{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T16:17:10Z","timestamp":1791476230165,"version":"4.3.4"},"reference-count":40,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2020,12,1]],"date-time":"2020-12-01T00:00:00Z","timestamp":1606780800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,12,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>Multiple sclerosis is a common autoimmune inflammatory disease of the central nervous system. There are several underlying mechanisms for the pathogenesis of the disease, including inflammation, oligodendrocyte apoptosis and oxidative stress.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>The mechanism of action of shikonin was investigated in the C57BL\/6 experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key findings<\/jats:title>\n                    <jats:p>The results revealed that EAE induction significantly increased the extent of demyelination in the corpus callosum tissues of the animals, while treatment of the mice with shikonin significantly decreased the extent of demyelination. Real-time polymerase chain reaction-based analysis of the brain samples from the EAE mice revealed significant enhancement in the expression levels of tumour necrosis factor-\u03b1 (TNF-\u03b1), interferon-\u03b3 (IFN-\u03b3) and Bax genes as well as a reduction in the expression levels of transforming growth factor-\u00df (TGF-\u03b2) and Bcl2. But, shikonin treatment significantly reduced the expression levels of TNF-\u03b1, IFN-\u03b3 and Bax. On the other hand, the expression levels of TGF-\u03b2 and Bcl2 as well as the activity of glutathione peroxidase-1 (GPX-1) enzyme were significantly increased following the shikonin treatment.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This study emphasized the immune-modulatory and antioxidative effects of shikonin, which may have an important healing effect on the severity of EAE.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/jphp.13364","type":"journal-article","created":{"date-parts":[[2020,9,28]],"date-time":"2020-09-28T16:37:10Z","timestamp":1601311030000},"page":"1970-1976","source":"Crossref","is-referenced-by-count":24,"title":["Shikonin ameliorates experimental autoimmune encephalomyelitis (EAE) via immunomodulatory, anti-apoptotic and antioxidative activity"],"prefix":"10.1093","volume":"72","author":[{"given":"Mehrdad","family":"Nasrollahzadeh Sabet","sequence":"first","affiliation":[{"name":"School of Medicine, Aja University of Medical Science , Tehran,","place":["Iran"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sajjad","family":"Biglari","sequence":"additional","affiliation":[{"name":"School of Medicine, Aja University of Medical Science , Tehran,","place":["Iran"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hamid Reza","family":"Khorram Khorshid","sequence":"additional","affiliation":[{"name":"Individualized Medicine and Genometabolomics Research Center, Hope Generation Foundation , Tehran,","place":["Iran"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4519-8298","authenticated-orcid":false,"given":"Emran","family":"Esmaeilzadeh","sequence":"additional","affiliation":[{"name":"School of Medicine, Aja University of Medical Science , Tehran,","place":["Iran"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,12,1]]},"reference":[{"key":"2024110604212935700_jphp13364-cit-0001","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ncl.2017.08.002","article-title":"Multiple sclerosis: mechanisms of disease and strategies for myelin and axonal repair","volume":"36","author":"Lemus","year":"2018","journal-title":"Neurol Clin"},{"key":"2024110604212935700_jphp13364-cit-0002","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12974-018-1263-9","article-title":"Anti-CD52 antibody treatment depletes B cell aggregates in the central nervous system in a mouse model of multiple sclerosis","volume":"15","author":"Simon","year":"2018","journal-title":"J Neuroinflammation"},{"key":"2024110604212935700_jphp13364-cit-0003","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/j.tins.2005.01.006","article-title":"Multiple sclerosis: novel perspectives on newly forming lesions","volume":"28","author":"Matute","year":"2005","journal-title":"Trends Neurosci"},{"key":"2024110604212935700_jphp13364-cit-0004","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.msard.2018.09.035","article-title":"Thymosins in multiple sclerosis and its experimental models: moving from basic to clinical application","volume":"27","author":"Severa","year":"2019","journal-title":"Mult Scler Relat Disord."},{"key":"2024110604212935700_jphp13364-cit-0005","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1034\/j.1600-065X.2000.17709.x","article-title":"Chemokines and chemokine receptors in inflammation of the nervous system: manifold roles and exquisite regulation","volume":"177","author":"Huang","year":"2000","journal-title":"Immunol Rev"},{"key":"2024110604212935700_jphp13364-cit-0006","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1038\/383787a0","article-title":"Functional diversity of helper T lymphocytes","volume":"383","author":"Abbas","year":"1996","journal-title":"Nature"},{"key":"2024110604212935700_jphp13364-cit-0007","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1111\/j.1365-2567.2007.02719.x","article-title":"Immunological decision-making: how does the immune system decide to mount a helper T-cell response?","volume":"123","author":"Kaiko","year":"2008","journal-title":"Immunology"},{"key":"2024110604212935700_jphp13364-cit-0008","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1007\/s001090050101","article-title":"Role of macrophages\/microglia in multiple sclerosis and experimental allergic encephalomyelitis","volume":"75","author":"Benveniste","year":"1997","journal-title":"J Mol Med"},{"key":"2024110604212935700_jphp13364-cit-0009","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1177\/1352458507080111","article-title":"Oxidative stress and excitotoxicity: a therapeutic issue in multiple sclerosis?","volume":"14","author":"Gonsette","year":"2008","journal-title":"Mult Scler J"},{"key":"2024110604212935700_jphp13364-cit-0010","doi-asserted-by":"crossref","first-page":"AN20120088","DOI":"10.1042\/AN20120088","article-title":"Increased carbonylation, protein aggregation and apoptosis in the spinal cord of mice with experimental autoimmune encephalomyelitis","volume":"5","author":"Dasgupta","year":"2013","journal-title":"ASN Neuro"},{"issue":"3","key":"2024110604212935700_jphp13364-cit-0011","doi-asserted-by":"crossref","first-page":"AN20110064","DOI":"10.1042\/AN20110064","article-title":"Protein carbonylation and aggregation precede neuronal apoptosis induced by partial glutathione depletion","volume":"4","author":"Dasgupta","year":"2012","journal-title":"ASN Neuro"},{"key":"2024110604212935700_jphp13364-cit-0012","first-page":"4113","article-title":"Necrostatin-1 ameliorates the pathogenesis of experimental autoimmune encephalomyelitis by suppressing apoptosis and necroptosis of oligodendrocyte precursor cells","volume":"18","author":"Wang","year":"2019","journal-title":"Exp Ther Med"},{"key":"2024110604212935700_jphp13364-cit-0013","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/j.jneuroim.2018.06.002","article-title":"Sildenafil ameliorates EAE by decreasing apoptosis in the spinal cord of C57BL\/6 mice","volume":"321","author":"Duarte-Silva","year":"2018","journal-title":"J Neuroimmunol"},{"key":"2024110604212935700_jphp13364-cit-0014","doi-asserted-by":"crossref","first-page":"9022","DOI":"10.1038\/srep09022","article-title":"Kirenol attenuates experimental autoimmune encephalomyelitis by inhibiting differentiation of Th1 and th17 cells and inducing apoptosis of effector T cells","volume":"5","author":"Xiao","year":"2015","journal-title":"Sci Rep"},{"key":"2024110604212935700_jphp13364-cit-0015","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1111\/j.1600-0404.2009.01295.x","article-title":"Mitoxantrone treatment in multiple sclerosis induces TH2-type cytokines","volume":"122","author":"Vogelgesang","year":"2010","journal-title":"Acta Neurol Scand"},{"key":"2024110604212935700_jphp13364-cit-0016","doi-asserted-by":"crossref","first-page":"2018","DOI":"10.1016\/S0140-6736(02)12023-X","article-title":"Mitoxantrone in progressive multiple sclerosis: a placebo-controlled, double-blind, randomised, multicentre trial","volume":"360","author":"Hartung","year":"2002","journal-title":"Lancet"},{"key":"2024110604212935700_jphp13364-cit-0017","doi-asserted-by":"crossref","first-page":"e00231","DOI":"10.1002\/prp2.231","article-title":"Anti-inflammatory, antiapoptotic, and antioxidant activity of fluoxetine","volume":"4","author":"Caiaffo","year":"2016","journal-title":"Pharmacol Res Perspect"},{"key":"2024110604212935700_jphp13364-cit-0018","doi-asserted-by":"crossref","first-page":"1590","DOI":"10.1007\/s11064-013-1061-9","article-title":"Shikonin protects dopaminergic cell line PC12 against 6-hydroxydopamine-mediated neurotoxicity via both glutathione-dependent and independent pathways and by inhibiting apoptosis","volume":"38","author":"Esmaeilzadeh","year":"2013","journal-title":"Neurochem Res"},{"key":"2024110604212935700_jphp13364-cit-0019","volume-title":"The Concomitant Effect of Shikonin and Glutathione Peroxidase-1 on Enhanced Survival of Dopaminergic Neurons against Parkinsonian Toxicity","author":"Esmaeilzadeh"},{"key":"2024110604212935700_jphp13364-cit-0020","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1016\/j.it.2005.08.014","article-title":"Virtues and pitfalls of EAE for the development of therapies for multiple sclerosis","volume":"26","author":"Steinman","year":"2005","journal-title":"Trends Immunol"},{"key":"2024110604212935700_jphp13364-cit-0021","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1002\/ddr.21540","article-title":"Curcumin ameliorates experimental autoimmune encephalomyelitis in a C57BL\/6 mouse model","volume":"80","author":"Esmaeilzadeh","year":"2019","journal-title":"Drug Dev Res"},{"key":"2024110604212935700_jphp13364-cit-0022","volume-title":"Glutathione Peroxidase: Activity and Steady-State Level of mRNA","author":"St Clair","year":"1996"},{"key":"2024110604212935700_jphp13364-cit-0023","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1089\/jir.2011.0065","article-title":"Cytokines in autoimmunity: role in induction, regulation, and treatment","volume":"31","author":"Moudgil","year":"2011","journal-title":"J Interferon Cytokine Res"},{"key":"2024110604212935700_jphp13364-cit-0024","first-page":"34","article-title":"Effect of gamma radiation on selected indicators of oxygen metabolism in erythrocytes of patients with multiple sclerosis","volume":"26","author":"Dudek","year":"1992","journal-title":"Neurol Neurochir Pol"},{"key":"2024110604212935700_jphp13364-cit-0025","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1046\/j.0953-816x.2000.01412.x","article-title":"LPS\/IFN-\u03b3 cytotoxicity in oligodendroglial cells: role of nitric oxide and protection by the anti-inflammatory cytokine IL-10","volume":"13","author":"Molina-Holgado","year":"2001","journal-title":"Eur J Neurosci"},{"key":"2024110604212935700_jphp13364-cit-0026","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1007\/BF02740619","article-title":"The effects of interferon-\u03b3 on the central nervous system","volume":"14","author":"Popko","year":"1997","journal-title":"Mol Neurobiol"},{"key":"2024110604212935700_jphp13364-cit-0027","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1191\/0269215503cr688oa","article-title":"Assessing mood in patients with multiple sclerosis","volume":"17","author":"Groom","year":"2003","journal-title":"Clin Rehabil"},{"key":"2024110604212935700_jphp13364-cit-0028","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1016\/j.neuropharm.2015.07.013","article-title":"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","volume":"99","author":"Mohajeri","year":"2015","journal-title":"Neuropharmacology"},{"key":"2024110604212935700_jphp13364-cit-0029","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1007\/s00005-017-0458-6","article-title":"Effects of IFN-\u03b21a and IFN-\u03b21b treatment on the expression of cytokines, inducible NOS (NOS type II), and myelin proteins in animal model of multiple sclerosis","volume":"65","author":"Lubina-D\u0105browska","year":"2017","journal-title":"Arch Immunol Ther Exp"},{"key":"2024110604212935700_jphp13364-cit-0030","doi-asserted-by":"crossref","first-page":"141","DOI":"10.5115\/acb.2012.45.3.141","article-title":"Mechanism of experimental autoimmune encephalomyelitis in Lewis rats: recent insights from macrophages","volume":"45","author":"Shin","year":"2012","journal-title":"Anat Cell Biol"},{"key":"2024110604212935700_jphp13364-cit-0031","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1016\/j.jaut.2011.06.003","article-title":"Distinct pathological patterns in relapsing\u2013remitting and chronic models of experimental autoimmune encephalomyelitis and the neuroprotective effect of glatiramer acetate","volume":"37","author":"Aharoni","year":"2011","journal-title":"J Autoimmun"},{"key":"2024110604212935700_jphp13364-cit-0032","doi-asserted-by":"crossref","first-page":"E5038","DOI":"10.1073\/pnas.1505955112","article-title":"IFN-\u03b3 ameliorates autoimmune encephalomyelitis by limiting myelin lipid peroxidation","volume":"112","author":"Sosa","year":"2015","journal-title":"Proc Natl Acad Sci"},{"key":"2024110604212935700_jphp13364-cit-0033","doi-asserted-by":"crossref","first-page":"3343","DOI":"10.1002\/eji.200526065","article-title":"Reduced suppressive effect of CD4+ CD25high regulatory T cells on the T cell immune response against myelin oligodendrocyte glycoprotein in patients with multiple sclerosis","volume":"35","author":"Haas","year":"2005","journal-title":"Eur J Immunol"},{"key":"2024110604212935700_jphp13364-cit-0034","first-page":"303","volume-title":"Transforming Growth Factor-Beta: Recent Advances on its Role in Immune Tolerance. Suppression and Regulation of Immune Responses","author":"Mantel","year":"2010"},{"key":"2024110604212935700_jphp13364-cit-0035","doi-asserted-by":"crossref","first-page":"s265","DOI":"10.1007\/s10072-003-0170-7","article-title":"Inflammation and degeneration in multiple sclerosis","volume":"24","author":"Br\u00fcck","year":"2003","journal-title":"Neurol Sci"},{"key":"2024110604212935700_jphp13364-cit-0036","first-page":"170","article-title":"Current immunotherapies for multiple sclerosis and neuromyelitis optica spectrum disorders: the similarities and differences","volume":"6","author":"Zhang","year":"2019","journal-title":"Neuroimmunol Neuroinflamm"},{"key":"2024110604212935700_jphp13364-cit-0037","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1007\/s00415-005-0037-3","article-title":"Oxidative stress in serum and peripheral blood leukocytes in patients with different disease courses of multiple sclerosis","volume":"253","author":"Koch","year":"2006","journal-title":"J Neurol"},{"key":"2024110604212935700_jphp13364-cit-0038","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1111\/j.1471-4159.2007.04506.x","article-title":"Inhibition of the myosin light chain kinase prevents hypoxia-induced blood\u2013brain barrier disruption","volume":"102","author":"Kuhlmann","year":"2007","journal-title":"J Neurochem"},{"key":"2024110604212935700_jphp13364-cit-0039","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/j.ejphar.2010.06.027","article-title":"Shikonin protects mouse brain against cerebral ischemia\/reperfusion injury through its antioxidant activity","volume":"643","author":"Wang","year":"2010","journal-title":"Eur J Pharmacol"},{"key":"2024110604212935700_jphp13364-cit-0040","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41598-017-18058-7","article-title":"Shikonin protects PC12 cells against \u03b2-amyloid peptide-induced cell injury through antioxidant and antiapoptotic activities","volume":"8","author":"Tong","year":"2018","journal-title":"Sci Rep"}],"container-title":["Journal of Pharmacy and Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/jphp.13364","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/jphp.13364","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/academic.oup.com\/jpp\/article-pdf\/72\/12\/1970\/60434669\/jphp13364.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jpp\/article-pdf\/72\/12\/1970\/60434669\/jphp13364.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,11,5]],"date-time":"2024-11-05T23:23:48Z","timestamp":1730849028000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jpp\/article\/72\/12\/1970\/6132687"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,12,1]]},"references-count":40,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2020,12,1]]},"published-print":{"date-parts":[[2020,12,1]]}},"URL":"https:\/\/doi.org\/10.1111\/jphp.13364","relation":{"has-preprint":[{"id-type":"doi","id":"10.21203\/rs.3.rs-29517\/v1","asserted-by":"object"}]},"ISSN":["0022-3573","2042-7158"],"issn-type":[{"value":"0022-3573","type":"print"},{"value":"2042-7158","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2020,12]]},"published":{"date-parts":[[2020,12,1]]}}}