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点。因此，抗氧化剂治疗被认为是治疗铅相关认知障碍的有前途的策略。在这里，我们测试了黄芪甲苷IV（AS-IV）通过依赖Nrf2的抗氧化剂机制改善与铅相关的认知缺陷的假设。从4周龄开始，雄性Nrf2-KO和WT小鼠通过管饲法接受了含有2000 ppm铅和/或AS-IV的饮用水，持续了8周。莫里斯水迷宫测试和生化分析被用来研究AS-IV的认知增强和抗氧化作用。使用RT-PCR和western blot技术分析了涉及的信号通路。值得注意的是，AS-IV可以减轻铅中毒小鼠的Morris基于水迷宫的认知障碍。重要的，Nrf2-KO小鼠丧失了AS-IV的认知增强作用。同时，AS-IV可抑制乙酸铅（PbAc）诱导的氧化应激，如MDA所测。从机制上讲，AS-IV可以在转录和翻译水平上调GCLc和HO-1的表达，但不能上调SOD，TrxR活性，GCLm，Trx1和NQO1的表达。有趣的是，AS-IV诱导Nrf2在细胞核中蓄积，而Nrf2 mRNA水平未发生变化。此外，AS-IV处理导致磷酸化Akt（活性形式）和磷酸化GSK-3β（非活性形式）水平升高，但磷酸化Fyn水平降低。总体而言，我们的研究结果表明，AS-IV可能靶向Nrf2来减轻铅触发的氧化应激和随后的认知障碍，