title: Melatonin synergistically increases resveratrol-induced heme oxygenase-1 expression through the inhibition of ubiquitin-dependent proteasome pathway: a possible role in neuroprotection.
abstract: 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.
authors.affiliation: Departments of Neurology Pharmacology Rehabilitation, Center for Geriatric Neuroscience Research, Institute of Biomedical Science and Technology, School of Medicine, Konkuk University, Seoul, Korea.
authors.forename: Kyoung Ja
authors.initials: KJ
authors.lastname: Kwon
authors.forename: Jung Nam
authors.initials: JN
authors.lastname: Kim
authors.forename: Min Kyeong
authors.initials: MK
authors.lastname: Kim
authors.forename: Jongmin
authors.initials: J
authors.lastname: Lee
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Ignarro
authors.forename: Hee-Jin
authors.initials: HJ
authors.lastname: Kim
authors.forename: Chan Young
authors.initials: CY
authors.lastname: Shin
authors.forename: Seol-Heui
authors.initials: SH
authors.lastname: Han
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D015153:Blotting, Western; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D047468:Immunoprecipitation; D066298:In Vitro Techniques; D008550:Melatonin / Q000494:pharmacology; D051379:Mice; D018696:Neuroprotective Agents / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D000077185:Resveratrol; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013267:Stilbenes / Q000494:pharmacology*; D025801:Ubiquitin / Q000378:metabolism*
chemical_list: D000975:Antioxidants; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; D013267:Stilbenes; D025801:Ubiquitin; D051547:Heme Oxygenase-1; D046988:Proteasome Endopeptidase Complex; D008550:Melatonin; D000077185:Resveratrol