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.

Caloric restriction, resveratrol and melatonin: Role of SIRT1 and implications for aging and related-diseases

“…In ovariectomized and obesity rats with associated metabolic alterations, the combination of resveratrolmelatonin effectively normalized anthropometrical, biochemical, and histopathological parameters (Majumdar et al, 2014). The authors indicated that resveratrol and melatonin may act on dif- Finally, the presence of both melatonin and resveratrol in some Mediterranean foods and beverages Vitalini et al, 2013) adds a new factor to the hypothesis of health potential benefits associated with Mediterranean dietary patterns (Kwon et al, 2011;Iriti and Vitalini, 2012). In this view, it is interesting that both melatonin and resveratrol are present in red wine and in other constituents of the Mediterranean diet, and they would have synergistic preventive effects compared to the diets that contain only a single compound.…”

“…Melatonin has also been shown to potentiate the neuroprotective effect of resveratrol against oxidative injury by enhancing heme oxygenase-1 (HO-1) expression, and moreover, their combined use provided neuroprotection against oxidative stress in rat primary neurons and astrocytes, possibly via stability control of HO-1 protein through modulation of PI3K-Akt-GSK3␤ pathways. These results suggest that the combination of melatonin and resveratrol could be an effective way to control oxidative stress and neuroinflammatory processes in the brain, providing new means to treat neurodegenerative disorders (Kwon et al, 2011).…”

Effect of Melatonin and Resveratrol against Memory Impairment and Hippocampal Damage in a Rat Model of Vascular Dementia

“…Melatonin and resveratrol are the potent free radical scavengers and also regulate the gene expression level of several antioxidants and prooxidant enzymes; this may be another possible mechanism of neuroprotection offered by melatonin and resveratrol against chronic cerebral hypoperfusion-induced cognitive deficits. A previous study found that melatonin potentiated the neuroprotective effect of resveratrol via increasing resveratrol-induced heme oxygenase-1 expression [61,62] . This could be the reason for the protective effect of the melatonin and resveratrol combination regimen against oxidative injury.…”

Novel Regulatory Mechanism of Canonical Wnt Signaling by Dopamine D2Receptor through Direct Interaction with β-Catenin

“…Primary cortical neuronal cultures have been described previously (Kwon et al, 2011), and the cells were transfected using Lipofectamine 2000 (Invitrogen). For immunocytochemistry, cells were fixed with ice-cold 4% paraformaldehyde in phosphate-buffered saline, pH 7.4 for 1 h. Cells were incubated with phosphate-buffered saline containing 3% fetal bovine serum and 1% bovine serum albumin for 1 h, then incubated with FLAG antibody overnight at 4°C.…”