Department of Preventive Medicine and Public Health Laboratory Sciences, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, China.
Department of Preventive Medicine and Public Health Laboratory Sciences, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, China; Institute of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu 212013, China.
Toxicology. 2019 Sep 1;425:152248. doi: 10.1016/j.tox.2019.152248. Epub 2019 Jul 19.
Methylmercury (MeHg) is a ubiquitous environmental toxicant that leads to long-lasting neurological deficits in animals and humans. Curcumin, a polyphenol obtained from the rhizome of turmeric, has well-known antioxidant functions. Here, we evaluated curcumin's efficacy in mitigating MeHg-induced cytotoxicity and further investigated the underlying mechanism of this neuroprotection in primary rat astrocytes. Pretreatment with curcumin (2, 5, 10 and 20 μM for 3, 6, 12 or 24 h) protected against MeHg-induced (5 μM for 6 h) cell death in a time and dose-dependent manner. Curcumin (2, 5, 10 or 20 μM) pretreatment for 12 h significantly ameliorated the MeHg-induced astrocyte injury and oxidative stress, as evidenced by morphological alterations, lactate dehydrogenase (LDH) release, reactive oxygen species (ROS) generation, and glutathione (GSH) and catalase (CAT) levels. Moreover, curcumin pretreatment increased Nrf2 nuclear translocation and downstream enzyme expression, heme oxygenase-1 (HO-1) and NADPH quinone reductase-1 (NQO1). Knockdown of Nrf2 with siRNA attenuated the protective effect of curcumin against MeHg-induced cell death. However, both the pan-protein kinase C (PKC) inhibitor, Ro 31-8220, and the selective PKCδ inhibitor, rottlerin, failed to suppress the curcumin-activated Nrf2/Antioxidant Response Element(ARE) pathway and attenuate the protection exerted by curcumin. Taken together, these findings confirm that curcumin protects against MeHg-induced neurotoxicity by activating the Nrf2/ARE pathway and this protection is independent of PKCδ activation. More studies are needed to understand the mechanisms of curcumin cytoprotection.
甲基汞（MeHg）是一种普遍存在的环境毒物，可导致动物和人类出现持久的神经功能缺陷。姜黄素是一种从姜黄根茎中提取的多酚，具有众所周知的抗氧化功能。在这里，我们评估了姜黄素减轻 MeHg 诱导的细胞毒性的功效，并进一步研究了这种神经保护作用在原代大鼠星形胶质细胞中的潜在机制。姜黄素（2、5、10 和 20μM 预处理 3、6、12 或 24 小时）以时间和剂量依赖的方式保护细胞免受 MeHg（5μM，6 小时）诱导的细胞死亡。姜黄素（2、5、10 或 20μM）预处理 12 小时可显著改善 MeHg 诱导的星形胶质细胞损伤和氧化应激，表现为形态改变、乳酸脱氢酶（LDH）释放、活性氧（ROS）生成以及谷胱甘肽（GSH）和过氧化氢酶（CAT）水平。此外，姜黄素预处理增加了 Nrf2 的核转位和下游酶表达，血红素加氧酶-1（HO-1）和 NADPH 醌还原酶-1（NQO1）。用 siRNA 敲低 Nrf2 减弱了姜黄素对 MeHg 诱导的细胞死亡的保护作用。然而，蛋白激酶 C（PKC）全抑制剂 Ro 31-8220 和 PKCδ 选择性抑制剂 rottlerin 均不能抑制姜黄素激活的 Nrf2/抗氧化反应元件（ARE）通路并减弱姜黄素的保护作用。综上所述，这些发现证实姜黄素通过激活 Nrf2/ARE 通路来保护细胞免受 MeHg 诱导的神经毒性，这种保护作用与 PKCδ 的激活无关。需要进一步研究以了解姜黄素细胞保护作用的机制。
