Abstract 696: Dextromethorphan is a Novel Inhibitor of Inflammation and Atherosclerosis that Targets NADPH Oxidase
Objective: Macrophage and its derived superoxide and cytokines contribute to the inflammation in atherosclerosis. Recently, dextromethorphan (DM), a common cough-suppressing ingredient with high safety profile, was found to inhibit activation of microglia, the resident macrophages in nervous system. We investigated whether DM could reduce macrophage activation and influence the atherosclerotic lesion formation in mice.
Methods and Results: THP-1 cells were cultured and differentiated into macrophages. DM pretreatment (0.01, 0.1 or 1 μM) significantly suppressed the macrophage production of tumor necrosis factor-α and interleukin-6 after lipopolysaccharide (LPS) (100 ng/ml) or oxidized low-density lipoprotein (10 μg/ml) stimulation. DM pretreatment (1 μM) also suppressed the elevation of macrophage superoxide production after LPS stimulation (231,616 ± 27,153 vs 559,558 ± 69,451 relative light unit (RLU)/10 min/mL, p < 0.001) measured by lucigenin-enhanced chemiluminescence (LEC). Actually, DM treatment (1 μM) directly reduced the macrophage NADPH oxidase activity measured by LEC (750,872 ± 283,772 vs 1739,607 ± 389,990 RLU/15 min/mL, p < 0.001). ApoE deficient mice were fed with DM (40 mg/kg/day, n = 8) or water (n = 9) for 10 weeks. The production of superoxide from the aorta was significantly reduced in the DM treatment group (378,839 ± 83,584 vs 533,821 ± 145,403 RLU/15 min, p < 0.01) determined by LEC. DM treatment also suppressed the elevation of fluorescence intensity detected by oxidative fluorescent microtopography in the sections of left carotid artery of these mice indicating the decrease of superoxide production in the arteries. DM treatment for 10 weeks significantly reduced the severity of aortic atherosclerotic lesions reported as atherosclerotic area/total aortic area in Oil-red stain (10 mg/kg/day, n = 9, 8.2 ± 3.8%, p < 0.001; 20 mg/kg/day, n = 9, 5.0 ± 2.0%, p < 0.001; 40 mg/kg/day, n = 9, 4.6 ± 3.6%, p < 0.001 vs controls, n = 10, 16.9 ± 4.3%) in the apoE-deficient mice.
Conclusions: DM decreased the macrophage NADPH oxidase activity and reduced the production of cytokine and superoxide in macrophages and mice. Its novel anti-inflammatory effect reduced the atherosclerotic lesion in the apoE deficient mice.