Abstract
Neuroinflammation, glial activation, and oxidative injury are the main pathological mechanisms of demyelination in multiple sclerosis (MS). Arbutin, a natural polyphenol compound, possesses antioxidant, anti-inflammatory, and neuroprotective properties whose therapeutic potential has not been studied in the experimental animal models of MS. In the present study, the efficiency of arbutin on lysolecthin (LPC)-induced local demyelination model was investigated. Demyelination was induced by micro-injection of 2 μl LPC (1%) into the rat optic chiasm and the treated group received daily injection of arbutin (50 mg/kg, i.p) during 2 weeks. Visual-evoked potential (VEP) recordings were used to functionally assess the visual pathway. Gene expression analysis was done to evaluate the arbutin effect on the inflammatory, stress oxidative-related mediators, and myelin markers. The myelin-specific staining was performed to assess demyelination and GFAP staining as an astrocyte marker. We found that arbutin significantly reduced P1-latency of VEPs waves and demyelination at 7 and 14 days post-demyelination. Arbutin decreased inflammatory cytokines (IL-1B, IL-17, TNF-α) and iNOS mRNA expression level. In addition, the expression level of anti-inflammatory cytokine (IL-10) and antioxidant mediators (Nrf-2 and HO-1) was enhanced by arbutin treatment. Arbutin increased MBP and Olig2 expression levels in demyelination context. Finally, arbutin attenuated GFAP as an astrocyte marker. Finally, this study demonstrates that arbutin improves functional recovery and myelin repair in the demyelinated optic chiasm through attenuation of inflammation, astrocyte activation, and oxidative stress. These findings might open new promising avenues for treating demyelinating disorders such as multiple sclerosis.
Similar content being viewed by others
Abbreviations
- GFAP:
-
Glial fibrillary acidic protein
- HO-1:
-
Heme oxygenase-1
- IL-1B:
-
Interleukin-1beta
- IL-17:
-
Interleukin-17
- IL-10:
-
Interleukin-10
- iNOS:
-
Inducible nitric oxide synthase
- LPC:
-
Lysophosphatidylcholine
- MS:
-
Multiple sclerosis
- MBP:
-
Myelin basic protein
- Nrf-2:
-
Nuclear factor erythroid2-related factor-2
- OPCs:
-
Oligodendrocyte precursor cells
- ROS:
-
Reactive oxygen species
- TNF-α:
-
Tumor necrosis factor alpha
- VEP:
-
Visual-evoked potential
References
Imitola J, Chitnis T, Khoury SJ (2005) Cytokines in multiple sclerosis: from bench to bedside. Pharmacol Ther 106(2):163–177. https://doi.org/10.1016/j.pharmthera.2004.11.007
Hauser SL, Oksenberg JR (2006) The neurobiology of multiple sclerosis: genes, inflammation, and neurodegeneration. Neuron 52(1):61–76. https://doi.org/10.1016/j.neuron.2006.09.011
Beck R, Schatz N, Savino J (1983) Involvement of the optic chiasm, optic tract and geniculo-calcarine visual system in multiple sclerosis. Bull Soc Belge Ophtalmol 208:159
Feinstein A (2005) The clinical neuropsychiatry of multiple sclerosis. CNS Spectr 10(5):362
Guazzo EP (2005) A technique for producing demyelination of the rat optic nerves. J Clin Neurosci 12(1):54–58. https://doi.org/10.1016/j.jocn.2004.08.002
Shivane AG, Chakrabarty A (2007) Multiple sclerosis and demyelination. Curr Diagn Pathol 13(3):193–202
Kawanokuchi J, Mizuno T, Takeuchi H, Kato H, Wang J, Mitsuma N, Suzumura A (2006) Production of interferon-gamma by microglia. Mult Scler 12(5):558–564. https://doi.org/10.1177/1352458506070763
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):261–268. https://doi.org/10.1007/s00415-004-0348-9
Farez MF, Correale J (2016) Sphingosine 1-phosphate signaling in astrocytes: implications for progressive multiple sclerosis. J Neurol Sci 361:60–65. https://doi.org/10.1016/j.jns.2015.12.022
Hagemeier K, Bruck W, Kuhlmann T (2012) Multiple sclerosis—remyelination failure as a cause of disease progression. Histol Histopathol 27(3):277–287. https://doi.org/10.14670/HH-27.277
Butts BD, Houde C, Mehmet H (2008) Maturation-dependent sensitivity of oligodendrocyte lineage cells to apoptosis: implications for normal development and disease. Cell Death Differ 15(7):1178–1186. https://doi.org/10.1038/cdd.2008.70
Wang C, Cai Z, Wang W, Wei M, Kou D, Li T, Yang Z, Guo H et al (2019) Piperine attenuates cognitive impairment in an experimental mouse model of sporadic Alzheimer’s disease. J Nutr Biochem 70:147–155. https://doi.org/10.1016/j.jnutbio.2019.05.009
Ahmadian SR, Ghasemi-Kasman M, Pouramir M, Sadeghi F (2019) Arbutin attenuates cognitive impairment and inflammatory response in pentylenetetrazol-induced kindling model of epilepsy. Neuropharmacology 146:117–127. https://doi.org/10.1016/j.neuropharm.2018.11.038
Baradaran S, Moghaddam AH, Ghasemi-Kasman M (2018) Hesperetin reduces myelin damage and ameliorates glial activation in lysolecithin-induced focal demyelination model of rat optic chiasm. Life Sci 207:471–479
Mohajeri M, Sadeghizadeh M, Najafi F, Javan M (2015) Polymerized nano-curcumin attenuates neurological symptoms in EAE model of multiple sclerosis through down regulation of inflammatory and oxidative processes and enhancing neuroprotection and myelin repair. Neuropharmacology 99:156–167. https://doi.org/10.1016/j.neuropharm.2015.07.013
Shahaboddin ME, Pouramir M, Moghadamnia AA, Parsian H, Lakzaei M, Mir H (2011) Pyrus biossieriana Buhse leaf extract: an antioxidant, antihyperglycaemic and antihyperlipidemic agent. Food Chem 126(4):1730–1733. https://doi.org/10.1016/j.foodchem.2010.12.069
Yousefi F, Mahjoub S, Pouramir M, Khadir F (2013) Hypoglycemic activity of Pyrus biossieriana Buhse leaf extract and arbutin: inhibitory effects on alpha amylase and alpha glucosidase. Caspian J Intern Med 4(4):763–767
Li H, Jeong YM, Kim SY, Kim MK, Kim DS (2011) Arbutin inhibits TCCSUP human bladder cancer cell proliferation via up-regulation of p21. Pharmazie 66(4):306–309
Nawarak J, Huang-Liu R, Kao SH, Liao HH, Sinchaikul S, Chen ST, Cheng SL (2009) Proteomics analysis of A375 human malignant melanoma cells in response to arbutin treatment. Biochim Biophys Acta 1794(2):159–167. https://doi.org/10.1016/j.bbapap.2008.09.023
Lee HJ, Kim KW (2012) Anti-inflammatory effects of arbutin in lipopolysaccharide-stimulated BV2 microglial cells. Inflamm Res 61(8):817–825. https://doi.org/10.1007/s00011-012-0474-2
Pecivova J, Nosal R, Svitekova K, Macickova T (2014) Arbutin and decrease of potentially toxic substances generated in human blood neutrophils. Interdiscip Toxicol 7(4):195–200. https://doi.org/10.2478/intox-2014-0028
Ye J, Guan M, Lu Y, Zhang D, Li C, Zhou C (2019) Arbutin attenuates LPS-induced lung injury via Sirt1/ Nrf2/ NF-kappaBp65 pathway. Pulm Pharmacol Ther 54:53–59. https://doi.org/10.1016/j.pupt.2018.12.001
Sun KH, Tang SJ, Chen CY, Lee TP, Feng CK, Yu CL, Sun GH (2005) Monoclonal ribosomal P autoantibody inhibits the expression and release of IL-12, TNF-alpha and iNOS in activated RAW macrophage cell line. J Autoimmun 24(2):135–143. https://doi.org/10.1016/j.jaut.2005.01.002
Loboda A, Damulewicz M, Pyza E, Jozkowicz A, Dulak J (2016) Role of Nrf2/HO-1 system in development, oxidative stress response and diseases: an evolutionarily conserved mechanism. Cell Mol Life Sci 73(17):3221–3247. https://doi.org/10.1007/s00018-016-2223-0
Wang T, Chen C, Yang L, Zeng Z, Zeng M, Jiang W, Liu L, Zhao M (2019) Role of Nrf2/HO-1 signal axis in the mechanisms for oxidative stress-relevant diseases. Zhong Nan Da Xue Xue Bao Yi Xue Ban 44(1):74–80. https://doi.org/10.11817/j.issn.1672-7347.2019.01.012
Cheng HT, Yen CJ, Chang CC, Huang KT, Chen KH, Zhang RY, Lee PY, Miaw SC et al (2015) Ferritin heavy chain mediates the protective effect of heme oxygenase-1 against oxidative stress. Biochim Biophys Acta 1850(12):2506–2517. https://doi.org/10.1016/j.bbagen.2015.09.018
Dadgar M, Pouramir M, Dastan Z, Ghasemi-Kasman M, Ashrafpour M, Moghadamnia AA, Khafri S, Pourghasem M (2018) Arbutin attenuates behavioral impairment and oxidative stress in an animal model of Parkinson’s disease. Avicenna J Phytomed 8(6):533–542
Khanal T, Kim HG, Hwang YP, Kong MJ, Kang MJ, Yeo HK, Kim DH, Jeong TC et al (2011) Role of metabolism by the human intestinal microflora in arbutin-induced cytotoxicity in HepG2 cell cultures. Biochem Biophys Res Commun 413(2):318–324. https://doi.org/10.1016/j.bbrc.2011.08.094
Hall SM (1972) The effect of injections of lysophosphatidyl choline into white matter of the adult mouse spinal cord. J Cell Sci 10(2):535–546
Mozafari S, Javan M, Sherafat MA, Mirnajafi-Zadeh J, Heibatollahi M, Pour-Beiranvand S, Tiraihi T, Ahmadiani A (2011) Analysis of structural and molecular events associated with adult rat optic chiasm and nerves demyelination and remyelination: possible role for 3rd ventricle proliferating cells. NeuroMolecular Med 13(2):138–150. https://doi.org/10.1007/s12017-011-8143-0
Pourabdolhossein F, Mozafari S, Morvan-Dubois G, Mirnajafi-Zadeh J, Lopez-Juarez A, Pierre-Simons J, Demeneix BA, Javan M (2014) Nogo receptor inhibition enhances functional recovery following lysolecithin-induced demyelination in mouse optic chiasm. PLoS One 9(9):e106378. https://doi.org/10.1371/journal.pone.0106378
Sherafat MA, Javan M, Mozafari S, Mirnajafi-Zadeh J, Motamedi F (2011) Castration attenuates myelin repair following lysolecithin induced demyelination in rat optic chiasm: an evaluation using visual evoked potential, marker genes expression and myelin staining. Neurochem Res 36(10):1887–1895. https://doi.org/10.1007/s11064-011-0510-6
Ishikawa T, Fujiwara A, Takechi K, Ago J, Matsumoto N, Rahman MA, Kamei C (2008) Changes of visual evoked potential induced by lateral geniculate nucleus kindling in rats. Epilepsy Res 79(2–3):146–150. https://doi.org/10.1016/j.eplepsyres.2008.01.001
Kuroda K, Fujiwara A, Takeda Y, Kamei C (2009) Effects of narcotics, including morphine, on visual evoked potential in rats. Eur J Pharmacol 602(2–3):294–297. https://doi.org/10.1016/j.ejphar.2008.11.048
Plemel JR, Michaels NJ, Weishaupt N, Caprariello AV, Keough MB, Rogers JA, Yukseloglu A, Lim J et al (2018) Mechanisms of lysophosphatidylcholine-induced demyelination: a primary lipid disrupting myelinopathy. Glia 66(2):327–347. https://doi.org/10.1002/glia.23245
Schilling T, Eder C (2010) Importance of lipid rafts for lysophosphatidylcholine-induced caspase-1 activation and reactive oxygen species generation. Cell Immunol 265(2):87–90. https://doi.org/10.1016/j.cellimm.2010.08.003
Paxinos G, Watson C (2007) The rat brain in stereotaxic coorinates.456. doi:Hardcover ISBN: 9780125476126
Pourabdolhossein F, Gil-Perotin S, Garcia-Belda P, Dauphin A, Mozafari S, Tepavcevic V, Manuel Garcia Verdugo J, Baron-Van Evercooren A (2017) Inflammatory demyelination induces ependymal modifications concomitant to activation of adult (SVZ) stem cell proliferation. Glia 65(5):756–772. https://doi.org/10.1002/glia.23124
Mandler M, Valera E, Rockenstein E, Mante M, Weninger H, Patrick C, Adame A, Schmidhuber S et al (2015) Active immunization against alpha-synuclein ameliorates the degenerative pathology and prevents demyelination in a model of multiple system atrophy. Mol Neurodegener 10:10. https://doi.org/10.1186/s13024-015-0008-9
Mozafari S, Sherafat MA, Javan M, Mirnajafi-Zadeh J, Tiraihi T (2010) Visual evoked potentials and MBP gene expression imply endogenous myelin repair in adult rat optic nerve and chiasm following local lysolecithin induced demyelination. Brain Res 1351:50–56. https://doi.org/10.1016/j.brainres.2010.07.026
You Y, Klistorner A, Thie J, Graham SL (2011) Latency delay of visual evoked potential is a real measurement of demyelination in a rat model of optic neuritis. Invest Ophthalmol Vis Sci 52(9):6911–6918. https://doi.org/10.1167/iovs.11-7434
Jordan CA, Friedrich VL Jr, Godfraind C, Cardellechio CB, Holmes KV, Dubois-Dalcq M (1989) Expression of viral and myelin gene transcripts in a murine CNS demyelinating disease caused by a coronavirus. Glia 2(5):318–329. https://doi.org/10.1002/glia.440020505
Lopez Juarez A, He D, Richard Lu Q (2016) Oligodendrocyte progenitor programming and reprogramming: toward myelin regeneration. Brain Res 1638(Pt B):209–220. https://doi.org/10.1016/j.brainres.2015.10.051
Takebayashi J, Ishii R, Chen J, Matsumoto T, Ishimi Y, Tai A (2010) Reassessment of antioxidant activity of arbutin: multifaceted evaluation using five antioxidant assay systems. Free Radic Res 44(4):473–478. https://doi.org/10.3109/10715761003610760
Pott F, Gingele S, Clarner T, Dang J, Baumgartner W, Beyer C, Kipp M (2009) Cuprizone effect on myelination, astrogliosis and microglia attraction in the mouse basal ganglia. Brain Res 1305:137–149. https://doi.org/10.1016/j.brainres.2009.09.084
Klistorner A, Graham SL, Martins A, Grigg JR, Arvind H, Kumar RS, James AC, Billson FA (2007) Multifocal blue-on-yellow visual evoked potentials in early glaucoma. Ophthalmology 114(9):1613–1621. https://doi.org/10.1016/j.ophtha.2006.11.037
Mousavi Majd A, Ebrahim Tabar F, Afghani A, Ashrafpour S, Dehghan S, Gol M, Ashrafpour M, Pourabdolhossein F (2018) Inhibition of GABA A receptor improved spatial memory impairment in the local model of demyelination in rat hippocampus. Behav Brain Res 336:111–121. https://doi.org/10.1016/j.bbr.2017.08.046
Freeman L, Guo H, David CN, Brickey WJ, Jha S, Ting JP (2017) NLR members NLRC4 and NLRP3 mediate sterile inflammasome activation in microglia and astrocytes. J Exp Med 214(5):1351–1370. https://doi.org/10.1084/jem.20150237
Naeimi R, Safarpour F, Hashemian M, Tashakorian H, Ahmadian SR, Ashrafpour M, Ghasemi-Kasman M (2018) Curcumin-loaded nanoparticles ameliorate glial activation and improve myelin repair in lyolecithin-induced focal demyelination model of rat corpus callosum. Neurosci Lett 674:1–10. https://doi.org/10.1016/j.neulet.2018.03.018
Naeimi R, Baradaran S, Ashrafpour M, Moghadamnia AA, Ghasemi-Kasman M (2018) Querectin improves myelin repair of optic chiasm in lyolecithin-induced focal demyelination model. Biomed Pharmacother 101:485–493. https://doi.org/10.1016/j.biopha.2018.02.125
Lassmann H, van Horssen J (2016) Oxidative stress and its impact on neurons and glia in multiple sclerosis lesions. Biochim Biophys Acta 1862(3):506–510. https://doi.org/10.1016/j.bbadis.2015.09.018
Ousman SS, David S (2000) Lysophosphatidylcholine induces rapid recruitment and activation of macrophages in the adult mouse spinal cord. Glia 30(1):92–104
Tarbali S, Khezri S (2016) Vitamin D3 attenuates oxidative stress and cognitive deficits in a model of toxic demyelination. Iran J Basic Med Sci 19(1):80–88
Luo Q, Yan X, Bobrovskaya L, Ji M, Yuan H, Lou H, Fan P (2017) Anti-neuroinflammatory effects of grossamide from hemp seed via suppression of TLR-4-mediated NF-kappaB signaling pathways in lipopolysaccharide-stimulated BV2 microglia cells. Mol Cell Biochem 428(1–2):129–137. https://doi.org/10.1007/s11010-016-2923-7
Baowen Q, Yulin Z, Xin W, Wenjing X, Hao Z, Zhizhi C, Xingmei D, Xia Z et al (2010) A further investigation concerning correlation between anti-fibrotic effect of liposomal quercetin and inflammatory cytokines in pulmonary fibrosis. Eur J Pharmacol 642(1–3):134–139. https://doi.org/10.1016/j.ejphar.2010.05.019
Tucsek Z, Radnai B, Racz B, Debreceni B, Priber JK, Dolowschiak T, Palkovics T, Gallyas F Jr et al (2011) Suppressing LPS-induced early signal transduction in macrophages by a polyphenol degradation product: a critical role of MKP-1. J Leukoc Biol 89(1):105–111. https://doi.org/10.1189/jlb.0610355
Couper KN, Blount DG, Riley EM (2008) IL-10: the master regulator of immunity to infection. J Immunol 180(9):5771–5777. https://doi.org/10.4049/jimmunol.180.9.5771
Saraiva M, O’Garra A (2010) The regulation of IL-10 production by immune cells. Nat Rev Immunol 10(3):170–181. https://doi.org/10.1038/nri2711
Salmaggi A, Dufour A, Eoli M, Corsini E, La Mantia L, Massa G, Nespolo A, Milanese C (1996) Low serum interleukin-10 levels in multiple sclerosis: further evidence for decreased systemic immunosuppression? J Neurol 243(1):13–17. https://doi.org/10.1007/bf00878525
Correale J, Gilmore W, McMillan M, Li S, McCarthy K, Le T, Weiner LP (1995) Patterns of cytokine secretion by autoreactive proteolipid protein-specific T cell clones during the course of multiple sclerosis. J Immunol 154(6):2959–2968
Daneshdoust D, Khalili-Fomeshi M, Ghasemi-Kasman M, Ghorbanian D, Hashemian M, Gholami M, Moghadamnia A, Shojaei A (2017) Pregabalin enhances myelin repair and attenuates glial activation in lysolecithin-induced demyelination model of rat optic chiasm. Neuroscience 344:148–156. https://doi.org/10.1016/j.neuroscience.2016.12.037
Khezri S, Dasht Bozorgi N, Rahmani F (2016) The effect of caffeine on the myelin repair following experimental demyelination induction in the adult rat hippocampus. J Cell Mol Res 8(1):15–24
Tanaka Y, Yokoo H, Komori T, Makita Y, Ishizawa T, Hirose T, Ebato M, Shibahara J et al (2005) A distinct pattern of Olig2-positive cellular distribution in papillary glioneuronal tumors: a manifestation of the oligodendroglial phenotype? Acta Neuropathol 110(1):39–47. https://doi.org/10.1007/s00401-005-1018-4
Franklin RJ, Ffrench-Constant C (2008) Remyelination in the CNS: from biology to therapy. Nat Rev Neurosci 9(11):839–855. https://doi.org/10.1038/nrn2480
Levine JM, Reynolds R (1999) Activation and proliferation of endogenous oligodendrocyte precursor cells during ethidium bromide-induced demyelination. Exp Neurol 160(2):333–347. https://doi.org/10.1006/exnr.1999.7224
Picard-Riera N, Decker L, Delarasse C, Goude K, Nait-Oumesmar B, Liblau R, Pham-Dinh D, Baron-Van Evercooren A (2002) Experimental autoimmune encephalomyelitis mobilizes neural progenitors from the subventricular zone to undergo oligodendrogenesis in adult mice. Proc Natl Acad Sci U S A 99(20):13211–13216. https://doi.org/10.1073/pnas.192314199
Chari DM, Blakemore WF (2002) Efficient recolonisation of progenitor-depleted areas of the CNS by adult oligodendrocyte progenitor cells. Glia 37(4):307–313
Acknowledgments
This work was supported by a grant from the Deputy of Research and Technology (No. 9603818), Babol University of Medical Sciences, Babol, Iran and was performed as a part of a Medical doctor thesis in the Physiology Department at Babol University of Medical Sciences. The authors would like to appreciate the kind assistance and support of Dr. Mohammad Javan during the study. The authors are thankful to Mr. Saeed Maniati from Babol University of Medical Sciences for designing the graphical abstract.
Author information
Authors and Affiliations
Contributions
Study design was done by Fereshteh Pourabdolhossein, Mahdi Pouramir, and Manuchehr Ashrafpour. Data collection was done by Forough Ebrahim-Tabar and Atena Nazari. Data analysis was done by Forough Ebrahim-Tabar, Atena Nazari and Fereshteh Pourabdolhossein. Manuscript preparation was done by Forough Ebrahim-Tabar and Fereshteh Pourabdolhossein. Final approval of the manuscript before submission was by Forough Ebrahim-Tabar, Fereshteh Pourabdolhossein, Atena Nazari, Mahdi Pouramir, and Manuchehr Ashrafpour.
Corresponding author
Ethics declarations
All experimental procedures were conducted based on the principles and procedures described in the National Institutes of Health guidelines for the care and use of laboratory animals and approved by the ethical committee of the Babol University of Medical Sciences (IR.MUBABOL.HRI.REC.1396.75).
Conflict of Interest
The authors declare that they have no conflict of interest.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Highlights
• Arbutin improves functional recovery and myelin repair in demyelination model of the rat optic chiasm.
• Arbutin enhances OPC population and MBP expression in the rat demyelinated optic chiasm.
• Arbutin reduces the levels of inflammatory mediators and astrocytes activation in demyelination context.
• Arbutin increases the level of IL-10 and antioxidant gene markers in a LPC-induced demyelination model
Electronic supplementary material
ESM 1
(DOCX 15 kb)
Rights and permissions
About this article
Cite this article
Ebrahim-Tabar, F., Nazari, A., Pouramir, M. et al. Arbutin Improves Functional Recovery and Attenuates Glial Activation in Lysolecethin-Induced Demyelination Model in Rat Optic Chiasm. Mol Neurobiol 57, 3228–3242 (2020). https://doi.org/10.1007/s12035-020-01962-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12035-020-01962-x