Division of Pharmaceutical Sciences, Department of Pharmacology, Mylan School of Pharmacy, Duquesne University, Pittsburgh, PA, USA.
Department of Pharmaceutical Sciences, Manchester University College of Pharmacy, Natural and Health Sciences, Fort Wayne, IN, USA.
Arch Toxicol. 2018 Feb;92(2):669-677. doi: 10.1007/s00204-017-2073-z. Epub 2017 Oct 4.
Age-related motor deficits, such as loss of balance and coordination, are caused, in part, by loss of dopaminergic neurons. Oxidative stress is known to play a role in this neuronal loss. Resveratrol, a natural antioxidant with anticancer and anti-inflammatory potential, has been shown to protect dopaminergic-like cells (SH-SY5Y) against oxidative stress. However, the low bioavailability of resveratrol makes it worthwhile to explore newer compounds with similar properties. Piceid (RV8), an analog of resveratrol, has greater bioavailability than resveratrol, and our studies found that piceid (10, 20, 30 µM) protects SH-SY5Y cells against oxidative stress. Our investigations also found that the neuroprotection afforded by piceid was decreased when the MAP kinases, ERK1/2 and ERK5, were independently inhibited. Since oxidative stress is considered a master operator of apoptosis, our study also scrutinized dopamine-induced apoptosis and whether caspase-3/7 and Bcl-2 are involved, following piceid pretreatment followed by dopamine exposure. Our findings suggested that piceid pretreatment inhibited the dopamine-induced increase in caspase-3/7 activity and dopamine-induced loss of Bcl-2 expression. Overall, these findings suggest that the neuroprotective effects of piceid are mediated via the activation of ERK1/2, ERK5, and inhibition of apoptosis caused by oxidative stress.
与年龄相关的运动功能障碍，如平衡和协调能力丧失，部分是由多巴胺能神经元丧失引起的。氧化应激被认为在这种神经元丧失中起作用。白藜芦醇是一种具有抗癌和抗炎潜力的天然抗氧化剂，已被证明可保护多巴胺能样细胞（SH-SY5Y）免受氧化应激。然而，白藜芦醇的生物利用度低，因此值得探索具有相似特性的新型化合物。白藜芦醇类似物白藜芦醇苷（RV8）的生物利用度高于白藜芦醇，我们的研究发现白藜芦醇苷（10、20、30 μM）可保护 SH-SY5Y 细胞免受氧化应激。我们的研究还发现，当 MAP 激酶 ERK1/2 和 ERK5 被独立抑制时，白藜芦醇苷提供的神经保护作用会降低。由于氧化应激被认为是细胞凋亡的主要调控因子，我们的研究还研究了多巴胺诱导的细胞凋亡，以及 caspase-3/7 和 Bcl-2 是否参与其中，在白藜芦醇苷预处理后再暴露于多巴胺。我们的研究结果表明，白藜芦醇苷预处理可抑制多巴胺诱导的 caspase-3/7 活性增加和多巴胺诱导的 Bcl-2 表达丧失。总的来说，这些发现表明白藜芦醇苷的神经保护作用是通过激活 ERK1/2、ERK5 和抑制氧化应激引起的细胞凋亡来介导的。
