Combination therapy with lenalidomide and nanoceria ameliorates CNS autoimmunity.

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.

• Authors: Erez Eitan, Emmette R Hutchison, Nigel H Greig, David Tweedie, Hasan Celik, Soumita Ghosh, Kenneth W Fishbein, Richard G Spencer, Carl Y Sasaki, Paritosh Ghosh, Soumen Das, Susheela Chigurapati, James Raymick, Sumit Sarkar, Srinivasulu Chigurupati, Sudipta Seal, Mark P Mattson
• Journal: Experimental neurology (Exp Neurol) Vol. 273 Pg. 151-60 (Nov 2015) ISSN: 1090-2430 [Electronic] United States
• PMID: 26277686 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)
• Copyright: Published by Elsevier Inc.

Chemical References

• Cytokines
• Immunologic Factors
• RNA, Messenger
• Cerium
• Thalidomide
• ceric oxide
• Lenalidomide

Topics

• Analysis of Variance
• Animals
• Autoimmunity (drug effects)
• Cells, Cultured
• Central Nervous System (drug effects, immunology, pathology)
• Cerium (therapeutic use)
• Cytokines (genetics, metabolism)
• Disease Models, Animal
• Encephalomyelitis, Autoimmune, Experimental (drug therapy)
• Female
• Flow Cytometry
• Gene Expression Regulation (drug effects)
• Immunologic Factors (therapeutic use)
• Lenalidomide
• Magnetic Resonance Imaging
• Mice
• Mice, Inbred C57BL
• RNA, Messenger
• Thalidomide (analogs & derivatives, therapeutic use)
• Time Factors