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Cardiovascular Research Advance Access first published online on February 3, 2009
This version [Corrected Proof] published online on February 24, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp043
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.

Dextromethorphan reduces oxidative stress and inhibits atherosclerosis and neointima formation in mice

Shu-Lin Liu1, Yi-Heng Li2,3, Guey-Yueh Shi1,3,*, Sei-Hui Tang1,3, Shinn-Jong Jiang1,3, Chia-Wei Huang1, Ping-Yen Liu2,3, Jau-Shyong Hong4 and Hua-Lin Wu1,3,*

1 Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan, Republic of China
2 Department of Internal Medicine, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan, Republic of China
3 Cardiovascular Research Center, National Cheng Kung University, Tainan 701, Taiwan, Republic of China
4 Neuropharmacology Section, Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA

* Corresponding author. Tel: +886 6 235 3535 5541; fax: +886 6 302 8037.E-mail address: halnwu{at}mail.ncku.edu.tw (H.-L.W.) or gyshi{at}mail.ncku.edu.tw (G.-Y.S.)

Aims: 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.

Methods and 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 p47phox and p67phox 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.

Conclusion: Our data show that DXM, with its novel effect in reducing oxidative stress, significantly reduces atherosclerosis and neointima formation in mice.

KEYWORDS Atherosclerosis; Macrophages; Anti-oxidants

Time for primary review: 17 days


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