed  Article  CAS  Google Scholar 

  • Zheng W, Ren S, Graziano JH (1998) Manganese inhibits mitochondrial aconitase: a mechanism of manganese neurotoxicity. Brain Res 799:334–342

    PubMed  Article  CAS  Google Scholar 

Download references

Acknowledgment

This work was supported by National Natural Science Foundation of China Grant #30571545 (WL), #30471434 (WL), and #30771768 (JC).

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Wenjing Luo or Jingyuan Chen.

Additional information

Mingchao Liu and Tongjian Cai contributed equally to this work.

Electronic supplementary material

Below is the link to the electronic supplementary material.

(TIF 696 kb)

(TIF 172 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Liu, M., Cai, T., Zhao, F. et al. Effect of Microglia Activation on Dopaminergic Neuronal Injury Induced by Manganese, and Its Possible Mechanism. Neurotox Res 16, 42–49 (2009). https://doi.org/10.1007/s12640-009-9045-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12640-009-9045-x

Keywords

  • Manganese
  • Microglia
  • Dopaminergic neuron
  • Inducible nitric oxide synthase
  • Tumor necrosis factor-α
  • Interleukin-1β