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Journal of Molecular Neuroscience

, Volume 64, Issue 4, pp 543–550 | Cite as

Differential Expression of Klotho in the Brain and Spinal Cord is Associated with Total Antioxidant Capacity in Mice with Experimental Autoimmune Encephalomyelitis

  • Mohammad Sajad Emami Aleagha
  • Mohammad Hossein Harirchian
  • Shahram Lavasani
  • Mohammad Javan
  • Abdolamir Allameh
Article

Abstract

Recently, we reported a positive correlation between Klotho, as an anti-aging protein, and the total antioxidant capacity (TAC) in cerebrospinal fluid (CSF) of multiple sclerosis (MS) patients. However, there is no information about the Klotho and TAC changes within the central nervous system (CNS). Thus, the current study aimed to employ an experimental autoimmune encephalomyelitis (EAE) model in C57BL/6 mice using MOG35–55 peptide to examine the relationship between Klotho and TAC within the CNS. To this end, the brain and spinal cord were obtained at the onset and peak stages of EAE as well as non-EAE mice (sham/control groups). The Klotho expression was assessed in the brain and spinal cord of different experimental groups at mRNA (qPCR) and protein (ELISA) levels. Also, TAC level was determined in the tissues of different experimental groups. The results showed that Klotho expression in the brain at the onset and peak stages of EAE were significantly lower than that in non-EAE mice. Conversely, Klotho expression in the spinal cord at the onset of EAE was significantly higher than that of non-EAE mice, while Klotho was comparable at the peak stage of EAE and non-EAE mice. The pattern of TAC alteration in the brain and spinal cord of EAE mice was similar to that of Klotho expression. In conclusion, for the first time, this study demonstrated a significant positive correlation between Klotho and TAC changes during the pathogenesis of EAE. It is suggested that Klotho may have neuroprotective activity through the regulation of redox system.

Keywords

Klotho Experimental Autoimmune Encephalomyelitis (EAE) Total Antioxidant Capacity (TAC) Brain Spinal cord 

Notes

Acknowledgements

This study was financially supported by a research grant (number 962470) provided by NIMAD (National Institute for Medical Research Development), Ministry of Health and Medical Education, Islamic Republic of Iran. Technical advice and support of the Ideal Tashkhis Atieh Company (Tehran, Iran) for immunoassays is acknowledged. The authors also wish to thank Dr. Shahab Moradkhani who assisted in the proof-reading of the revised version of this manuscript.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

References

  1. Ahmadi M, Aleagha MSE, Harirchian MH, Yarani R, Tavakoli F, Siroos B (2016) Multiple sclerosis influences on the augmentation of serum Klotho concentration. J Neurol Sci 362:69–72CrossRefPubMedGoogle Scholar
  2. Aleagha MSE, Siroos B, Ahmadi M, Balood M, Palangi A, Haghighi AN, Harirchian MH (2015) Decreased concentration of Klotho in the cerebrospinal fluid of patients with relapsing–remitting multiple sclerosis. J Neuroimmunol 281:5–8CrossRefGoogle Scholar
  3. Balasubramanian P, Longo VD (2010) Linking Klotho, Nrf2, MAP kinases and aging. Aging (Albany NY) 2(10):632–633CrossRefGoogle Scholar
  4. Benzie IF, Strain JJ (1996) The ferric reducing ability of plasma (FRAP) as a measure of “antioxidant power”: the FRAP assay. Anal Biochem 239(1):70–76CrossRefPubMedGoogle Scholar
  5. Bernardes D, Oliveira-Lima OC, da Silva TV, Faraco CCF, Leite HR, Juliano MA et al (2013) Differential brain and spinal cord cytokine and BDNF levels in experimental autoimmune encephalomyelitis are modulated by prior and regular exercise. J Neuroimmunol 264(1):24–34CrossRefPubMedGoogle Scholar
  6. Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72(1–2):248–254CrossRefPubMedGoogle Scholar
  7. Cararo-Lopes MM, Mazucanti CHY, Scavone C, Kawamoto EM, Berwick DC (2017) The relevance of α-KLOTHO to the central nervous system: some key questions. Ageing Res Rev 36:137–148CrossRefPubMedGoogle Scholar
  8. Chen C-D, Sloane JA, Li H, Aytan N, Giannaris EL, Zeldich E, Bansal R (2013) The antiaging protein Klotho enhances oligodendrocyte maturation and myelination of the CNS. J Neurosci 33(5):1927–1939CrossRefPubMedPubMedCentralGoogle Scholar
  9. Christy AL, Walker ME, Hessner MJ, Brown MA (2013) Mast cell activation and neutrophil recruitment promotes early and robust inflammation in the meninges in EAE. J Autoimmun 42:50–61CrossRefPubMedGoogle Scholar
  10. Gilgun-Sherki Y, Melamed E, Offen D (2004) The role of oxidative stress in the pathogenesis of multiple sclerosis: the need for effective antioxidant therapy. J Neurol 251(3):261–268CrossRefPubMedGoogle Scholar
  11. Grigoriadis N, Pesch V (2015) A basic overview of multiple sclerosis immunopathology. Eur J Neurol 22(S2):3–13CrossRefPubMedGoogle Scholar
  12. Imura A, Iwano A, Tohyama O, Tsuji Y, Nozaki K, Hashimoto N et al (2004) Secreted Klotho protein in sera and CSF: implication for post-translational cleavage in release of Klotho protein from cell membrane. FEBS Lett 565(1–3):143–147CrossRefPubMedGoogle Scholar
  13. Karami M, Mehrabi F, Allameh A, Kakhki MP, Amiri M, Aleagha MSE (2017) Klotho gene expression decreases in peripheral blood mononuclear cells (PBMCs) of patients with relapsing-remitting multiple sclerosis. J Neurol Sci 381:305–307CrossRefPubMedGoogle Scholar
  14. Kuerten S, Kostova-Bales DA, Frenzel LP, Tigno JT, Tary-Lehmann M, Angelov DN, Lehmann PV (2007) MP4-and MOG: 35–55-induced EAE in C57BL/6 mice differentially targets brain, spinal cord and cerebellum. J Neuroimmunol 189(1):31–40CrossRefPubMedPubMedCentralGoogle Scholar
  15. Kuerten S, Javeri S, Tary-Lehmann M, Lehmann PV, Angelov DN (2008) Fundamental differences in the dynamics of CNS lesion development and composition in MP4-and MOG peptide 35–55-induced experimental autoimmune encephalomyelitis. Clin Immunol 129(2):256–267CrossRefPubMedPubMedCentralGoogle Scholar
  16. Kuro-o M (2008) Klotho as a regulator of oxidative stress and senescence. Biol Chem 389(3):233–241CrossRefPubMedGoogle Scholar
  17. Kuro-o M, Matsumura Y, Aizawa H, Kawaguchi H, Suga T, Utsugi T et al (1997) Mutation of the mouse Klotho gene leads to a syndrome resembling ageing. Nature 390(6655):45–51CrossRefPubMedGoogle Scholar
  18. Li S-A, Watanabe M, Yamada H, Nagai A, Kinuta M, Takei K (2004) Immunohistochemical localization of Klotho protein in brain, kidney, and reproductive organs of mice. Cell Struct Funct 29(4):91–99CrossRefPubMedGoogle Scholar
  19. Maekawa Y, Ishikawa K, Yasuda O, Oguro R, Hanasaki H, Kida I et al (2009) Klotho suppresses TNF-α-induced expression of adhesion molecules in the endothelium and attenuates NF-κB activation. Endocrine 35(3):341–346CrossRefPubMedGoogle Scholar
  20. Maltese G, Psefteli PM, Rizzo B, Srivastava S, Gnudi L, Mann GE, Siow R (2017) The anti-ageing hormone Klotho induces Nrf2-mediated antioxidant defences in human aortic smooth muscle cells. J Cell Mol Med 21(3):621–627CrossRefPubMedGoogle Scholar
  21. Marques F, Mesquita SD, Sousa JC, Coppola G, Gao F, Geschwind DH et al (2012) Lipocalin 2 is present in the EAE brain and is modulated by natalizumab. Front Cell Neurosci 6:33CrossRefPubMedPubMedCentralGoogle Scholar
  22. Moreno JA, Izquierdo MC, Sanchez-Niño MD, Suárez-Alvarez B, Lopez-Larrea C, Jakubowski A et al (2011) The inflammatory cytokines TWEAK and TNFα reduce renal Klotho expression through NFκB. J Am Soc Nephrol 22(7):1315–1325CrossRefPubMedPubMedCentralGoogle Scholar
  23. Nagai T, Yamada K, Kim H-C, Kim Y-S, Noda Y, Imura A et al (2003) Cognition impairment in the genetic model of aging Klotho gene mutant mice: a role of oxidative stress. FASEB J 17(1):50–52CrossRefPubMedGoogle Scholar
  24. Rüther BJ, Scheld M, Dreymueller D, Clarner T, Kress E, Brandenburg LO, Fallier-Becker P (2017) Combination of cuprizone and experimental autoimmune encephalomyelitis to study inflammatory brain lesion formation and progression. Glia 65(12):1900–1913CrossRefPubMedGoogle Scholar
  25. Simmons SB, Liggitt D, Goverman JM (2014) Cytokine-regulated neutrophil recruitment is required for brain but not spinal cord inflammation during experimental autoimmune encephalomyelitis. J Immunol 193(2):555–563CrossRefPubMedPubMedCentralGoogle Scholar
  26. Steinman L (1996) Multiple sclerosis: a coordinated immunological attack against myelin in the central nervous system. Cell 85(3):299–302CrossRefPubMedGoogle Scholar
  27. Teocchi MA, Ferreira AÉD, de Oliveira EPDL, Tedeschi H, D’Souza-Li L (2013) Hippocampal gene expression dysregulation of Klotho, nuclear factor kappa B and tumor necrosis factor in temporal lobe epilepsy patients. J Neuroinflammation 10(1):53CrossRefPubMedPubMedCentralGoogle Scholar
  28. Thurston RD, Larmonier CB, Majewski PM, Ramalingam R, Midura-Kiela M, Laubitz D et al (2010) Tumor necrosis factor and interferon-γ down-regulate Klotho in mice with colitis. Gastroenterology 138(4):1384–1394 e1382CrossRefPubMedGoogle Scholar
  29. Witkowski JM, Soroczyńska-Cybula M, Bryl E, Smoleńska Ż, Jóźwik A (2007) Klotho—a common link in physiological and rheumatoid arthritis-related aging of human CD4+ lymphocytes. J Immunol 178(2):771–777CrossRefPubMedGoogle Scholar
  30. Yao SQ, Li ZZ, Huang QY, Li F, Wang ZW, Augusto E, Zheng RY (2012) Genetic inactivation of the adenosine A2A receptor exacerbates brain damage in mice with experimental autoimmune encephalomyelitis. J Neurochem 123(1):100–112CrossRefPubMedGoogle Scholar
  31. Zargari M, Allameh A, Sanati MH, Tiraihi T, Lavasani S, Emadyan O (2007) Relationship between the clinical scoring and demyelination in central nervous system with total antioxidant capacity of plasma during experimental autoimmune encephalomyelitis development in mice. Neurosci Lett 412(1):24–28CrossRefPubMedGoogle Scholar
  32. Zeldich E, Chen C-D, Colvin TA, Bove-Fenderson EA, Liang J, Zhou TBT et al (2014) The neuroprotective effect of Klotho is mediated via regulation of members of the redox system. J Biol Chem 289(35):24700–24715CrossRefPubMedPubMedCentralGoogle Scholar
  33. Zeldich E, Chen C-D, Avila R, Medicetty S, Abraham CR (2015) The anti-aging protein Klotho enhances remyelination following cuprizone-induced demyelination. J Mol Neurosci 57(2):185–196CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Clinical Biochemistry, Faculty of Medical SciencesTarbiat Modares UniversityTehranIran
  2. 2.Iranian Center of Neurological Research, Neuroscience Institute, Imam Khomeini Hospital ComplexTehran University of Medical SciencesTehranIran
  3. 3.Department of BiologyLundSweden
  4. 4.Department of Physiology, Faculty of Medical SciencesTarbiat Modares UniversityTehranIran

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