Skip to main content
SpringerLink
Log in

The Beneficial Effects of Resveratrol on Experimental Autoimmune Encephalomyelitis (EAE) in C57BL/6J Mouse Model

  • Experimental Papers
  • Published:
Journal of Evolutionary Biochemistry and Physiology Aims and scope Submit manuscript

Abstract

Multiple sclerosis (MS) is a disease of the central nervous system of unknown cause and limited therapeutical treatments. In this study we analyzed the effects of resveratrol (RSV), a polyphenolic compound with well-known neuroprotective effects, on neuronal damage in brain tissue caused by experimental autoimmune encephalomyelitis (EAE)—an established model of multiple sclerosis, using C57BL/6J female mice. A total of 40 C57BL/6J female mice were divided equally into four groups: control, EAE, RSV and RSV + EAE. 14 days after induction of EAE with myelin oligodendrocyte glycoprotein MOG35-55 and pertussis toxin, mice were treated via oral gavage with RSV at the doses of 20 mg/kg per day for 7 days. According to our results RSV treatment prevented oxidative stress caused by EAE via a decrease in lipid peroxidation and an increase in the elements of the antioxidant defense systems in brain tissue. The histopathological changes in caspase-3 and IL-17 activity and cytokine levels (TNF-α and IL-1β) induced by EAE in mouse brain tissue were reversed by RSV treatment. Moreover, elevated TNF-α and IL-1β levels, induced by EAE, were diminished in blood serum, and neurological deficits were reversed in EAE mice treated with RSV. Our findings suggest that RSV treatment effectively prevents oxidative, immunological, and histological changes in the brain caused by EAE and the beneficial effects of RSV are likely to result from its strong antioxidant and anti-inflammatory properties.

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.
Fig. 5.
Fig. 6.
Fig. 7.
Fig. 8.

Similar content being viewed by others

Abbreviations

18β-GA:

18β-glycetinetic acid

CAT:

catalase

CMC:

carboxymethyl cellulose

CNS:

central nervous system

DTNB:

5,5'-dithio-bis [2-nitrobenzoic acid]

EAE:

experimental autoimmune encephalomyelitis

GPx:

glutathione peroxidase

GSH:

total glutathione

GSSG:

glutathione disulfide

H2O2 :

hydrogen peroxide

H–E:

hematoxylin-eosin

IHC:

immunohistochemical

IL-17:

interleukin-17

IL-1β:

interleukin-1 Beta

MOG35-55 :

myelin oligodendroglial glycoprotein peptide

MS:

multiple sclerosis

NADPH:

Nicotinamide Adenine Dinucleotide Phosphate

NBT:

nitro blue tetrazolium

NF-Κb:

nuclear factor kappa B

PBS:

phosphate-buffered saline

ROS:

reactive oxygen species

RSV:

resveratrol

SOD:

CuZn-superoxide dismutase

TBARS:

thiobarbituric acid reactive substances

TCA:

trichloroacetic acid

TNF-a:

tumor necrosis factor alpha

References

  1. Zhang K, Ge Z, Xue Z, Huang W, Mei M, Zhang Q, Li Y, Li W, Zhang Zh, Zhang Z, Zhang L, Wang H, Cai J, Yao Z, Zhang R, Da Y (2015) Chrysin suppresses human CD14+ monocyte-derived dendritic cells and ameliorates experimental autoimmune encephalomyelitis. J Neuroimmunol 288: 13–20. https://doi.org/10.1016/j.jneuroim.2015.08.017

    Article  CAS  PubMed  Google Scholar 

  2. Croxford AL, Kurschus FC, Waisman A (2018) Mouse models for multiple sclerosis: historical facts and future implications. Biochim Biophys Acta 1812: 177–183. https://doi.org/10.1016/j.bbadis.2010.06.010

    Article  CAS  Google Scholar 

  3. Jiang Y, Zou Y, Chen S, Zhu C, Wu A, Liu Y, Ma L, Zhu D, Ma X, Liu M, Kang Z, Pi R, Peng F, Wang Q, Chen X (2013) The anti-inflammatory effect of donepezil on experimental autoimmune encephalomyelitis in C57 BL/6 mice. Neuropharmacology 73: 415-424. https://doi.org/10.1016/j.neuropharm.2013.06.023

    Article  CAS  PubMed  Google Scholar 

  4. Prud’homme GJ (2000) Gene therapy of autoimmune diseases with vectorsencoding regulatory cytokines or inflammatory cytokine inhibitors. J Gene Med 2: 222–232. https://doi.org/10.1002/1521-2254(200007/08)2:4<222::AID-JGM117>3.0.CO;2-P

    Article  PubMed  Google Scholar 

  5. Wang D, Li SP, Fu JS, Zhang S, Bai L, Guo L (2016) Resveratrol defends blood-brain barrierintegrity in experimental autoimmune encephalomyelitis mice. J Neurophysiol 116(5): 2173-2179. https://doi.org/10.1152/jn.00510.2016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Kamisli S, Ciftci O, Taslidere A, Basak Turkmen N, Ozcan C (2018) The beneficial effects of 18β-glycyrrhetinic acid on the experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mouse model. Immunopharmacol Immunotoxicol 40(4): 344–352. https://doi.org/10.1080/08923973.2018.1490318

    Article  CAS  PubMed  Google Scholar 

  7. Solleiro-Villavicencio H, Rivas-Arancibia S (2018) Effect of chronic oxidative stress on neuroinflammatory response mediated by CD4+ T cells in neurodegenerative diseases. Front Cell Neurosci 12: 114. https://doi.org/10.3389/fncel.2018.00114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Feng J, Tao T, Yan W, Chen CS, Qin X (2014) Curcumin inhibits mitochondrial injury and apoptosis from the early stage in EAE mice. Oxid Med Cell Longev 2014: 1. https://doi.org/10.1155/2014/728751

    Article  CAS  Google Scholar 

  9. Lee DH, Gold R, Linker RA (2012) Mechanisms of oxidative damage in multiple sclerosis and neurodegenerative diseases: therapeutic modulation via fumaric acid esters. IJMS 13: 11783–11803. https://doi.org/10.3390/ijms130911783

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Komiyama Y, Nakae S, Matsuki T, Nambu A, Ishigame H, Kakuta S, Sudo K, Iwakura Y (2006) IL-17 plays an important role in the development of experimental autoimmune encephalomyelitis. J Immunol 177: 566–573. https://doi.org/10.4049/jimmunol.177.1.566

    Article  CAS  PubMed  Google Scholar 

  11. Ciftci O, Ozcan C, Kamisli O, Cetin A, Basak N, Aytac B (2015) Hesperidin, a citrus flavonoid, has the ameliorative effects against experimental autoimmune encephalomyelitis (EAE) in a C57BL/J6 mouse model. Neurochem Res 40: 1111–1120. https://doi.org/10.1007/s11064-015-1571-8

    Article  CAS  PubMed  Google Scholar 

  12. Zeng Y, Song C, Ding X, Ji X, Yi L, Zhu K (2007) Baicalin reduces the severity of experimental autoimmune encephalomyelitis. Braz J Med Biol Res 40: 1003-1010. https://doi.org/10.1590/s0100-879x2006005000115

    Article  CAS  PubMed  Google Scholar 

  13. Jiang Y, Zou Y, Chen S, Zhu C, Wu A, Liu Y, Ma L, Zhu D, Ma X, Liu M, Kang Z, Pi R, Peng F, Wang Q, Chen X (2013) The anti-inflammatory effect of donepezil on experimental autoimmune encephalomyelitis in C57 BL/6 mice. Neuropharmacology 73: 415-424. https://doi.org/10.1016/j.neuropharm.2013.06.023

    Article  CAS  PubMed  Google Scholar 

  14. Feng J, Tao T, Yan W, Chen CS, Qin X (2014) Curcumin inhibits mitochondrial injury and apoptosis from the early stage in EAE mice. Oxid Med Cell Longev 2014: 728751. https://doi.org/10.1155/2014/728751

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Malhotra A, Bath S, Elbarbry F (2015) An organ system approach to explore the antioxidative, anti-inflammatory, and cytoprotective actions of resveratrol. Oxid Med Cell Longev 2015: 803971. https://doi.org/10.1155/2015/803971

    Article  PubMed  PubMed Central  Google Scholar 

  16. Salehi B, Mishra AP, Nigam M, Sener B, Kilic M, Sharifi-Rad M, Fokou PVT, Martins N, Sharifi-Rad J (2018) Resveratrol: A Double-Edged Sword in Health Benefits. Biomedicines 6(3): 91. https://doi.org/10.3390/biomedicines6030091

    Article  CAS  PubMed Central  Google Scholar 

  17. Gülçin I (2010) Antioxidant properties of resveratrol: A structure–activity insight.Innov. Food Sci Emerg Technol 11: 210–218. https://doi.org/10.1016/j.ifset.2009.07.002

    Article  CAS  Google Scholar 

  18. Kong F, Zhang R, Zhao X, Zheng G, Wang Z, Wang P (2017) Resveratrol raises in vitro anticancer effects of paclitaxel in NSCLC cell line A549 through COX-2 expression. J Physiol Pharmacol 21: 465–474. https://doi.org/10.4196/kjpp.2017.21.5.465

    Article  CAS  Google Scholar 

  19. Fonseca-Kelly Z, Nassrallah M, Uribe J, Khan RS, Dine K, Dutt M, Shindler KS (2012) Resveratrol neuroprotection in a chronic mouse model of multiple sclerosis. Frontiers in Neurolog 3: 3–84. https://doi.org/10.3389/fneur.2012.00084

    Article  Google Scholar 

  20. Yagi K (1988) Simple assay for the level of total lipid peroxides in serum or plasma. Molecular Biology 108: 101–106. https://doi.org/10.1385/0-89603-472-0:101

    Article  Google Scholar 

  21. Sedlak J, Lindsay RH (1968) Estimation of total, protein-bound, and nonprotein sulfhydryl groups in tissue with Ellman’s reagent. Analytical Biochemistry 25(1): 192–205. https://doi.org/10.1016/0003-2697(68)90092-4

    Article  CAS  PubMed  Google Scholar 

  22. Sun Y, Oberley LW, Li Y (1988) A simple method for clinical assay of superoxide dismutase. Clinical Chemistry 34(3): 497–500. https://doi.org/10.1093/clinchem/34.3.497

    Article  CAS  PubMed  Google Scholar 

  23. Aebi H (1984) Catalase in vitro. Methods in enzymology. Elsevier 105: 121–126. https://doi.org/10.1016/s0076-6879(84)05016-3

    Article  CAS  Google Scholar 

  24. Paglia DE, Valentine WN (1967) Studies on the quantitative and qualitative characterization of erythrocyte glutathione peroxidase. J Lab Clin Med 70: 158–169. https://doi.org/10.5555/uri:pii:0022214367900765

    Article  CAS  PubMed  Google Scholar 

  25. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with folin phenol reagent. Journal of Biological Chemistry 193(1): 265–275. https://doi.org/10.1016/S0021-9258(19)52451-6

    Article  CAS  PubMed  Google Scholar 

  26. Allen I, Brankin B (1993) Pathogenesis of multiple sclerosis-the immune diathesis and the role of viruses. J Neuropathol Exp Neurol 52: 95–105. https://doi.org/10.1097/00005072-199303000-00001

    Article  CAS  PubMed  Google Scholar 

  27. di Penta A, Moreno B, Reix S, Fernandez-Diez B, Villanueva M, Errea O, Escala N, Vandenbroeck K, Comella JX, Villoslada P (2013) Oxidative stress and proinflammatory cytokinescontribute to demyelination and axonal damage in a cerebellar culture model of neuroinflammation. PLoS One 8: e54722. https://doi.org/10.1371/journal.pone.0054722

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Ghareghani M, Zibara K, Sadeghi H, Farhadi N (2018) Spasticity treatment ameliorates the efficacy ofmelatonin therapy in experimental autoimmune encephalomyelitis (EAE) mouse model ofmultiple sclerosis. Cell Mol Neurobiol 38(5): 1145–1151. https://doi.org/10.1007/s10571-018-0580-y

    Article  CAS  PubMed  Google Scholar 

  29. Venturini CD, Merlo S, Souto AA, Fernandes M da C, Gomez R, Rhoden CR (2010) Resveratrol and red wine function as antioxidants in the nervous system without cellular proliferative effects during experimental diabetes.Oxid Med Cell Longev 3(6): 434–441. https://doi.org/10.4161/oxim.3.6.14741

    Article  PubMed  PubMed Central  Google Scholar 

  30. Simão F, Matté A, Matté C, Soares FM, Wyse AT, Netto CA, Salbego CG (2011) Resveratrol prevents oxidative stress and inhibition of Na(+)K(+)-ATPase activity induced by transient global cerebral ischemia in rats. J Nutr Biochem 22(10): 921–928. https://doi.org/10.1016/j.jnutbio.2010.07.013

    Article  CAS  PubMed  Google Scholar 

  31. Mosayebi G, Ghazavi A, Salehi H, Payani MA, Khazae MR (2007) Effect of sesame oil on the inhibition of experimental autoimmune encephalomyelitis in C57BL/6 mice. Pak J Biol Sci 10: 1790–1796. https://doi.org/10.3923/pjbs.2007.1790.1796

    Article  CAS  PubMed  Google Scholar 

  32. Wang D, Li SP, Fu JS, Zhang S, Bai L, Guo L (2016) Resveratrol defends blood-brain barrier integrity in experimental autoimmune encephalomyelitis mice. J Neurophysiol 116(5): 2173–2179. https://doi.org/10.1152/jn.00510.2016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Shindler KS, Ventura E, Dutt M, Elliott P, Fitzgerald DC, Rostami A (2010) Oral resveratrol reduces neuronal damage in a model of multiple sclerosis. J Neuroophthalmol 30(4): 328–339. https://doi.org/10.1097/WNO.0b013e3181f7f833

    Article  PubMed  PubMed Central  Google Scholar 

  34. Gandy K, Zhang J, Nagarkatti P, Nagarkatti M (2019) Resveratrol (3, 5, 4'-Trihydroxy-trans-Stilbene) Attenuates a Mouse Model of Multiple Sclerosis by Altering the miR-124/Sphingosine Kinase 1 Axis in Encephalitogenic T Cells in the Brain. J Neuroimmune Pharmacol 14(3): 462–477. https://doi.org/10.1007/s11481-019-09842-5

    Article  PubMed  PubMed Central  Google Scholar 

  35. Sato F, Martinez NE, Shahid M, Rose JW, Carlson NG, Tsunoda I (2013) Resveratrol exacerbates both autoimmune and viral models of multiple sclerosis. Am J Pathol 183(5): 1390–1396. https://doi.org/10.1016/j.ajpath.2013.07.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Dong YT, Cao K, Tan LC, Wang XL, Qi XL, Xiao Y, Guan ZZ (2018) Stimulation of SIRT1 Attenuates the Level of Oxidative Stress in the Brains of APP/PS1 Double Transgenic Mice and in Primary Neurons Exposed to Oligomers of the Amyloid-β Peptide. J Alzheimers Dis 63(1): 283–301. https://doi.org/10.3233/JAD-171020

    Article  CAS  PubMed  Google Scholar 

  37. Yan L, Guo MS, Zhang Y, Yu L, Wu JM, Tang Y, Ai W, Zhu FD, Law BY, Chen Q, Yu CL, Wong VK, Li H, Li M, Zhou XG, Qin DL, Wu AG (2022) Dietary Plant Polyphenols as the Potential Drugs in Neurodegenerative Diseases: Current Evidence, Advances, and Opportunities. Oxid Med Cell Longev 2022: 5288698. https://doi.org/10.1155/2022/5288698

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Chu F, Shi M, Zheng C, Shen D, Zhu J, Zheng X, Cui L (2018) The roles of macrophages and microglia in multiple sclerosis and experimental autoimmune encephalomyelitis. J Neuroimmunol 318: 1–7. https://doi.org/10.1016/j.jneuroim.2018.02.015

    Article  CAS  PubMed  Google Scholar 

  39. Bjelobaba I, Begovic-Kupresanin V, Pekovic S, Lavrnja I (2018) Animal models of multiple sclerosis: focus on experimental autoimmune encephalomyelitis. J Neuro Res 96: 1021–1042. https://doi.org/10.1002/jnr.24224

    Article  CAS  Google Scholar 

  40. Zhou ZX (2018) Anti-inflammatory activity of resveratrol prevents inflammation by inhibiting NF-kB in animal models of acute pharyngitis. Mol Med Rep 17: 1269–1274. https://doi.org/10.3892/mmr.2017.7933

    Article  CAS  PubMed  Google Scholar 

  41. Idriss HT, Naismith JH (2000) TNF alpha and the TNF receptor superfamily: structure-function relationship(s). Microsc Res Tech 50: 184–195. https://doi.org/10.1002/1097-0029(20000801)50:3<184::AID-JEMT2>3.0.CO;2-H

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Author information

Authors and Affiliations

  1. University of Inonu, Faculty of Medicine, Department of Neurology, 44280, Malatya, Turkey

    M. Tecellioğlu

  2. University of Inonu, Faculty of Pharmacy, Department of Pharmaceutical Toxicology, 44280, Malatya, Turkey

    N. Başak Türkmen & H. Yüce

  3. University of Pamukkale, Faculty of Medicine, Department of Pharmacology, Denizli, Turkey

    O. Ciftçi

  4. University of Inonu, Faculty of Medicine, Department of Histology and Embryology, 44280, Malatya, Turkey

    A. Taşlıdere

  5. Malatya Training and Research Hospital, Department of Neurology, Malatya, Turkey

    T. Ekmekyapar

  6. University of Bezmialem, Faculty of Medicine, Department of Brain and neurosurgery, İstanbul, Turkey

    M. N. Öztanır

  7. Unıversity of Health Sciences, Faculty of Medicine,Department of Neurology, Bursa, Turkey

    C. Özcan

Authors
  1. M. Tecellioğlu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. N. Başak Türkmen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. O. Ciftçi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A. Taşlıdere
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. T. Ekmekyapar
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. H. Yüce
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. M. N. Öztanır
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. C. Özcan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to N. Başak Türkmen.

Ethics declarations

Conflıct of Interest

The authors have declared no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tecellioğlu, M., Türkmen, N.B., Ciftçi, O. et al. The Beneficial Effects of Resveratrol on Experimental Autoimmune Encephalomyelitis (EAE) in C57BL/6J Mouse Model. J Evol Biochem Phys 58, 1041–1054 (2022). https://doi.org/10.1134/S0022093022040093

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1134/S0022093022040093

Keywords:

Search

Navigation