Tempol ameliorates murine viral encephalomyelitis by preserving the blood-brain barrier, reducing viral load, and lessening inflammation.
Multiple sclerosis (MS) is a progressive inflammatory and/or demyelinating disease of the human central nervous system (CNS). Most of the knowledge about the pathogenesis of MS has been derived from murine models, such as experimental autoimmune encephalomyelitis and viral encephalomyelitis. Here, we infected female C57BL/6 mice with a neurotropic strain of the mouse hepatitis virus (MHV-59A) to evaluate whether treatment with the multifunctional antioxidant tempol (4-hydroxy-2,2,6,6-tetramethyl-1-piperidinyloxy) affects the ensuing encephalomyelitis. In untreated animals, neurological symptoms developed quickly: 90% of infected mice died 10 days after virus inoculation and the few survivors presented neurological deficits. Treatment with tempol (24 mg/kg, ip, two doses on the first day and daily doses for 7 days plus 2 mM tempol in the drinking water ad libitum) profoundly altered the disease outcome: neurological symptoms were attenuated, mouse survival increased up to 70%, and half of the survivors behaved as normal mice. Not surprisingly, tempol substantially preserved the integrity of the CNS, including the blood-brain barrier. Furthermore, treatment with tempol decreased CNS viral titers, macrophage and T lymphocyte infiltration, and levels of markers of inflammation, such as expression of inducible nitric oxide synthase, transcription of tumor necrosis factor-alpha and interferon-gamma, and protein nitration. The results indicate that tempol ameliorates murine viral encephalomyelitis by altering the redox status of the infectious environment that contributes to an attenuated CNS inflammatory response. Overall, our study supports the development of therapeutic strategies based on nitroxides to manage neuroinflammatory diseases, including MS.
Tsuhako
Maria Heloisa
MH
Laboratório de Imunologia Viral, Instituto Butantan, 05503-900 São Paulo, Brazil. mariaheloisa@butantan.gov.br
Augusto
Ohara
O
Linares
Edlaine
E
Chadi
Gerson
G
Giorgio
Selma
S
Pereira
Carlos A
CA
D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage*; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000473:pathology / Q000821:virology; D018352:Coronavirus Infections / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D003497:Cyclic N-Oxides / Q000008:administration & dosage*; D004679:Encephalomyelitis; D005260:Female; D006801:Humans; D007249:Inflammation; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009103:Multiple Sclerosis / Q000188:drug therapy; D006517:Murine hepatitis virus / Q000472:pathogenicity / Q000502:physiology*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D013113:Spin Labels; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics; D019562:Viral Load / Q000187:drug effects*
D000975:Antioxidants; D003497:Cyclic N-Oxides; D013113:Spin Labels; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II; C001803:tempol