Get access

Melatonin improves neuroplasticity by upregulating the growth-associated protein-43 (GAP-43) and NMDAR postsynaptic density-95 (PSD-95) proteins in cultured neurons exposed to glutamate excitotoxicity and in rats subjected to transient focal cerebral ischemia even during a long-term recovery period

Authors

  • Wei-Sheng Juan,

    1. Neurophysiology Laboratory, Institute of Biomedical Engineering & Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
    Search for more papers by this author
    • These two authors have made equal contributions to the study.
  • Sheng-Yang Huang,

    1. Neurophysiology Laboratory, Institute of Biomedical Engineering & Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
    Search for more papers by this author
    • These two authors have made equal contributions to the study.
  • Che-Chao Chang,

    1. Neurophysiology Laboratory, Institute of Biomedical Engineering & Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
    Search for more papers by this author
  • Yu-Chang Hung,

    1. Neurophysiology Laboratory, Institute of Biomedical Engineering & Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
    Search for more papers by this author
  • Yu-Wen Lin,

    1. Neurophysiology Laboratory, Institute of Biomedical Engineering & Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
    Search for more papers by this author
  • Tsung-Ying Chen,

    1. Neurophysiology Laboratory, Institute of Biomedical Engineering & 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
    Search for more papers by this author
  • Ai-Hua Lee,

    1. Neurophysiology Laboratory, Institute of Biomedical Engineering & Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
    Search for more papers by this author
  • Ai-Chiang Lee,

    1. Neurophysiology Laboratory, Institute of Biomedical Engineering & Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
    Search for more papers by this author
  • Tian-Shung Wu,

    1. Neurophysiology Laboratory, Institute of Biomedical Engineering & Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
    2. Department of Chemistry, National Cheng Kung University, Tainan, Taiwan
    Search for more papers by this author
  • E-Jian Lee

    Corresponding author
    1. Neurophysiology Laboratory, Institute of Biomedical Engineering & Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
    • Address reprint requests to E-Jian Lee, Department of Surgery, National Cheng Kung University Medical center and Medical School, 138 Sheng-Li Road, Tainan 70428, Taiwan.

      E-mail: ejian@mail.ncku.edu.tw

    Search for more papers by this author

Abstract

Recent evidence shows that the NMDAR postsynaptic density-95 (PSD-95), growth-associated protein-43 (GAP-43), and matrix metalloproteinase-9 (MMP-9) protein enhance neuroplasticity at the subacute stage of stroke. Here, we evaluated whether melatonin would modulate the PSD-95, GAP-43, and MMP-9 proteins in cultured neurons exposed to glutamate excitotoxicity and in rats subjected to experimental stroke. Adult male Sprague–Dawley rats were treated with melatonin (5 mg/kg) or vehicle at reperfusion onset after transient occlusion of the right middle cerebral artery (tMCAO) for 90 min. Animals were euthanized for Western immunoblot analyses for the PSD-95 and GAP-43 proteins and gelatin zymography for the MMP-9 activity at 7 days postinsult. Another set of animals was sacrificed for histologic and Golgi–Cox-impregnated sections at 28 days postinsult. In cultured neurons exposed to glutamate excitotoxicity, melatonin significantly upregulated the GAP-43 and PSD-95 expressions and improved dendritic aborizations (< 0.05, respectively). Relative to controls, melatonin-treated stroke animals caused a significant improvement in GAP-43 and PSD-95 expressions as well as the MMP-9 activity in the ischemic brain (< 0.05). Consequently, melatonin also significantly promoted the dendritic spine density and reduced infarction in the ischemic brain, and improved neurobehaviors as well at 28 days postinsult (< 0.05, respectively). Together, melatonin upregulates GAP-43, PSD-95, and MMP-9 proteins, which likely accounts for its actions to improve neuroplasticity in cultured neurons exposed to glutamate excitotoxicity and to enhance long-term neuroprotection, neuroplasticity, and brain remodeling in stroke rats.

Ancillary