@2024 Afarand., IRAN
ISSN: 2252-0805 The Horizon of Medical Sciences 2018;24(3):172-181
ISSN: 2252-0805 The Horizon of Medical Sciences 2018;24(3):172-181
The Effects of Hypiran on the Oxidative Stress in the Animal Model of Multiple Sclerosis
ARTICLE INFO
Article Type
Original ResearchAuthors
Abdollahpourasl M (1)Khezri Sh (*)
Abtahi Froushani SM (2)
Cheraghi O (3)
(*) Department of Biology, Faculty of Science, Urmia University, Urmia , Iran
(1) Department of Biology, Faculty of Science, Urmia University, Urmia , Iran
(2) Department of Microbiology, Faculty of Veterinary Medicine, Urmia University, Urmia , Iran
(3) Department of Biochemistry, Faculty of Biological Science, Tarbiat Modares University, Tehran, Iran
Correspondence
Address: Department of Biology, Faculty of Science, Urmia University, Urmia, IranPhone: +98 (44) 31942122
Fax: +98 (44) 32753172
sh.khezri@urmia.ac.ir
Article History
Received: December 2, 2017Accepted: May 22, 2018
ePublished: July 23, 2018
ABSTRACT
Aims
Hypiran is a commercial hydro-alcoholic extract of Hypericum perforatum.
Its anti-inflammatory and immune modulatory benefits have been reported
in several documents. This study was conducted to investigate the beneficial
potential of Hypiran in the treatment of ameliorating experimental autoimmune
encephalomyelitis (EAE).
Materials & Methods In this experimental study, EAE was induced by guinea pig spinal cord homogenate and complete Freund’s adjuvant in 30 male Wistar rats (6-8 weeks old, weighing 100± 20 g). Hypiran administration (110 mg/kgP.O.-daily) was initiated at day 12 post-immunization, when the rats developed a disability score. The brains and blood samples were collected on the day 36 and used for MDA, FRAP, NO and MPO experiments.
Findings Hypiran-therapy led to a better situation in EAE rats. The lipid peroxidation level (MDA assay) was significantly increased in brain tissues of the EAE rat compared to that of the normal control one (P<0.001). Treatment with hypiran could significantly reduce the MDA levels in brain tissues of the EAE rats compared to that of the EAE rats without treatment. Moreover, Serum analysis showed that hypiran could significantly decline the nitric oxide levels as well as myeloperoxidase activity of the EAE rats compared to that of the EAE rats without treatment. Moreover, docking server analysis indicated that the hypiran could inhibit the MAO enzyme.
Conclusion It seems that hypiran may be as a promising strategy to be treatment of Multiple Sclerosis patients.
Materials & Methods In this experimental study, EAE was induced by guinea pig spinal cord homogenate and complete Freund’s adjuvant in 30 male Wistar rats (6-8 weeks old, weighing 100± 20 g). Hypiran administration (110 mg/kgP.O.-daily) was initiated at day 12 post-immunization, when the rats developed a disability score. The brains and blood samples were collected on the day 36 and used for MDA, FRAP, NO and MPO experiments.
Findings Hypiran-therapy led to a better situation in EAE rats. The lipid peroxidation level (MDA assay) was significantly increased in brain tissues of the EAE rat compared to that of the normal control one (P<0.001). Treatment with hypiran could significantly reduce the MDA levels in brain tissues of the EAE rats compared to that of the EAE rats without treatment. Moreover, Serum analysis showed that hypiran could significantly decline the nitric oxide levels as well as myeloperoxidase activity of the EAE rats compared to that of the EAE rats without treatment. Moreover, docking server analysis indicated that the hypiran could inhibit the MAO enzyme.
Conclusion It seems that hypiran may be as a promising strategy to be treatment of Multiple Sclerosis patients.
CITATION LINKS
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[3]Wingerchuk DM, Carter JL. Multiple sclerosis: Current and emerging disease-modifying therapies and treatment strategies. Mayo Clin Proc. 2014;89(2):225-40.
[4]Liu Y, Holdbrooks AT, De Sarno P, Rowse AL, Yanagisawa LL, Mc Farland BC, et al. Therapeutic efficacy of suppressing the Jak/STAT pathway in multiple models of experimental autoimmune encephalomyelitis. J Immunol. 2014;192(1):59-72.
[5]Pryce G, Riddall DR, Selwood DL, Giovannoni G, Baker D. Neuroprotection in experimental autoimmune encephalomyelitis and progressive multiple sclerosis by cannabis-based cannabinoids. J Neuroimmune Pharmacol. 2015;10(2):281-92.
[6]Liu Y, Holdbrooks AT, Meares GP, Buckley JA, Benveniste EN, Qin H. Preferential recruitment of neutrophils into the cerebellum and brainstem contributes to the atypical experimental autoimmune encephalomyelitis phenotype. J Immunol. 2015;195(3):841-52.
[7]Kleemann B, Loos B, Scriba TJ, Lang D, Davids LM. St John's Wort (Hypericum perforatum L.) photomedicine: Hypericin-photodynamic therapy induces metastatic melanoma cell death. PLoS One. 2014;9(7):e103762.
[8]Russo E, Scicchitano F, Whalley BJ, Mazzitello C, Ciriaco M, Esposito S, et al. Hypericum perforatum: Pharmacokinetic, mechanism of action, tolerability, and clinical drug-drug interactions. Phytother Res. 2014;28(5):643-55.
[9]Anderson G, Kubera M, Duda W, Lasoń W, Berk M, Maes M. Increased IL-6 trans-signaling in depression: Focus on the tryptophan catabolite pathway, melatonin and neuroprogression. Pharmacol Rep. 2013;65(6):1647-54.
[10]Abtahi Froushani SM, Esmaili Gouvarchin Galee H, Khamisabadi M, Lotfallahzade B. Immunomudulatory effects of hydroalcoholic extract of Hypericum perforatum. Avicenna J Phytomed. 2015;5(1):62-8.
[11]Herold A, Cremer L, Călugaru A, Tamaş V, Ionescu F, Manea S, et al. Hydroalcoholic plant extracts with anti-inflammatory activity. Roum Arch Microbiol Immunol. 2003;62(1-2):117-29.
[12]Öztürk N, Kıyan HT. 233 - Evaluation of biological activities of Hypericum perforatum L. and Hypericum calycinum L. extracts. Free Radic Biol Med. 2016;100 Suppl:S107.
[13]Chen GQ, Chen YY, Wang XS, Wu SZ, Yang HM, Xu HQ, et al. Chronic caffeine treatment attenuates experimental autoimmune encephalomyelitis induced by guinea pig spinal cord homogenates in Wistar rats. Brain Res. 2010;1309:116-25.
[14]Cheraghi O, Dehghan GR, Mahdavi M, Rahbarghazi R, Rezabakhsh A, Nozad Charoudeh H, et al. Potent anti-angiogenic and cytotoxic effect of conferone on human colorectal adenocarcinoma HT-29 cells. Phytomedicine. 2016;23(4):398-405.
[15]Rabiei Z, Rafieian-Kopaei M, Heidarian E, Saghaei E, Mokhtari S. Effects of Zizyphus jujube extract on memory and learning impairment induced by bilateral electric lesions of the nucleus Basalis of Meynert in rat. Neurochem Res. 2014;39(2):353-60.
[16]Katalinic V, Modun D, Music I, Boban M. Gender differences in antioxidant capacity of rat tissues determined by 2,2'-azinobis (3-ethylbenzothiazoline 6-sulfonate; ABTS) and ferric reducing antioxidant power (FRAP) assays. Comp Biochem Physiol C Toxicol Pharmacol. 2005;140(1):47-52.
[17]Rezabakhsh A, Nabat E, Yousefi M, Montazersaheb S, Cheraghi O, Mehdizadeh A, et al. Endothelial cells' biophysical, biochemical, and chromosomal aberrancies in high-glucose condition within the diabetic range. Cell Biochem Funct. 2017;35(2):83-97.
[18]Love D, Barrett T, Hawkins C. P 038 - Role of the myeloperoxidase oxidant hypothiocyanous acid (HOSCN) in the adaption of cells to oxidative stress during inflammation. Free Radic Biol Med. 2017;108 Suppl 1:S30.
[19]Bikadi Z, Hazai E. Application of the PM6 semi-empirical method to modeling proteins enhances docking accuracy of AutoDock. J Cheminform. 2009;1:15.
[20]Huang N, Rizshsky L, Hauck CC, Nikolau BJ, Murphy PA, Birt DF. The inhibition of lipopolysaccharide-induced macrophage inflammation by 4 compounds in Hypericum perforatum extract is partially dependent on the activation of SOCS3. Phytochemistry. 2012;76:106-16.
[21]Kraus B, Wolff H, Elstner EF, Heilmann J. Hyperforin is a modulator of inducible nitric oxide synthase and phagocytosis in microglia and macrophages. Naunyn Schmiedebergs Arch Pharmacol. 2010;381(6):541-53.
[22]Huang HS, Liaw ET. Extraction optimization of flavonoids from Hypericum formosanum and matrix metalloproteinase-1 inhibitory activity. Molecules. 2017;22(12). pii: E2172.
[23]Abtahi Froushani SM, Delirezh N, Hobbenaghi R, Mosayebi G. Synergistic effects of atorvastatin and all-trans retinoic acid in ameliorating animal model of multiple sclerosis. Immunol Invest. 2014;43(1):54-68.
[24]Naziroglu M, Kutluhan S, Övey İS, Aykur M, Yurekli VA. Modulation of oxidative stress, apoptosis, and calcium entry in leukocytes of patients with multiple sclerosis by Hypericum perforatum. Nutr Neurosci. 2014;17(5):214-21.
[25]Sayre LM, Perry G, Smith MA. Oxidative stress and neurotoxicity. Chem Res Toxicol. 2008;21(1):172-88.
[26]Gowing E, Gendron S, Broux B, Lecuyer MA, Bourbonniere L, Larouche S, et al. Integrin alpha8 is a novel mediator of T lymphocyte migration across the CNS barriers. SAGE Publications. 2016;1352-4585.
[27]Wojkowska DW, Szpakowski P, Ksiazek-Winiarek D, Leszczynski M, Glabinski A. Interactions between neutrophils, Th17 cells, and chemokines during the initiation of experimental model of multiple sclerosis. Mediat Inflamm. 2014;2014:590409.
[28]Minagar A, Alexander JS. Blood-brain barrier disruption in multiple sclerosis. Mult Scler. 2003;9(6):540-9.
[29]Steinbach K, Piedavent M, Bauer S, Neumann JT, Friese MA. Neutrophils amplify autoimmune central nervous system infiltrates by maturing local APCs. J Immunol. 2013;191(9):4531-9.
[30]Mozaffari S, Esmaily H, Rahimi R, Baeeri M, Sanei Y, Asadi Shahmirzadi A, et al. Effects of Hypericum perforatum extract on rat irritable bowel syndrome. Pharmacogn Mag. 2011;7(27):213-23.
[31]Ljubisavljevic S, Stojanovic I, Pavlovic D, Sokolovic D, Stevanovic I. Aminoguanidine and N-acetyl-cysteine supress oxidative and nitrosative stress in EAE rat brains. Redox Rep. 2011;16(4):166-72.
[32]Zargari M, Allameh A, Sanati MH, Tiraihi T, Lavasani Sh, Emadyan O. 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. 2007;412(1):24-8.
[33]Shi R, Page JC, Tully M. Molecular mechanisms of acrolein-mediated myelin destruction in CNS trauma and disease. Free Radic Res. 2015;49(7):888-95.
[34]Mao P, Reddy PH. Is multiple sclerosis a mitochondrial disease?. Biochim Biophys Acta. 2010;1802(1):66-79.
[35]Calabrese V, Scapagnini G, Ravagna A, Bella R, Foresti R, Bates TE, et al. Nitric oxide synthase is present in the cerebrospinal fluid of patients with active multiple sclerosis and is associated with increases in cerebrospinal fluid protein nitrotyrosine and S-nitrosothiols and with changes in glutathione levels. J Neurosci Res. 2002;70(4):580-7.
[36]Waxman SG. Axonal conduction and injury in multiple sclerosis: The role of sodium channels. Nat Rev Neurosci. 2006;7(12):932-41.
[37]Van Der Walt A, Butzkueven H, Kolbe S, Marriott M, Alexandrou E, Gresle M, et al. Neuroprotection in multiple sclerosis: A therapeutic challenge for the next decade. Pharmacol Ther. 2010;126(1):82-93.
[38]Stys PK, Waxman SG, Ransom BR. Ionic mechanisms of anoxic injury in mammalian CNS white matter: Role of Na+ channels and Na(+)-Ca2+ exchanger. J Neurosci. 1992;12(2):430-9.
[39]Chataway J, Sawcer S, Feakes R, Coraddu F, Broadley S, Jones HB, et al. A screen of candidates from peaks of linkage: Evidence for the involvement of myeloperoxidase in multiple sclerosis. J Neuroimmunol. 1999;98(2):208-13.
[40]Zakrzewska-Pniewska B, Styczynska M, Podlecka A, Samocka R, Peplonska B, Barcikowska M, et al. Association of apolipoprotein E and myeloperoxidase genotypes to clinical course of familial and sporadic multiple sclerosis. Mult Scler. 2004;10(3):266-71.
[41]Minohara M, Matsuoka T, Li W, Osoegawa M, Ishizu T, Ohyagi Y, et al. Upregulation of myeloperoxidase in patients with opticospinal multiple sclerosis: Positive correlation with disease severity. J Neuroimmunol. 2006;178(1-2):156-60.
[42]Di Ciero Miranda M, De Bruin VM, Vale MR, Viana GS. Lipid peroxidation and nitrite plus nitrate levels in brain tissue from patients with Alzheimer's disease. Gerontology. 2000;46(4):179-84.
[43]Esteghamati AR, Zarban A, Doosti M. Evaulation of antioxidant status and oxidative stress markers in type II diabetes mellitus. Iran J Endocrinol Metab. 2002;3(4):239-45. [Persian]
[44]Musgrave T, Benson C, Wong G, Browne I, Tenorio G, Rauw G, et al. The MAO inhibitor phenelzine improves functional outcomes in mice with Experimental Autoimmune Encephalomyelitis (EAE). Brain Behav Immun. 2011;25(8):1677-88.
[2]Krupp LB, Tardieu M, Amato MP, Banwell B, Chitnis T, Dale RC, et al. International Pediatric Multiple Sclerosis Study Group criteria for pediatric multiple sclerosis and immune-mediated central nervous system demyelinating disorders: Revisions to the 2007 definitions. Mult Scler. 2013;19(10):1261-7.
[3]Wingerchuk DM, Carter JL. Multiple sclerosis: Current and emerging disease-modifying therapies and treatment strategies. Mayo Clin Proc. 2014;89(2):225-40.
[4]Liu Y, Holdbrooks AT, De Sarno P, Rowse AL, Yanagisawa LL, Mc Farland BC, et al. Therapeutic efficacy of suppressing the Jak/STAT pathway in multiple models of experimental autoimmune encephalomyelitis. J Immunol. 2014;192(1):59-72.
[5]Pryce G, Riddall DR, Selwood DL, Giovannoni G, Baker D. Neuroprotection in experimental autoimmune encephalomyelitis and progressive multiple sclerosis by cannabis-based cannabinoids. J Neuroimmune Pharmacol. 2015;10(2):281-92.
[6]Liu Y, Holdbrooks AT, Meares GP, Buckley JA, Benveniste EN, Qin H. Preferential recruitment of neutrophils into the cerebellum and brainstem contributes to the atypical experimental autoimmune encephalomyelitis phenotype. J Immunol. 2015;195(3):841-52.
[7]Kleemann B, Loos B, Scriba TJ, Lang D, Davids LM. St John's Wort (Hypericum perforatum L.) photomedicine: Hypericin-photodynamic therapy induces metastatic melanoma cell death. PLoS One. 2014;9(7):e103762.
[8]Russo E, Scicchitano F, Whalley BJ, Mazzitello C, Ciriaco M, Esposito S, et al. Hypericum perforatum: Pharmacokinetic, mechanism of action, tolerability, and clinical drug-drug interactions. Phytother Res. 2014;28(5):643-55.
[9]Anderson G, Kubera M, Duda W, Lasoń W, Berk M, Maes M. Increased IL-6 trans-signaling in depression: Focus on the tryptophan catabolite pathway, melatonin and neuroprogression. Pharmacol Rep. 2013;65(6):1647-54.
[10]Abtahi Froushani SM, Esmaili Gouvarchin Galee H, Khamisabadi M, Lotfallahzade B. Immunomudulatory effects of hydroalcoholic extract of Hypericum perforatum. Avicenna J Phytomed. 2015;5(1):62-8.
[11]Herold A, Cremer L, Călugaru A, Tamaş V, Ionescu F, Manea S, et al. Hydroalcoholic plant extracts with anti-inflammatory activity. Roum Arch Microbiol Immunol. 2003;62(1-2):117-29.
[12]Öztürk N, Kıyan HT. 233 - Evaluation of biological activities of Hypericum perforatum L. and Hypericum calycinum L. extracts. Free Radic Biol Med. 2016;100 Suppl:S107.
[13]Chen GQ, Chen YY, Wang XS, Wu SZ, Yang HM, Xu HQ, et al. Chronic caffeine treatment attenuates experimental autoimmune encephalomyelitis induced by guinea pig spinal cord homogenates in Wistar rats. Brain Res. 2010;1309:116-25.
[14]Cheraghi O, Dehghan GR, Mahdavi M, Rahbarghazi R, Rezabakhsh A, Nozad Charoudeh H, et al. Potent anti-angiogenic and cytotoxic effect of conferone on human colorectal adenocarcinoma HT-29 cells. Phytomedicine. 2016;23(4):398-405.
[15]Rabiei Z, Rafieian-Kopaei M, Heidarian E, Saghaei E, Mokhtari S. Effects of Zizyphus jujube extract on memory and learning impairment induced by bilateral electric lesions of the nucleus Basalis of Meynert in rat. Neurochem Res. 2014;39(2):353-60.
[16]Katalinic V, Modun D, Music I, Boban M. Gender differences in antioxidant capacity of rat tissues determined by 2,2'-azinobis (3-ethylbenzothiazoline 6-sulfonate; ABTS) and ferric reducing antioxidant power (FRAP) assays. Comp Biochem Physiol C Toxicol Pharmacol. 2005;140(1):47-52.
[17]Rezabakhsh A, Nabat E, Yousefi M, Montazersaheb S, Cheraghi O, Mehdizadeh A, et al. Endothelial cells' biophysical, biochemical, and chromosomal aberrancies in high-glucose condition within the diabetic range. Cell Biochem Funct. 2017;35(2):83-97.
[18]Love D, Barrett T, Hawkins C. P 038 - Role of the myeloperoxidase oxidant hypothiocyanous acid (HOSCN) in the adaption of cells to oxidative stress during inflammation. Free Radic Biol Med. 2017;108 Suppl 1:S30.
[19]Bikadi Z, Hazai E. Application of the PM6 semi-empirical method to modeling proteins enhances docking accuracy of AutoDock. J Cheminform. 2009;1:15.
[20]Huang N, Rizshsky L, Hauck CC, Nikolau BJ, Murphy PA, Birt DF. The inhibition of lipopolysaccharide-induced macrophage inflammation by 4 compounds in Hypericum perforatum extract is partially dependent on the activation of SOCS3. Phytochemistry. 2012;76:106-16.
[21]Kraus B, Wolff H, Elstner EF, Heilmann J. Hyperforin is a modulator of inducible nitric oxide synthase and phagocytosis in microglia and macrophages. Naunyn Schmiedebergs Arch Pharmacol. 2010;381(6):541-53.
[22]Huang HS, Liaw ET. Extraction optimization of flavonoids from Hypericum formosanum and matrix metalloproteinase-1 inhibitory activity. Molecules. 2017;22(12). pii: E2172.
[23]Abtahi Froushani SM, Delirezh N, Hobbenaghi R, Mosayebi G. Synergistic effects of atorvastatin and all-trans retinoic acid in ameliorating animal model of multiple sclerosis. Immunol Invest. 2014;43(1):54-68.
[24]Naziroglu M, Kutluhan S, Övey İS, Aykur M, Yurekli VA. Modulation of oxidative stress, apoptosis, and calcium entry in leukocytes of patients with multiple sclerosis by Hypericum perforatum. Nutr Neurosci. 2014;17(5):214-21.
[25]Sayre LM, Perry G, Smith MA. Oxidative stress and neurotoxicity. Chem Res Toxicol. 2008;21(1):172-88.
[26]Gowing E, Gendron S, Broux B, Lecuyer MA, Bourbonniere L, Larouche S, et al. Integrin alpha8 is a novel mediator of T lymphocyte migration across the CNS barriers. SAGE Publications. 2016;1352-4585.
[27]Wojkowska DW, Szpakowski P, Ksiazek-Winiarek D, Leszczynski M, Glabinski A. Interactions between neutrophils, Th17 cells, and chemokines during the initiation of experimental model of multiple sclerosis. Mediat Inflamm. 2014;2014:590409.
[28]Minagar A, Alexander JS. Blood-brain barrier disruption in multiple sclerosis. Mult Scler. 2003;9(6):540-9.
[29]Steinbach K, Piedavent M, Bauer S, Neumann JT, Friese MA. Neutrophils amplify autoimmune central nervous system infiltrates by maturing local APCs. J Immunol. 2013;191(9):4531-9.
[30]Mozaffari S, Esmaily H, Rahimi R, Baeeri M, Sanei Y, Asadi Shahmirzadi A, et al. Effects of Hypericum perforatum extract on rat irritable bowel syndrome. Pharmacogn Mag. 2011;7(27):213-23.
[31]Ljubisavljevic S, Stojanovic I, Pavlovic D, Sokolovic D, Stevanovic I. Aminoguanidine and N-acetyl-cysteine supress oxidative and nitrosative stress in EAE rat brains. Redox Rep. 2011;16(4):166-72.
[32]Zargari M, Allameh A, Sanati MH, Tiraihi T, Lavasani Sh, Emadyan O. 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. 2007;412(1):24-8.
[33]Shi R, Page JC, Tully M. Molecular mechanisms of acrolein-mediated myelin destruction in CNS trauma and disease. Free Radic Res. 2015;49(7):888-95.
[34]Mao P, Reddy PH. Is multiple sclerosis a mitochondrial disease?. Biochim Biophys Acta. 2010;1802(1):66-79.
[35]Calabrese V, Scapagnini G, Ravagna A, Bella R, Foresti R, Bates TE, et al. Nitric oxide synthase is present in the cerebrospinal fluid of patients with active multiple sclerosis and is associated with increases in cerebrospinal fluid protein nitrotyrosine and S-nitrosothiols and with changes in glutathione levels. J Neurosci Res. 2002;70(4):580-7.
[36]Waxman SG. Axonal conduction and injury in multiple sclerosis: The role of sodium channels. Nat Rev Neurosci. 2006;7(12):932-41.
[37]Van Der Walt A, Butzkueven H, Kolbe S, Marriott M, Alexandrou E, Gresle M, et al. Neuroprotection in multiple sclerosis: A therapeutic challenge for the next decade. Pharmacol Ther. 2010;126(1):82-93.
[38]Stys PK, Waxman SG, Ransom BR. Ionic mechanisms of anoxic injury in mammalian CNS white matter: Role of Na+ channels and Na(+)-Ca2+ exchanger. J Neurosci. 1992;12(2):430-9.
[39]Chataway J, Sawcer S, Feakes R, Coraddu F, Broadley S, Jones HB, et al. A screen of candidates from peaks of linkage: Evidence for the involvement of myeloperoxidase in multiple sclerosis. J Neuroimmunol. 1999;98(2):208-13.
[40]Zakrzewska-Pniewska B, Styczynska M, Podlecka A, Samocka R, Peplonska B, Barcikowska M, et al. Association of apolipoprotein E and myeloperoxidase genotypes to clinical course of familial and sporadic multiple sclerosis. Mult Scler. 2004;10(3):266-71.
[41]Minohara M, Matsuoka T, Li W, Osoegawa M, Ishizu T, Ohyagi Y, et al. Upregulation of myeloperoxidase in patients with opticospinal multiple sclerosis: Positive correlation with disease severity. J Neuroimmunol. 2006;178(1-2):156-60.
[42]Di Ciero Miranda M, De Bruin VM, Vale MR, Viana GS. Lipid peroxidation and nitrite plus nitrate levels in brain tissue from patients with Alzheimer's disease. Gerontology. 2000;46(4):179-84.
[43]Esteghamati AR, Zarban A, Doosti M. Evaulation of antioxidant status and oxidative stress markers in type II diabetes mellitus. Iran J Endocrinol Metab. 2002;3(4):239-45. [Persian]
[44]Musgrave T, Benson C, Wong G, Browne I, Tenorio G, Rauw G, et al. The MAO inhibitor phenelzine improves functional outcomes in mice with Experimental Autoimmune Encephalomyelitis (EAE). Brain Behav Immun. 2011;25(8):1677-88.