Departments of Neurology Pharmacology Rehabilitation, Center for Geriatric Neuroscience Research, Institute of Biomedical Science and Technology, School of Medicine, Konkuk University, Seoul, Korea.
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.
褪黑素是松果体分泌的一种吲哚胺，也是一种植物源性产物，白藜芦醇（RSV）是一种天然存在的多酚，由多种植物合成；这两种分子都具有神经保护和抗氧化作用。最近的研究表明，RSV 降低了阿尔茨海默病和中风的发病率，而褪黑素补充剂被发现可减缓 AD 认知障碍的进展。血红素加氧酶-1（HO-1）是一种诱导型和氧化还原调节酶，可提供组织特异性抗氧化作用。我们评估了褪黑素和 RSV 的共同给药是否通过 HO-1 在其神经保护特性方面表现出协同作用。RSV 显著增加了原代皮质神经元和星形胶质细胞中 HO-1 蛋白的表达水平，呈浓度依赖性，而褪黑素本身没有。与单独使用褪黑素或 RSV 相比，褪黑素+RSV 显示 HO-1 蛋白表达水平协同增加，但 HO-1 mRNA 水平没有增加，这是通过激活 PI3K-Akt 途径介导的。褪黑素+RSV 处理可显著减轻原代皮质神经元和器官型海马切片培养物中 H2O2 诱导的神经毒性。shRNA 阻断 HO-1 诱导可减弱褪黑素+RSV 诱导的 HO-1 诱导，并阻碍 H2O2 诱导的氧化应激的神经保护作用。MG132+RSV 的处理模拟了褪黑素+RSV 的作用，并且褪黑素+RSV 抑制了 HO-1 的泛素化。这些数据表明，褪黑素通过抑制泛素化依赖性蛋白酶体途径增强 HO-1 诱导，从而增强 RSV 对氧化损伤的神经保护作用，这可能为治疗神经退行性疾病提供有效手段。
