Qu Youyang, Liu Yu, Chen Li, Zhu Yanmei, Xiao Xingjun, Wang Di, Zhu Yulan
a Department of Neurology , The Second Affiliated Hospital of Harbin Medical University , Heilongjiang , China.
Neurol Res. 2018 Mar;40(3):211-220. doi: 10.1080/01616412.2018.1424685. Epub 2018 Jan 16.
Objectives Cadmium (Cd), an extremely noxious environmental pollutant is known to induce oxidative stress leading to neurodegenerative diseases. Nobiletin, a citrus flavonoid is reported to possess various pharmacological properties. This study investigates the effects of nobiletin over Cd-induced neuronal apoptosis in rodent experimental model. Methods To separate group of male Sprague Dawley rats, Cd (2 mL/kg/day) was subcutaneously injected for one month which results in a dose level of 1 mg/kg Cd. Couple of days prior to Cd injection, the treatment group rats regularly received nobiletin (50, 100, or 200 mg/kg b.wt) orally through the study period. Results Cd-induced ROS levels and malondialdehyde (MDA) content were inhibited by nobiletin and improved glutathione levels. Nobiletin reduced neuronal apoptosis induced by Cd and raised cleaved caspase-3 levels. Intriguingly, nobiletin blocked JNK and Erk1/2 phosphorylation and down-regulated the pathways. Raised expression of kinases - MKK and ASK1 were reduced by nobiletin. Discussion The suppressed expression of phosphatases - PP2A and PP5 were up-regulated on nobiletin treatment. Nobiletin significantly blocked the activation of Akt/mTOR signaling. Enhanced phosphorylation of S6K1, Akt, and 4E-BP1 induced by Cd was significantly inhibited by nobiletin. The raised levels of raptor and rictor proteins were remarkably down-regulated on nobiletin treatment. Collectively, the observations of this study indicate protective effects of nobiletin against Cd-induced neurotoxicity.
目的 镉（Cd）是一种极具毒性的环境污染物，已知会诱导氧化应激，导致神经退行性疾病。据报道，柑橘类黄酮川陈皮素具有多种药理特性。本研究调查了川陈皮素对啮齿动物实验模型中镉诱导的神经元凋亡的影响。方法 将雄性Sprague Dawley大鼠分组，皮下注射Cd（2 mL/kg/天），持续1个月，导致Cd剂量水平为1 mg/kg。在注射Cd前几天，治疗组大鼠在研究期间定期口服川陈皮素（50、100或200 mg/kg体重）。结果 川陈皮素抑制了镉诱导的活性氧水平和丙二醛（MDA）含量，并提高了谷胱甘肽水平。川陈皮素减少了镉诱导的神经元凋亡，并提高了裂解的半胱天冬酶-3水平。有趣的是，川陈皮素阻断了JNK和Erk1/2磷酸化，并下调了这些途径。川陈皮素降低了激酶-MKK和ASK1的表达升高。讨论 川陈皮素处理上调了磷酸酶-PP2A和PP5的抑制表达。川陈皮素显著阻断了Akt/mTOR信号的激活。川陈皮素显著抑制了镉诱导的S6K1、Akt和4E-BP1的磷酸化增强。川陈皮素处理显著下调了raptor和rictor蛋白的升高水平。总体而言，本研究的观察结果表明川陈皮素对镉诱导的神经毒性具有保护作用。
