title: Dextromethorphan reduces oxidative stress and inhibits atherosclerosis and neointima formation in mice.
abstract: OBJECTIVE
  Macrophage-related oxidative stress plays an important role in the inflammatory process in atherosclerosis. Recently, dextromethorphan (DXM), a common cough-suppressing ingredient with a high safety profile, was found to inhibit the activation of microglia, the resident macrophage in the nervous system. We investigated whether DXM could reduce macrophage production of cytokines and superoxide and the resultant influence on atherosclerosis formation in mice.
  
  
  RESULTS
  We used in vitro and in vivo studies to evaluate the DXM inhibitory effect on oxidative stress. Dextromethorphan pretreatment significantly suppressed the production of tumour necrosis factor-alpha, monocyte chemoattractant protein-1, interleukin-6, interleukin-10, and superoxide in macrophage cell culture after stimulation. Indeed, DXM reduced macrophage nicotinamide adenine dinucleotide phosphate oxidase activity by decreasing membrane translocation of p47(phox) and p67(phox) through the inhibition of protein kinase C and extracellular signal-regulated kinase activation. The anti-atherosclerosis effect of DXM was tested using two animal models, apolipoprotein E (apoE)-deficient mice and a mouse carotid ligation model. Dextromethorphan treatment (10-40 mg/kg/day) for 10 weeks in apoE-deficient mice significantly reduced superoxide production in their polymorphonuclear leukocytes and aortas. It significantly decreased the severity of aortic atherosclerosis in the apoE-deficient mice and decreased carotid neointima formation after ligation in C57BL/6 mice.
  
  
  CONCLUSIONS
  Our data show that DXM, with its novel effect in reducing oxidative stress, significantly reduces atherosclerosis and neointima formation in mice.
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan, Republic of China.
authors.forename: Shu-Lin
authors.initials: SL
authors.lastname: Liu
authors.forename: Yi-Heng
authors.initials: YH
authors.lastname: Li
authors.forename: Guey-Yueh
authors.initials: GY
authors.lastname: Shi
authors.forename: Sei-Hui
authors.initials: SH
authors.lastname: Tang
authors.forename: Shinn-Jong
authors.initials: SJ
authors.lastname: Jiang
authors.forename: Chia-Wei
authors.initials: CW
authors.lastname: Huang
authors.forename: Ping-Yen
authors.initials: PY
authors.lastname: Liu
authors.forename: Jau-Shyong
authors.initials: JS
authors.lastname: Hong
authors.forename: Hua-Lin
authors.initials: HL
authors.lastname: Wu
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002339:Carotid Arteries / Q000601:surgery; D020212:Carotid Artery Injuries / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D016207:Cytokines / Q000378:metabolism; D003915:Dextromethorphan / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D006965:Hyperplasia; D008026:Ligation; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D019255:NADPH Oxidases / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D010750:Phosphoproteins / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D021381:Protein Transport; D013481:Superoxides / Q000378:metabolism; D017539:Tunica Intima / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology
chemical_list: D000975:Antioxidants; D001057:Apolipoproteins E; D016207:Cytokines; D008070:Lipopolysaccharides; D010750:Phosphoproteins; C079789:neutrophil cytosol factor 67K; D013481:Superoxides; D003915:Dextromethorphan; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1; D011493:Protein Kinase C; D048049:Extracellular Signal-Regulated MAP Kinases