title: Low dose dextromethorphan attenuates moderate experimental autoimmune encephalomyelitis by inhibiting NOX2 and reducing peripheral immune cells infiltration in the spinal cord.
abstract: Dextromethorphan (DM) is a dextrorotary morphinan and a widely used component of cough medicine. Relatively high doses of DM in combination with quinidine are used for the treatment of mood disorders for patients with multiple sclerosis (MS). However, at lower doses, morphinans exert anti-inflammatory activities through the inhibition of NOX2-dependent superoxide production in activated microglia. Here we investigated the effects of high (10 mg/kg, i.p., "DM-10") and low (0.1 mg/kg, i.p., "DM-0.1") doses of DM on the development and progression of mouse experimental autoimmune encephalomyelitis (EAE), an animal model of MS. We found no protection by high dose DM treatment. Interestingly, a minor late attenuation by low dose DM treatment was seen in severe EAE that was characterized by a chronic disease course and a massive spinal cord infiltration of CD45(+) cells including T-lymphocytes, macrophages and neutrophils. Furthermore, in a less severe form of EAE, where lower levels of CD4(+) and CD8(+) T-cells, Iba1(+) microglia/macrophages and no significant infiltration of neutrophils were seen in the spinal cord, the treatment with DM-0.1 was remarkably more beneficial. The effect was the most significant at the peak of disease and was associated with an inhibition of NOX2 expression and a decrease in infiltration of monocytes and lymphocytes into the spinal cord. In addition, chronic treatment with low dose DM resulted in decreased demyelination and reduced axonal loss in the lumbar spinal cord. Our study is the first report to show that low dose DM is effective in treating EAE of moderate severity. Our findings reveal that low dose morphinan DM treatment may represent a new promising protective strategy for treating MS.
authors.affiliation: Department of Cell Biology and Human Anatomy, School of Medicine, University of California-Davis, 2425 Stockton Blvd, Sacramento, 95817 CA, USA.
authors.forename: Olga V
authors.initials: OV
authors.lastname: Chechneva
authors.forename: Florian
authors.initials: F
authors.lastname: Mayrhofer
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Daugherty
authors.forename: David E
authors.initials: DE
authors.lastname: Pleasure
authors.forename: Jau-Shyong
authors.initials: JS
authors.lastname: Hong
authors.forename: Wenbin
authors.initials: W
authors.lastname: Deng
mesh_terms: D000818:Animals; D018791:CD4 Lymphocyte Count; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects; D003711:Demyelinating Diseases / Q000473:pathology; D003915:Dextromethorphan / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D006023:Glycoproteins / Q000096:biosynthesis; D007150:Immunohistochemistry; D018655:Lymphocyte Count; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors*; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects; D063308:Myelin-Oligodendrocyte Glycoprotein; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors*; D018696:Neuroprotective Agents; D020556:Neutrophil Infiltration / Q000187:drug effects; D010446:Peptide Fragments / Q000096:biosynthesis; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D013481:Superoxides / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
chemical_list: D018691:Excitatory Amino Acid Antagonists; D006023:Glycoproteins; D008562:Membrane Glycoproteins; D063308:Myelin-Oligodendrocyte Glycoprotein; D018696:Neuroprotective Agents; D010446:Peptide Fragments; C445081:myelin oligodendrocyte glycoprotein (35-55); D013481:Superoxides; D012313:RNA; D003915:Dextromethorphan; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases