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PRECLINICAL STUDY

A Novel Inhibitory Effect of Naloxone on Macrophage Activation and Atherosclerosis Formation in Mice

Shu-Lin Liu, MS^_*,, Yi-Heng Li, MD, PhD^,, Guey-Yueh Shi, PhD^_*,, Yung-Huan Chen, MS^_*, Chia-Wei Huang, MS^_*,, Jau-Shyong Hong, PhD^|| and Hua-Lin Wu, PhD^_*,,_*

^_* Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
Cardiovascular Research Center, College of Medicine, National Cheng Kung University, Tainan, Taiwan
Department of Internal Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
^|| Neuropharmacology Section, Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina

Manuscript received April 13, 2006; revised manuscript received June 6, 2006, accepted July 3, 2006.

^_* Reprint requests and correspondence: Dr. Hua-Lin Wu, Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan. (Email: halnwu{at}mail.ncku.edu.tw).

OBJECTIVES: We investigated whether naloxone could reduce macrophage activation and influence atherosclerotic lesion formation in mice.

BACKGROUND: Macrophages play an important role in the inflammatory process in atherosclerosis. Naloxone could inhibit activation of microglia, the resident macrophage in the nervous system.

METHODS: The anti-inflammatory effect of naloxone was evaluated by stimulating the macrophage cell culture and FVB mice with lipopolysaccharide or oxidized low-density lipoprotein with and without naloxone pretreatment. Apolipoprotein-E (apoE)-deficient mice received naloxone injection for 10 weeks, and the severity of aortic atherosclerosis was measured. The left common carotid arteries of C57BL/6 mice were ligated near the carotid bifurcation. The mice then received naloxone injection for 4 weeks after ligation, and the severity of neointima formation was evaluated.

RESULTS: Naloxone pretreatment significantly suppressed the production of tumor necrosis factor- (TNF-), interleukin-6, monocyte chemoattractant protein-1, and superoxide in macrophages after stimulation. In FVB mice, naloxone reduced the TNF- level in circulation, inflammatory cell infiltration in lungs, and superoxide production in aorta. Naloxone injection significantly decreased the severity of aortic atherosclerosis in the apoE-deficient mice and carotid neointima formation in the C57BL/6 mice after ligation.

CONCLUSIONS: Naloxone, with its novel anti-inflammatory effect, significantly reduces atherosclerosis and neointima formation in mice.

Abbreviations and Acronyms   apoE = apolipoprotein-E   DHE = dihydroethidium   EEL = external elastic lamina   ELISA = enzyme-linked immunosorbent assay   HDL = high-density lipoprotein   IEL = internal elastic lamina   IL-6 = interleukin-6   LPS = lipopolysaccharide   MCP-1 = monocyte chemoattractant protein-1   MTT = 3 (4,5-dimethylthiazol-2-yl) 2, 5-diphenyltetrazolium bromide   NADPH = nicotinamide adenine dinucleotide phosphate   N/M = neointima/media area ratio   oxLDL = oxidized low-density lipoprotein   PBS = phosphate-buffered saline   RLU = relative light units   THP-1 = human acute monocytic leukemia cell line   TNF- = tumor necrosis factor-

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