Melatonin inhibits matrix metalloproteinase-9 (MMP-9) activation in the lipopolysaccharide (LPS)-stimulated RAW 264.7 and BV2 cells and a mouse model of meningitis

Authors

  • Che-Chao Chang,

    1. Neurophysiology Laboratory, Neurosurgical Service, Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
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    • These two authors have made equal contributions to the study.

  • Chih-Hao Tien,

    1. Neurophysiology Laboratory, Neurosurgical Service, Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
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    • These two authors have made equal contributions to the study.

  • E-Jian Lee,

    1. Neurophysiology Laboratory, Neurosurgical Service, Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
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  • Wei-Sheng Juan,

    1. Neurophysiology Laboratory, Neurosurgical Service, Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
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  • Ying-Hsin Chen,

    1. Neurophysiology Laboratory, Neurosurgical Service, Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
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  • Yu-Chang Hung,

    1. Neurophysiology Laboratory, Neurosurgical Service, Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
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  • Tsung-Ying Chen,

    1. Neurophysiology Laboratory, Neurosurgical Service, Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
    2. Department of Anesthesiology, Buddhist Tzu-Chi University and Buddhist Tzu Chi General Hospital, Hualien, Taiwan
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  • Hung-Yi Chen,

    1. Neurophysiology Laboratory, Neurosurgical Service, Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
    2. Institute of Pharmacy, China Medical University, Taichung, Taiwan
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  • Tian-Shung Wu

    1. Institute of Pharmacy, China Medical University, Taichung, Taiwan
    2. Department of Chemistry, National Cheng Kung University, Tainan, Taiwan
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Address reprint requests to E-Jian Lee, Department of Surgery, National Cheng Kung University Medical College and Hospital, 138 Sheng-Li Road, Tainan 70428, Taiwan.
E-mail: ejian@mail.ncku.edu.tw

Abstract

Abstract:  We explored anti-inflammatory potential of melatonin against the lipopolysaccharide (LPS)-induced inflammation in vivo and in vitro. RAW 264.7 and BV2 cells were stimulated by LPS, followed by the treatment with melatonin or vehicle at various time intervals. In a mouse model of meningitis induced by LPS, melatonin (5 mg/kg) or vehicle was intravenously injected at 30 min postinsult. The activity of matrix metalloproteinase-2 (MMP-2) and metalloproteinase-9 (MMP-9) was determined by gelatin zymography. Nuclear factor-kappa B (NFκB) translocation and binding activity were determined by immunocytochemistry and electrophoretic mobility shift assay (EMSA). Our results showed that either pretreatment or cotreatment with melatonin at 50–500 μm effectively inhibited the LPS-induced proMMP-9 activation in the RAW 264.7 and BV2 cells, respectively (< 0.05). This melatonin-induced proMMP-9 inhibition remained effective when treatment was delayed up to 2 and 6 hr postinsult for RAW 264.7 and BV2 cells, respectively (< 0.05 for both groups). Additionally, melatonin significantly attenuated the rises of circulatory and cerebral MMP-9 activity, respectively (< 0.05) and reduced the loss of body weight (< 0.05) in mice with meningitis. Moreover, melatonin (50 μm) effectively inhibited nuclear factor-kappa B (NFκB) translocation and binding activity in the LPS-treated RAW 264.7 and BV2 cells, respectively (< 0.05). These results demonstrate direct inhibitory actions of melatonin against postinflammatory NFκB translocation and MMP-9 activation and highlight its ability to inhibit systemic and cerebral MMP-9 activation following brain inflammation.

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