Central Laboratory, Shanghai Institute of Geriatrics, Huadong Hospital, Shanghai Medical College, Fudan University, 221 West Yan An Road, Shanghai 200040, PR China.
Mech Ageing Dev. 2013 Mar;134(3-4):89-97. doi: 10.1016/j.mad.2012.12.005. Epub 2013 Jan 8.
Oxidative stress contributes to a chronic inflammatory process referred to as "inflamm-aging". Acetylcholinesterase inhibitors (AChEI) can enhance cholinergic transmission and act as anti-inflammatory agents via immunocompetent cells expressing α-7 acetylcholine receptors (AChR). The present study explores the possible role of huperzine A, a reversible and selective AChEI, against D-gal-induced oxidative damage, cell toxicity and inflamm-aging in rat livers. In two-month-old rats with normal liver function, an 8-week administration of D-gal (300 mg/kg subcutaneously (s.c.) injected), significantly increased hepatic impairment, ROS generation and oxidative damage, hepatic senescence, nuclear factor-kappa B (NF-κB) activation and inflammatory responses. An 8-week co-administration of both D-gal (300 mg/kg s.c.) and huperzine A (0.1 mg/kg s.c.) not only significantly decreased hepatic function impairment, ROS generation, oxidative damage, but also suppressed inflamm-aging by inhibiting hepatic replicative senescence, AChE activity, IκBα degradation, NF-κB p65 nuclear translocation and inflammatory responses. The expression levels of pro-inflammatory cytokine mRNA and proteins, such as TNFα, IL-1β and IL-6 decrease significantly, and the protein levels of the anti-inflammatory cytokine IL-10 display an obvious increase. These findings indicated that D-gal-induced hepatic injury and inflamm-aging in the rat liver was associated with the development of a pro-inflammatory phenotype in this organ. D-gal induced damage-associated molecular patterns (DAMPs) because oxidative damages might play an important role in D-gal-induced hepatic sterile inflammation. Huperzine A exhibited protective effects against D-gal-induced hepatotoxicity and inflamm-aging by inhibiting AChE activity and via the activation of the cholinergic anti-inflammatory pathway. The huperzine A mechanism might be involved in the inhibition of DAMPs-mediated NF-κB nuclear localization and activation.
氧化应激导致一种被称为“炎性衰老”的慢性炎症过程。乙酰胆碱酯酶抑制剂（AChEI）可以通过表达α-7 乙酰胆碱受体（AChR）的免疫活性细胞增强胆碱能传递并发挥抗炎作用。本研究探讨了一种可逆和选择性的 AChEI，即石杉碱甲，对 D-半乳糖诱导的氧化损伤、细胞毒性和大鼠肝脏炎性衰老的可能作用。在肝功能正常的两个月大的大鼠中，8 周的 D-半乳糖（300mg/kg 皮下注射）给药显著增加了肝损伤、ROS 生成和氧化损伤、肝衰老、核因子-κB（NF-κB）激活和炎症反应。8 周同时给予 D-半乳糖（300mg/kg 皮下注射）和石杉碱甲（0.1mg/kg 皮下注射）不仅显著降低了肝功能损伤、ROS 生成、氧化损伤，还通过抑制肝复制性衰老、AChE 活性、IκBα降解、NF-κB p65核易位和炎症反应来抑制炎性衰老。促炎细胞因子 mRNA 和蛋白质（如 TNFα、IL-1β 和 IL-6）的表达水平显著降低，抗炎细胞因子 IL-10 的蛋白水平明显升高。这些发现表明，D-半乳糖诱导的大鼠肝损伤和炎性衰老与该器官中促炎表型的发展有关。D-半乳糖诱导的损伤相关分子模式（DAMPs），因为氧化损伤可能在 D-半乳糖诱导的肝无菌性炎症中发挥重要作用。石杉碱甲通过抑制 AChE 活性和激活胆碱能抗炎途径，对 D-半乳糖诱导的肝毒性和炎性衰老表现出保护作用。石杉碱甲的机制可能涉及抑制 DAMPs 介导的 NF-κB 核定位和激活。
