Erez Eitan1, Emmette R Hutchison1, Nigel H Greig2, David Tweedie2, Hasan Celik3, Soumita Ghosh3, Kenneth W Fishbein3, Richard G Spencer3, Carl Y Sasaki4, Paritosh Ghosh4, Soumen Das5, Susheela Chigurapati6, James Raymick7, Sumit Sarkar7, Srinivasulu Chigurupati7, Sudipta Seal8, Mark P Mattson9. 1. Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, MD 21224, USA. 2. Translational Gerontology Branch, National Institute on Aging Intramural Research Program, Baltimore, MD 21224, USA. 3. Laboratory of Clinical Investigation, National Institute on Aging Intramural Research Program, Baltimore, MD 21224, USA. 4. Laboratory of Immunology, National Institute on Aging Intramural Research Program, Baltimore, MD 21224, USA. 5. Material Science and Engineering College of Medicine, University of Central Florida, Orlando, FL 32816, USA. 6. Arkansas Regional Laboratory, Office of Regulatory Affairs, U.S. Food and Drug Administration, 3900 NCTR Road, Building 26, Jefferson, AR 72079, USA. 7. Division of Neurotoxicology, National Center for Toxicological Research/FDA, Jefferson, AR 72079, USA. 8. Advanced Materials Processing and Analysis Centre, Nanoscience Technology Center, Mechanical Materials Aerospace Engineering, University of Central Florida, Orlando, Fl 32816, USA. 9. Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, MD 21224, USA; Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: mark.mattson@nih.gov.
Abstract
OBJECTIVE: Multiple sclerosis (MS) is a debilitating neurological disorder involving an autoimmune reaction to oligodendrocytes and degeneration of the axons they ensheath in the CNS. Because the damage to oligodendrocytes and axons involves local inflammation and associated oxidative stress, we tested the therapeutic efficacy of combined treatment with a potent anti-inflammatory thalidomide analog (lenalidomide) and novel synthetic anti-oxidant cerium oxide nanoparticles (nanoceria) in the experimental autoimmune encephalomyelitis (EAE) mouse model of MS. METHODS: C57BL/6 mice were randomly assigned to a control (no EAE) group, or one of the four myelin oligodendrocyte glycoprotein-induced EAE groups: vehicle, lenalidomide, nanoceria, or lenalidomide plus nanoceria. During a 23 day period, clinical EAE symptoms were evaluated daily, and MRI brain scans were performed at 11-13 days and 20-22 days. Histological and biochemical analyses of brain tissue samples were performed to quantify myelin loss and local inflammation. RESULTS: Lenalidomide treatment alone delayed symptom onset, while nanoceria treatment had no effect on symptom onset or severity, but did promote recovery; lenalidomide and nanoceria each significantly attenuated white matter pathology and associated inflammation. Combined treatment with lenalidomide and nanoceria resulted in a near elimination of EAE symptoms, and reduced white matter pathology and inflammatory cell responses to a much greater extent than either treatment alone. INTERPRETATION: By suppressing inflammation and oxidative stress, combined treatment with lenalidomide and nanoceria can reduce demyelination and associated neurological symptoms in EAE mice. Our preclinical data suggest a potential application of this combination therapy in MS. Published by Elsevier Inc.
OBJECTIVE:Multiple sclerosis (MS) is a debilitating neurological disorder involving an autoimmune reaction to oligodendrocytes and degeneration of the axons they ensheath in the CNS. Because the damage to oligodendrocytes and axons involves local inflammation and associated oxidative stress, we tested the therapeutic efficacy of combined treatment with a potent anti-inflammatory thalidomide analog (lenalidomide) and novel synthetic anti-oxidant cerium oxide nanoparticles (nanoceria) in the experimental autoimmune encephalomyelitis (EAE) mouse model of MS. METHODS: C57BL/6 mice were randomly assigned to a control (no EAE) group, or one of the four myelin oligodendrocyte glycoprotein-induced EAE groups: vehicle, lenalidomide, nanoceria, or lenalidomide plus nanoceria. During a 23 day period, clinical EAE symptoms were evaluated daily, and MRI brain scans were performed at 11-13 days and 20-22 days. Histological and biochemical analyses of brain tissue samples were performed to quantify myelin loss and local inflammation. RESULTS:Lenalidomide treatment alone delayed symptom onset, while nanoceria treatment had no effect on symptom onset or severity, but did promote recovery; lenalidomide and nanoceria each significantly attenuated white matter pathology and associated inflammation. Combined treatment with lenalidomide and nanoceria resulted in a near elimination of EAE symptoms, and reduced white matter pathology and inflammatory cell responses to a much greater extent than either treatment alone. INTERPRETATION: By suppressing inflammation and oxidative stress, combined treatment with lenalidomide and nanoceria can reduce demyelination and associated neurological symptoms in EAE mice. Our preclinical data suggest a potential application of this combination therapy in MS. Published by Elsevier Inc.
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