Combination therapy with lenalidomide and nanoceria ameliorates CNS autoimmunity.
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.


CONCLUSIONS
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.
Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, MD 21224, USA.
Erez
E
Eitan
Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, MD 21224, USA.
Emmette R
ER
Hutchison
Translational Gerontology Branch, National Institute on Aging Intramural Research Program, Baltimore, MD 21224, USA.
Nigel H
NH
Greig
Translational Gerontology Branch, National Institute on Aging Intramural Research Program, Baltimore, MD 21224, USA.
David
D
Tweedie
Laboratory of Clinical Investigation, National Institute on Aging Intramural Research Program, Baltimore, MD 21224, USA.
Hasan
H
Celik
Laboratory of Clinical Investigation, National Institute on Aging Intramural Research Program, Baltimore, MD 21224, USA.
Soumita
S
Ghosh
Laboratory of Clinical Investigation, National Institute on Aging Intramural Research Program, Baltimore, MD 21224, USA.
Kenneth W
KW
Fishbein
Laboratory of Clinical Investigation, National Institute on Aging Intramural Research Program, Baltimore, MD 21224, USA.
Richard G
RG
Spencer
Laboratory of Immunology, National Institute on Aging Intramural Research Program, Baltimore, MD 21224, USA.
Carl Y
CY
Sasaki
Laboratory of Immunology, National Institute on Aging Intramural Research Program, Baltimore, MD 21224, USA.
Paritosh
P
Ghosh
Material Science and Engineering College of Medicine, University of Central Florida, Orlando, FL 32816, USA.
Soumen
S
Das
Arkansas Regional Laboratory, Office of Regulatory Affairs, U.S. Food and Drug Administration, 3900 NCTR Road, Building 26, Jefferson, AR 72079, USA.
Susheela
S
Chigurapati
Division of Neurotoxicology, National Center for Toxicological Research/FDA, Jefferson, AR 72079, USA.
James
J
Raymick
Division of Neurotoxicology, National Center for Toxicological Research/FDA, Jefferson, AR 72079, USA.
Sumit
S
Sarkar
Division of Neurotoxicology, National Center for Toxicological Research/FDA, Jefferson, AR 72079, USA.
Srinivasulu
S
Chigurupati
Advanced Materials Processing and Analysis Centre, Nanoscience Technology Center, Mechanical Materials Aerospace Engineering, University of Central Florida, Orlando, Fl 32816, USA.
Sudipta
S
Seal
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.
Mark P
MP
Mattson
D000704:Analysis of Variance; D000818:Animals; D015551:Autoimmunity / Q000187:drug effects*; D002478:Cells, Cultured; D002490:Central Nervous System / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D002563:Cerium / Q000627:therapeutic use*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy*; D005260:Female; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000187:drug effects; D007155:Immunologic Factors / Q000627:therapeutic use*; D000077269:Lenalidomide; D008279:Magnetic Resonance Imaging; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000627:therapeutic use; D013997:Time Factors
D016207:Cytokines; D007155:Immunologic Factors; D012333:RNA, Messenger; D002563:Cerium; D013792:Thalidomide; C030583:ceric oxide; D000077269:Lenalidomide
Cerebral ventricles; Cerium oxide nanoparticles; Demyelination; EAE; Multiple sclerosis