EXPERIMENTAL IMMUNOLOGY
Therapeutic effects of pegylated-interferon-α2a in a mouse model of multiple sclerosis
Submission date: 2016-05-07
Final revision date: 2016-06-24
Acceptance date: 2016-08-16
Publication date: 2018-03-30
Cent Eur J Immunol 2018;43(1):9-17
KEYWORDS
ABSTRACT
Introduction:
Experimental autoimmune encephalomyelitis (EAE) is an animal model of multiple sclerosis (MS). EAE is mainly mediated by adaptive and innate immune responses that lead to an inflammatory demyelination and axonal damage. The aim of the present research was to examine the therapeutic efficacy of Peg interferon alpha 2a (Peg-IFN α-2a) as a serine protease inhibitor on EAE model.
Material and methods:
EAE induction was performed in female C57BL/6 mice by myelin oligodendrocyte glycoprotein (35-55) (MOG35-55) in Complete Freund’s Adjuvant (CFA) emulsion, and Peg-IFN α-2a was used for the treatment of EAE. During the course of the study, clinical evaluation was assessed, and on day 21 post-immunisation blood samples were taken from the heart of mice for evaluation of IL-6, and enzymatic and non-enzymatic antioxidants. The mice were sacrificed and the brains and cerebellums were removed for histological analysis.
Results:
Our findings indicated that Peg-IFN α-2a had beneficial effects on EAE by attenuation of the severity and a delay in the onset of disease. Histological analysis showed that treatment with Peg-IFN α-2a can reduce inflammation criteria. Moreover, in Peg-IFN α-2a-treated mice the serum level of IL-6 was significantly less than in controls, and total antioxidant capacity was significantly more than in the control animals.
Conclusions:
These data indicate that Peg-IFN α-2a as an anti-serine protease with immunomodulatory properties may be useful for the treatment of MS.
Experimental autoimmune encephalomyelitis (EAE) is an animal model of multiple sclerosis (MS). EAE is mainly mediated by adaptive and innate immune responses that lead to an inflammatory demyelination and axonal damage. The aim of the present research was to examine the therapeutic efficacy of Peg interferon alpha 2a (Peg-IFN α-2a) as a serine protease inhibitor on EAE model.
Material and methods:
EAE induction was performed in female C57BL/6 mice by myelin oligodendrocyte glycoprotein (35-55) (MOG35-55) in Complete Freund’s Adjuvant (CFA) emulsion, and Peg-IFN α-2a was used for the treatment of EAE. During the course of the study, clinical evaluation was assessed, and on day 21 post-immunisation blood samples were taken from the heart of mice for evaluation of IL-6, and enzymatic and non-enzymatic antioxidants. The mice were sacrificed and the brains and cerebellums were removed for histological analysis.
Results:
Our findings indicated that Peg-IFN α-2a had beneficial effects on EAE by attenuation of the severity and a delay in the onset of disease. Histological analysis showed that treatment with Peg-IFN α-2a can reduce inflammation criteria. Moreover, in Peg-IFN α-2a-treated mice the serum level of IL-6 was significantly less than in controls, and total antioxidant capacity was significantly more than in the control animals.
Conclusions:
These data indicate that Peg-IFN α-2a as an anti-serine protease with immunomodulatory properties may be useful for the treatment of MS.
REFERENCES (52)
2.
McDonald WI, Compston A, Edan G, et al. (2001): Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 50: 121-127.
3.
Naddafi F, Reza Haidari M, Azizi G, et al. (2013): Novel therapeutic approach by nicotine in experimental model of multiple sclerosis. Innov Clin Neurosci 10: 20-25.
4.
Azizi G, Navabi SS, Al-Shukaili A, et al. (2015): The Role of Inflammatory Mediators in the Pathogenesis of Alzheimer’s Disease. Sultan Qaboos Univ Med J 15: e305-316.
5.
Mirshafiey A, Asghari B, Ghalamfarsa G, et al. (2014): The significance of matrix metalloproteinases in the immunopathogenesis and treatment of multiple sclerosis. Sultan Qaboos Univ Med J 14: e13-25.
6.
Javanbakht MH, Sadria R, Djalali M, et al. (2014): Soy protein and genistein improves renal antioxidant status in experimental nephrotic syndrome. Nefrologia 34: 483-490.
7.
Ferreira B, Mendes F, Osório N, et al. (2013): Glutathione in multiple sclerosis. Br J Biomed Sci 70: 75-79.
8.
Bouzid D, Mansour RB, Amouri A, et al. (2013): Oxidative stress markers in intestinal mucosa of Tunisian inflammatory bowel disease patients. Saudi J Gastroenterol 19: 131-135.
9.
Qi X, Guy J, Nick H, et al. (1997): Increase of manganese superoxide dismutase, but not of Cu/Zn-SOD, in experimental optic neuritis. Invest Ophthalmol Vis Sci 38: 1203-1212.
10.
Deponte M (2013): Glutathione catalysis and the reaction mechanisms of glutathione-dependent enzymes. Biochim Biophys Acta 1830: 3217-3266.
11.
Meister A (1988): Glutathione metabolism and its selective modification. J Biol Chem 263: 17205-17208.
12.
Mannervik B (1987): The enzymes of glutathione metabolism: an overview. Biochem Soc Trans 15: 717-718.
13.
Smith IK, Vierheller TL, Thorne CA (1988): Assay of glutathione reductase in crude tissue homogenates using 5,5’-dithiobis(2-nitrobenzoic acid). Anal Biochem 175: 408-413.
14.
Erta M, Quintana A, Hidalgo J (2012): Interleukin-6, a major cytokine in the central nervous system. Int J Biol Sci 8: 1254-1266.
15.
Serada S, Fujimoto M, Mihara M, et al. (2008): IL-6 blockade inhibits the induction of myelin antigen-specific Th17 cells and Th1 cells in experimental autoimmune encephalomyelitis. Proc Natl Acad Sci U S A 105: 9041-9046.
16.
Lock C, Hermans G, Pedotti R, et al. (2002): Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis. Nat Med 8: 500-508.
17.
Cho HS, Mason K, Ramyar KX, et al. (2003): Structure of the extracellular region of HER2 alone and in complex with the Herceptin Fab. Nature 421: 756-760.
18.
Langrish CL, Chen Y, Blumenschein WM, et al. (2005): IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med 201: 233-240.
19.
Maimone D, Gregory S, Arnason BG, Reder AT (1991): Cytokine levels in the cerebrospinal fluid and serum of patients with multiple sclerosis. J Neuroimmunol 32: 67-74.
20.
Stelmasiak Z, Kozioł-Montewka M, Dobosz B, et al. (2000): Interleukin-6 concentration in serum and cerebrospinal fluid in multiple sclerosis patients. Med Sci Monit 6: 1104-1108.
21.
Ireland SJ, Blazek M, Harp CT, et al. (2012): Antibody-independent B cell effector functions in relapsing remitting multiple sclerosis: clues to increased inflammatory and reduced regulatory B cell capacity. Autoimmunity 45: 400-414.
22.
Maimone D, Guazzi GC, Annunziata P (1997): IL-6 detection in multiple sclerosis brain. J Neurol Sci 146: 59-65.
23.
Yan J, Liu J, Lin CY, et al. (2012): Interleukin-6 gene promoter-572 C allele may play a role in rate of disease progression in multiple sclerosis. Int J Mol Sci 13: 13667-13679.
24.
Okuda Y, Sakoda S, Bernard CC, et al. (1998): IL-6-deficient mice are resistant to the induction of experimental autoimmune encephalomyelitis provoked by myelin oligodendrocyte glycoprotein. Int Immunol 10: 703-708.
25.
Greer JM, Kuchroo VK, Sobel RA, Lees MB (1992): Identification and characterization of a second encephalitogenic determinant of myelin proteolipid protein (residues 178-191) for SJL mice. J Immunol 149: 783-788.
26.
Beck J, Rondot P, Catinot L, et al. (1988): Increased production of interferon gamma and tumor necrosis factor precedes clinical manifestation in multiple sclerosis: do cytokines trigger off exacerbations? Acta Neurol Scand 78: 318-323.
27.
Lopez-Diego RS, Weiner HL (2008): Novel therapeutic strategies for multiple sclerosis – a multifaceted adversary. Nat Rev Drug Discov 7: 909-925.
28.
Azizi G, Goudarzvand M, Afraei S, et al. (2015): Therapeutic effects of dasatinib in mouse model of multiple sclerosis. Immunopharmacol Immunotoxicol 37: 287-294.
29.
Afraei S, Azizi G, Zargar SJ, et al. (2015): New therapeutic approach by G2013 in experimental model of multiple sclerosis. Acta Neurol Belg 115: 259-266.
30.
Mirshafiey A, Ghalamfarsa G, Asghari B, et al. (2014): Receptor Tyrosine Kinase and Tyrosine Kinase Inhibitors: New Hope for Success in Multiple Sclerosis Therapy. Innov Clin Neurosci 11: 23-36.
31.
Azizi G, Haidari MR, Khorramizadeh M, et al. (2014): Effects of imatinib mesylate in mouse models of multiple sclerosis and in vitro determinants. Iran J Allergy Asthma Immunol 13: 198-206.
32.
Roche HL (2000): Clinical Pharmacology Review of Peg-interferon alfa-2a (Ro25-8310, PEGASYS).
33.
Reddy KR (2000): Controlled-release, pegylation, liposomal formulations: new mechanisms in the delivery of injectable drugs. Ann Pharmacother 34: 915-923.
34.
Strader DB, Wright T, Thomas DL, et al. (2004): Diagnosis, management, and treatment of hepatitis C. Hepatology 39: 1147-1171.
35.
Tong X, Arasappan A, Bennett F, et al. (2010): Preclinical characterization of the antiviral activity of SCH 900518 (narlaprevir), a novel mechanism-based inhibitor of hepatitis C virus NS3 protease. Antimicrob Agents Chemother 54: 2365-2370.
36.
Scarisbrick I (2008): The multiple sclerosis degradome: enzymatic cascades in development and progression of central nervous system inflammatory disease, in Advances in multiple Sclerosis and Experimental Demyelinating Diseases, Springer: 133-175.
37.
Eugster HP, Frei K, Kopf M, et al. (1998): IL-6-deficient mice resist myelin oligodendrocyte glycoprotein-induced autoimmune encephalomyelitis. Eur J Immunol 28: 2178-2187.
38.
Davitashvili D, Beridze M, Shakarishvili R, et al. (2012): The role of endogenous antiradical protective system in multiple sclerosis. Georgian Med News 205: 11-19.
39.
Ferretti G, Bacchetti T (2011): Peroxidation of lipoproteins in multiple sclerosis. J Neurol Sci 311: 92-97.
40.
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: 261-268.
41.
Haider L, Fischer MT, Frischer JM, et al. (2011): Oxidative damage in multiple sclerosis lesions. Brain 134: 1914-1924.
42.
Adamczyk-Sowa M, Pierzchala K, Sowa P, et al. (2014): Influence of melatonin supplementation on serum antioxidative properties and impact of the quality of life in multiple sclerosis patients. J Physiol Pharmacol 65: 543-550.
43.
Harris JRE, Budd R, Firestein G, et al. (2004): Nutrition and Rheumatic Diseases. In: Kelley’s Textbook of Rheumatology. 7th ed. Vol. 1. Elsevier & Saunders Inc, Philadelphia: 833-873.
44.
Clair E, Pisetsky W, Haynes F (2004): Rheumatoid Arthritis. 2nd ed. Lippincott & Wilkins Inc; USA: 3-4.
45.
Halliwell B, Gutteridge JM (1996): Free Radicals in Biology and Medicine. 1st ed. Clarendon Press, Oxford.
46.
Bauerova K, Bezek S (2000): Role of reactive oxygen and nitrogen species in etiopathogenesis of rheumatoid arthritis. General Physiol Biophys 18: 15-20.
47.
Heliövaara M, Knekt P, Aho K, et al. (1994): Serum antioxidants and risk of rheumatoid arthritis. Ann Rheum Dis 53: 51-53.
48.
Taysi S, Polat F, Gul M, et al. (2002): Lipid peroxidation, some extracellular antioxidants, and antioxidant enzymes in serum of patients with rheumatoid arthritis. Rheumatol Int 21: 200-204.
49.
Aryaeian N, Djalali M, Shahram F, et al. (2011): Beta-carotene, vitamin E, MDA, glutathione reductase and arylesterase activity levels in patients with active rheumatoid arthritis. Iran J Public Health 40: 102-109.
50.
Chiou YL, Chen YH, Ke T, et al. (2012): The effect of increased oxidative stress and ferritin in reducing the effectiveness of therapy in chronic hepatitis C patients. Clin Biochem 45: 1389-1393.
51.
Fedetz M, Matesanz F, Pascual M, et al. (2001): The -174/-597 promoter polymorphisms in the interleukin-6 gene are not associated with susceptibility to multiple sclerosis. J Neurol Sci 190: 69-72.
52.
Shahbazi M, Ebadi H, Fathi D, et al. (2010): HLA-DRB1*1501 intensifies the impact of IL-6 promoter polymorphism on the susceptibility to multiple sclerosis in an Iranian population. Mult Scler 16: 1173-1177.
Share
RELATED ARTICLE
| eISSN: | 1644-4124 |
| ISSN: | 1426-3912 |
We process personal data collected when visiting the website. The function of obtaining information about users and their behavior is carried out by voluntarily entered information in forms and saving cookies in end devices. Data, including cookies, are used to provide services, improve the user experience and to analyze the traffic in accordance with the Privacy policy. Data are also collected and processed by Google Analytics tool (more).
You can change cookies settings in your browser. Restricted use of cookies in the browser configuration may affect some functionalities of the website.
You can change cookies settings in your browser. Restricted use of cookies in the browser configuration may affect some functionalities of the website.
