Skip to main content
SpringerLink
Log in

Oligoprotective effect of metformin through the AMPK-dependent on restoration of mitochondrial hemostasis in the cuprizone-induced multiple sclerosis model

  • Original Paper
  • Published:
Journal of Molecular Histology Aims and scope Submit manuscript

Abstract

Oxidative stress with mitochondrial defects has a central role in the development and deterioration of Multiple sclerosis (MS). According to new findings of the effects of metformin on mitochondrial function, has attracted a lot of attention. Furthermore, it is suggested that metformin exerts its beneficial influence through AMP-activated protein kinase (AMPK) pathway. In the current study, we investigated the possible protective effects of metformin on oxidative stress and mitochondrial function by activating the AMPK pathway in the cuprizone-induced demyelination. Mice were fed with cuprizone for 6 weeks. Animals simultaneously received metformin. After sacrificing animals, myelinations, and gliosis, changes in transcription factor and biochemical analysis were assessed. Transmission electron microscopy and luxol fast blue staining revealed that the myelinated axons within corpus callosum of cuprizone-induced demyelination animals increased after administration of metformin. Metformin also upregulated the expression of mitochondrial biogenesis genes. Furthermore, the biochemical analysis demonstrated that metformin ameliorated the oxidative stress induced by cuprizone. Immunohistochemistry analysis showed that astrogliosis and microgliosis were decreased after metformin administration while it enhanced the number of oligodendrocytes. Our data implicated that metformin exerts its therapeutic effects on MS by AMPK signaling improved mitochondrial homeostasis and protected oligodendrocytes.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Addabbo F, Montagnani M, Goligorsky MS (2009) Mitochondria and reactive oxygen species. Hypertension 53:885–892

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ashabi G, Khodagholi F, Khalaj L, Goudarzvand M, Nasiri M (2014) Activation of AMP-activated protein kinase by metformin protects against global cerebral ischemia in male rats: interference of AMPK/PGC-1α pathway. Metab Brain Dis 29:47–58

    Article  CAS  PubMed  Google Scholar 

  • Baxi EG, DeBruin J, Tosi DM, Grishkan IV, Smith MD, Kirby LA, Strasburger HJ, Fairchild AN, Calabresi PA, Gocke AR (2015) Transfer of myelin-reactive th17 cells impairs endogenous remyelination in the central nervous system of cuprizone-fed mice. J Neurosci 35:8626–8639

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Borhani-Haghighi M, Kashani IR, Mohamadi Y, Pasbakhsh P (2018) Embryonic intraventricular transplantation of neural stem cells augments inflammation-induced prenatal brain injury. J Chem Neuroanat 94:54–62

    Article  CAS  PubMed  Google Scholar 

  • Borhani-Haghighi M, Mohamadi Y, Kashani IR (2019) utero transplantation of neural stem cells ameliorates maternal inflammation-induced prenatal white matter injury. J Cell Biochem 25:236. https://doi.org/10.1002/jcb.28548

    Article  CAS  Google Scholar 

  • Chang C et al (2015) AMPK-dependent phosphorylation of GAPDH triggers Sirt1 activation and is necessary for autophagy upon glucose starvation. Mol Cell 60:930–940

    Article  CAS  PubMed  Google Scholar 

  • Clarner T et al (2012) Myelin debris regulates inflammatory responses in an experimental demyelination animal model and multiple sclerosis lesions. Glia 60:1468–1480

    Article  PubMed  Google Scholar 

  • Culmsee C, Monnig J, Kemp BE, Mattson MP (2001) AMP-activated protein kinase is highly expressed in neurons in the developing rat brain and promotes neuronal survival following glucose deprivation. J Mol Neurosci 17:45–58

    Article  CAS  PubMed  Google Scholar 

  • Ekstrand MI et al (2004) Mitochondrial transcription factor A regulates mtDNA copy number in mammals. Hum Mol Genet 13:935–944

    Article  CAS  PubMed  Google Scholar 

  • Ghaiad HR, Nooh MM, El-Sawalhi MM, Shaheen AA (2017) Resveratrol promotes remyelination in cuprizone model of multiple sclerosis: biochemical and histological study. Mol Neurobiol 54:3219–3229

    Article  CAS  PubMed  Google Scholar 

  • Green AE (2013) AMP-activated protein kinase (AMPK) activation for the treatment of mitochondrial disease

  • Izzo A et al (2017) Metformin restores the mitochondrial network and reverses mitochondrial dysfunction in Down syndrome cells. Hum Mol Genet 26:1056–1069

    CAS  PubMed  Google Scholar 

  • Kang C, Ji LL (2013) Role of PGC-1α in muscle function and aging. J Sport Health Sci 2:81–86

    Article  Google Scholar 

  • Kang Z et al (2012) IL-17-induced Act1-mediated signaling is critical for cuprizone-induced demyelination. J Neurosci 32:8284–8292

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Karnewar S et al (2018) Metformin regulates mitochondrial biogenesis and senescence through AMPK mediated H3K79 methylation: relevance in age-associated vascular dysfunction. Biochimica et Biophysica Acta (BBA) 1864:1115–1128

    Article  CAS  Google Scholar 

  • Kashani IR et al (2014) Protective effects of melatonin against mitochondrial injury in a mouse model of multiple sclerosis. Exp Brain Res 232:2835–2846

    Article  CAS  PubMed  Google Scholar 

  • Keck F, Khan D, Roberts B, Agrawal N, Bhalla N, Narayanan A (2018) Mitochondrial-directed antioxidant reduces microglial-induced inflammation in murine in vitro model of TC-83 infection. Viruses 10:606

    Article  CAS  PubMed Central  Google Scholar 

  • Khallaghi B, Safarian F, Nasoohi S, Ahmadiani A, Dargahi L (2016) Metformin-induced protection against oxidative stress is associated with AKT/mTOR restoration in PC12 cells. Life Sci 148:286–292

    Article  CAS  PubMed  Google Scholar 

  • Kim J-H et al (2008) The non-provitamin A carotenoid, lutein, inhibits NF-κB-dependent gene expression through redox-based regulation of the phosphatidylinositol 3-kinase/PTEN/Akt and NF-κB-inducing kinase pathways: role of H2O2 in NF-κB activation. Free Radic Biol Med 45:885–896

    Article  CAS  PubMed  Google Scholar 

  • Liesa M et al (2008) Mitochondrial fusion is increased by the nuclear coactivator PGC-1β. PLoS ONE 3:e3613

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lu F, Selak M, O’Connor J, Croul S, Lorenzana C, Butunoi C, Kalman B (2000) Oxidative damage to mitochondrial DNA and activity of mitochondrial enzymes in chronic active lesions of multiple sclerosis. J Neurol Sci 177:95–103

    Article  CAS  PubMed  Google Scholar 

  • Lucchinetti C, Noseworthy J, Rodriguez M (1997) Promotion of endogeneous remyelination in multiple sclerosis. Mult Scler J 3:71–75

    Article  CAS  Google Scholar 

  • Mao P, Reddy PH (2010) Is multiple sclerosis a mitochondrial disease? Biochimica et Biophysica Acta (BBA) 1802:66–79

    Article  CAS  Google Scholar 

  • Mauriz E, Laliena A, Vallejo D, Tuñón M, Rodríguez-López J, Rodriguez-Perez R, García-Fernández M (2013) Effects of a low-fat diet with antioxidant supplementation on biochemical markers of multiple sclerosis long-term care residents. Nutr Hosp 28:2229

    CAS  PubMed  Google Scholar 

  • McManus MJ, Murphy MP, Franklin JL (2011) The mitochondria-targeted antioxidant MitoQ prevents loss of spatial memory retention and early neuropathology in a transgenic mouse model of Alzheimer’s disease. J Neurosci 31:15703–15715

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nahirnyj A, Livne-Bar I, Guo X, Sivak JM (2013) ROS detoxification and proinflammatory cytokines are linked by p38 MAPK signaling in a model of mature astrocyte activation. PLoS ONE 8:e83049

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nath N, Khan M, Paintlia MK, Hoda MN, Giri S (2009) Metformin attenuated the autoimmune disease of the central nervous system in animal models of multiple sclerosis. J Immunol 182:8005–8014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Noorzehi G et al (2018) Microglia polarization by methylprednizolone acetate accelerates cuprizone induced demyelination. J Mol Histol 49:471–479

    Article  CAS  PubMed  Google Scholar 

  • Ohno N et al (2014) Mitochondrial immobilization mediated by syntaphilin facilitates survival of demyelinated axons. Proc Natl Acad Sci 111:9953

    Article  CAS  PubMed  Google Scholar 

  • Ozdemir D et al (2005) Effect of melatonin on brain oxidative damage induced by traumatic brain injury in immature rats. Physiol Res 54:631

    CAS  PubMed  Google Scholar 

  • Paintlia AS, Mohan S, Singh I (2013a) Combinatorial effect of metformin and lovastatin impedes T-cell autoimmunity and neurodegeneration in experimental autoimmune encephalomyelitis. J Clin Cell Immunol 4:e113

    Article  CAS  Google Scholar 

  • Paintlia AS, Paintlia MK, Mohan S, Singh AK, Singh I (2013b) AMP-activated protein kinase signaling protects oligodendrocytes that restore central nervous system functions in an experimental autoimmune encephalomyelitis model. Am J Pathol 183:526–541

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Praet J, Guglielmetti C, Berneman Z, Van der Linden A, Ponsaerts P (2014) Cellular and molecular neuropathology of the cuprizone mouse model: clinical relevance for multiple sclerosis. Neurosci Biobehav Rev 47:485–505

    Article  CAS  PubMed  Google Scholar 

  • Sághy É et al (2016) TRPA1 deficiency is protective in cuprizone-induced demyelination—A new target against oligodendrocyte apoptosis. Glia 64:2166–2180

    Article  PubMed  Google Scholar 

  • Sahu BD, Kuncha M, Putcha UK, Sistla R (2013) Effect of metformin against cisplatin induced acute renal injury in rats: a biochemical and histoarchitectural evaluation. Exp Toxicol Pathol 65:933–940

    Article  CAS  PubMed  Google Scholar 

  • Sanadgol N, Golab F, Mostafaie A, Mehdizadeh M, Abdollahi M, Sharifzadeh M, Ravan H (2016) Ellagic acid ameliorates cuprizone-induced acute CNS inflammation via restriction of microgliosis and down-regulation of CCL2 and CCL3 pro-inflammatory chemokines. Cell Mol Biol 62:24–30

    CAS  PubMed  Google Scholar 

  • Scarpulla RC (2011) Metabolic control of mitochondrial biogenesis through the PGC-1 family regulatory network. Biochimica et Biophysica Acta (BBA) 1813:1269–1278

    Article  CAS  Google Scholar 

  • Smirnova L, Krotenko N, Grishko E, Krotenko N, Alifirova V, Ivanova S (2011) The state of the antioxidant system during therapy of patients with multiple sclerosis. Biochemistry (Moscow) Suppl Series B 5:76

    Article  Google Scholar 

  • Sözmen EG, Carmichael ST (2014) White matter repair in subcortical stroke. In: Baltan S, Carmichael ST, Matute C, Xi G, Zhang JH (eds) White matter injury in stroke and CNS disease. Springer, New York, pp 257–270

    Chapter  Google Scholar 

  • Tristan C, Shahani N, Sedlak TW, Sawa A (2011) The diverse functions of GAPDH: views from different subcellular compartments. Cell Signal 23:317–323

    Article  CAS  PubMed  Google Scholar 

  • Vallianou N, Gounari P, Skourtis A, Panagos J, Kazazis C (2014) Honey and its anti-inflammatory, anti-bacterial and anti-oxidant properties. Gen Med (Los Angel) 2:1–5

    Article  Google Scholar 

  • Van Horssen J, Witte ME, Schreibelt G, De Vries HE (2011) Radical changes in multiple sclerosis pathogenesis. Biochimica et Biophysica Acta (BBA) 1812:141–150

    Article  CAS  Google Scholar 

  • Wang G et al (2016) Activation of AMPK attenuates LPS-induced acute lung injury by upregulation of PGC1α and SOD1. Exp Ther Med 12:1551–1555

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wu H, Kanatous SB, Thurmond FA, Gallardo T, Isotani E, Bassel-Duby R, Williams RS (2002) Regulation of mitochondrial biogenesis in skeletal muscle by CaMK. Science 296:349–352

    Article  CAS  PubMed  Google Scholar 

  • Yun H et al (2014) AMP-activated protein kinase mediates the antioxidant effects of resveratrol through regulation of the transcription factor FoxO1. FEBS J 281:4421–4438

    Article  CAS  PubMed  Google Scholar 

  • Zou M-H et al (2004) Activation of the AMP-activated protein kinase by the anti-diabetic drug metformin in vivo: role of mitochondrial reactive nitrogen species. J Biol Chem 279:43940

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Tehran University of Medical Science supported this work and the results described in this paper is part of the student thesis for an MSc degree that was supported by Grant 95-03-30- 32879.

Author information

Authors and Affiliations

  1. Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

    Seyed Hossein Hosseini Largani, Maryam Borhani-Haghighi, Parichehr Pasbakhsh, Saied Nekoonam, Elham Shiri & Iraj Ragerdi Kashani

  2. Neuroscience Research Center, Iran University of Medical Sciences, Poursina Street, 1417613151, Tehran, Iran

    Vahid Pirhajati Mahabadi

  3. Institute of Neuroanatomy, Faculty of Medicine, RWTH Aachen University, Wendlingweg 2, 52074, Aachen, Germany

    Adib Zendehdel

Authors
  1. Seyed Hossein Hosseini Largani
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Maryam Borhani-Haghighi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Parichehr Pasbakhsh
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Vahid Pirhajati Mahabadi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Saied Nekoonam
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Elham Shiri
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Iraj Ragerdi Kashani
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Adib Zendehdel
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Iraj Ragerdi Kashani.

Ethics declarations

Conflict of interest

There are no conflicts of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Largani, S.H.H., Borhani-Haghighi, M., Pasbakhsh, P. et al. Oligoprotective effect of metformin through the AMPK-dependent on restoration of mitochondrial hemostasis in the cuprizone-induced multiple sclerosis model. J Mol Hist 50, 263–271 (2019). https://doi.org/10.1007/s10735-019-09824-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10735-019-09824-0

Keywords

Search

Navigation