de Oliveira Marcos Roberto, Peres Alessandra, Ferreira Gustavo Costa, Schuck Patrícia Fernanda, Bosco Simone Morelo Dal
Department of Chemistry/ICET, Federal University of Mato Grosso (UFMT), Av. Fernando Corrêa da Costa, 2367, Cuiaba, MT, CEP 78060-900, Brazil.
Health Basic Sciences Department, Federal University of Health Sciences of Porto Alegre, RS, Brazil.
Neurotox Res. 2016 Oct;30(3):367-79. doi: 10.1007/s12640-016-9620-x. Epub 2016 Apr 15.
Carnosic acid (CA; C20H28O4) is a phenolic diterpene found in rosemary (Rosmarinus officinalis L.) and exhibits protective properties, e.g., antioxidant, anti-inflammatory, antitumor, and antimicrobial activities. In this context, CA has been viewed as a neuroprotective agent due to its ability in rescuing neuronal cells from pro-oxidant and pro-apoptotic challenges. In the present work, we found that CA pretreatment at 1 µM for 12 h suppressed the mitochondria-related pro-oxidant and mitochondria-dependent pro-apoptotic effects of chlorpyrifos (CPF) in human neuroblastoma SH-SY5Y cells. CA prevented mitochondrial membrane potential disruption and decreased the levels of oxidative stress markers in mitochondrial membranes obtained from cells exposed to CPF. CA also inhibited cytochrome c release and activation of the caspases-9 and -3, as well as decreased DNA fragmentation, in CPF-treated cells. CA upregulated the content of glutathione (GSH) in mitochondria by a mechanism involving the activation of the phosphoinositide-3-kinase (PI3K)/Akt/nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway, since inhibition of PI3K/Akt or silencing of Nrf2 using siRNA strategy abolished the protection exerted by CA in SH-SY5Y cells. Therefore, CA protected mitochondria of SH-SY5Y cells through the activation of the PI3K/Akt/Nrf2 axis, causing upregulation of the mitochondrial GSH content and consequent antioxidant and anti-apoptotic effects.
鼠尾草酸（CA；C20H28O4）是一种存在于迷迭香（Rosmarinus officinalis L.）中的酚类二萜，具有多种保护特性，如抗氧化、抗炎、抗肿瘤和抗菌活性。在此背景下，由于CA能够将神经元细胞从促氧化剂和促凋亡挑战中拯救出来，它被视为一种神经保护剂。在本研究中，我们发现1 μM的CA预处理12小时可抑制毒死蜱（CPF）对人神经母细胞瘤SH-SY5Y细胞线粒体相关的促氧化和线粒体依赖性促凋亡作用。CA可防止线粒体膜电位破坏，并降低暴露于CPF的细胞线粒体膜中氧化应激标志物的水平。CA还抑制了CPF处理细胞中细胞色素c的释放以及半胱天冬酶-9和-3的激活，并减少了DNA片段化。CA通过激活磷脂酰肌醇-3-激酶（PI3K）/蛋白激酶B（Akt）/核因子红细胞2相关因子2（Nrf2）信号通路的机制上调了线粒体中谷胱甘肽（GSH）的含量，因为使用小干扰RNA（siRNA）策略抑制PI3K/Akt或沉默Nrf2消除了CA对SH-SY5Y细胞的保护作用。因此，CA通过激活PI3K/Akt/Nrf2轴保护SH-SY5Y细胞的线粒体，导致线粒体GSH含量上调，从而产生抗氧化和抗凋亡作用。
