Melatonin synergistically increases resveratrol-induced heme oxygenase-1 expression through the inhibition of ubiquitin-dependent proteasome pathway: a possible role in neuroprotection

J Pineal Res. 2011 Mar;50(2):110-23. doi: 10.1111/j.1600-079X.2010.00820.x. Epub 2010 Nov 15.


Melatonin is an indoleamine secreted by the pineal gland as well as a plant-derived product, and resveratrol (RSV) is a naturally occurring polyphenol synthesized by a variety of plant species; both molecules act as a neuroprotector and antioxidant. Recent studies have demonstrated that RSV reduced the incidence of Alzheimer's disease and stroke, while melatonin supplementation was found to reduce the progression of the cognitive impairment in AD. The heme oxygenase-1 (HO-1) is an inducible and redox-regulated enzyme that provides tissue-specific antioxidant effects. We assessed whether the co-administration of melatonin and RSV shows synergistic effects in terms of their neuroprotective properties through HO-1. RSV significantly increased the expression levels of HO-1 protein in a concentration-dependent manner both in primary cortical neurons and in astrocytes, while melatonin per se did not. Melatonin + RSV showed a synergistic increase in the expression levels of HO-1 protein but not in the HO-1 mRNA level compared to either melatonin or RSV alone, which is mediated by the activation of PI3K-Akt pathway. Treatment of melatonin + RSV significantly attenuated the neurotoxicity induced by H(2) O(2) in primary cortical neurons and also in organotypic hippocampal slice culture. The blockade of HO-1 induction by shRNA attenuated HO-1 induction by melatonin + RSV and hindered the neuroprotective effects against oxidative stress induced by H(2) O(2) . The treatment of MG132 + RSV mimicked the effects of melatonin + RSV, and melatonin + RSV inhibited ubiquitination of HO-1. These data suggest that melatonin potentiates the neuroprotective effect of RSV against oxidative injury, by enhancing HO-1 induction through inhibiting ubiquitination-dependent proteasome pathway, which may provide an effective means to treat neurodegenerative disorders.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antioxidants / pharmacology*
  • Blotting, Western
  • Cell Line
  • Cell Survival / drug effects
  • Heme Oxygenase-1 / genetics
  • Heme Oxygenase-1 / metabolism*
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • Immunoprecipitation
  • In Vitro Techniques
  • Melatonin / pharmacology
  • Mice
  • Neuroprotective Agents / pharmacology
  • Proteasome Endopeptidase Complex / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Reactive Oxygen Species / metabolism
  • Resveratrol
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Stilbenes / pharmacology*
  • Ubiquitin / metabolism*


  • Antioxidants
  • Neuroprotective Agents
  • Reactive Oxygen Species
  • Stilbenes
  • Ubiquitin
  • Heme Oxygenase-1
  • Proteasome Endopeptidase Complex
  • Melatonin
  • Resveratrol