Yu Chunlei, Zhang Jing, Li Xiaoming, Liu Jicheng, Niu Yingcai
The Institute of Medicine, Qiqihar Medical University, Qiqihar 161006, China.
Department of Hematology, the First Affiliated Hospital, Harbin Medical University, Harbin 150001, China.
Biochim Biophys Acta Mol Cell Res. 2021 Jan;1868(1):118853. doi: 10.1016/j.bbamcr.2020.118853. Epub 2020 Sep 15.
Recently, oxidative stress is a common denominator in the pathogenesis of metal-induced neurotoxicity. Thus, antioxidant therapy is considered as a promising strategy for treating lead-related cognitive impairment. Here, we tested the hypothesis that astragaloside IV (AS-IV) ameliorates lead-associated cognitive deficits through Nrf2-dependent antioxidant mechanisms. Male Nrf2-KO and WT mice received drinking water with 2000 ppm lead and/or AS-IV by gavage for 8 weeks starting at 4 weeks of age. Morris water maze test and biochemical assays were employed to study cognition-enhancing and antioxidant effects of AS-IV. The signaling pathways involved were analyzed using RT-PCR and western blot technology. Significantly, AS-IV attenuated Morris water maze-based cognitive impairment in lead-intoxicated mice. Importantly, cognition-enhancing effect of AS-IV was lost in Nrf2-KO mice. In parallel, AS-IV suppressed lead acetate (PbAc)-induced oxidative stress, as measured by MDA. Mechanistically, AS-IV can up-regulate the expressions of the GCLc and HO-1 at the level of transcription and translation, but not SOD, TrxR activity, GCLm, Trx1, and NQO1 expression. Interestingly, AS-IV induced accumulation of Nrf2 in the nucleus, whereas Nrf2 mRNA levels were unchanged. Furthermore, AS-IV treatment resulted in elevated levels of phosphorylated Akt (active form) and phosphorylated GSK-3β (inactive forms) but decreased level of phosphorylated Fyn. Collectively, our findings indicate that AS-IV may target Nrf2 to attenuate lead-triggered oxidative stress and subsequent cognitive impairments, suggesting that AS-IV is a potential candidate for the treatment of lead-associated cognitive diseases.
最近，氧化应激是金属诱导的神经毒性发病机制中的一个共同因素。因此，抗氧化治疗被认为是治疗铅相关认知障碍的一种有前景的策略。在此，我们检验了黄芪甲苷IV（AS-IV）通过Nrf2依赖性抗氧化机制改善铅相关认知缺陷的假设。雄性Nrf2基因敲除（Nrf2-KO）小鼠和野生型（WT）小鼠从4周龄开始，通过灌胃给予含2000 ppm铅和/或AS-IV的饮用水，持续8周。采用莫里斯水迷宫试验和生化分析来研究AS-IV的认知增强和抗氧化作用。使用逆转录-聚合酶链反应（RT-PCR）和蛋白质免疫印迹技术分析相关信号通路。值得注意的是，AS-IV减轻了铅中毒小鼠基于莫里斯水迷宫的认知障碍。重要的是，AS-IV在Nrf2-KO小鼠中失去了认知增强作用。同时，通过丙二醛（MDA）检测发现，AS-IV抑制了醋酸铅（PbAc）诱导的氧化应激。从机制上讲，AS-IV可以在转录和翻译水平上调谷氨酸-半胱氨酸连接酶催化亚基（GCLc）和血红素加氧酶-1（HO-1）的表达，但对超氧化物歧化酶（SOD）、硫氧还蛋白还原酶（TrxR）活性、谷氨酸-半胱氨酸连接酶调节亚基（GCLm）、硫氧还蛋白1（Trx1）和醌氧化还原酶1（NQO1）的表达没有影响。有趣的是，AS-IV诱导Nrf2在细胞核中积累，而Nrf2的mRNA水平没有变化。此外，AS-IV处理导致磷酸化的蛋白激酶B（Akt，活性形式）和磷酸化的糖原合成酶激酶-3β（GSK-3β，无活性形式）水平升高，但磷酸化的Fyn水平降低。总的来说，我们的研究结果表明，AS-IV可能靶向Nrf2以减轻铅引发的氧化应激及随后的认知障碍，这表明AS-IV是治疗铅相关认知疾病的潜在候选药物。
