Isoamericanin A ameliorates neuronal damage and alleviates vascular cognitive impairments by inhibiting oxidative stress through activation of the Nrf2 pathway.

IF 4.8 2区 医学 Q2 IMMUNOLOGY International immunopharmacology Pub Date : 2024-12-25 Epub Date: 2024-10-15 DOI:10.1016/j.intimp.2024.113366
Yanqiu Yang, Libin Xu, Xiaohu Yao, Yingjie Wang, Mingxia Fang, Di Zhou, Ning Li, Yue Hou
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Abstract

Oxidative stress is critically involved in the cognitive dysfunction and neuronal progressive degeneration in the vascular cognitive impairment (VCI). The natural lignan molecular isoamericanin A (ISOA) containing multiple hydroxyl groups has great potential for suppressing oxidative stress in VCI. The primary objective of this study was to delve into the pharmacological properties of ISOA against VCI, as well as to elucidate the mechanisms driving this effect from the perspective of antioxidative stress. Transient bilateral common carotid arteries occlusion (tBCCAO) mice model and hydrogen peroxide (H2O2) treated N2a cells were employed in vivo and in vitro, respectively. Behavioral tests showed that ISOA (5, 10 mg/kg) treatment alleviated learning, memorizing, and recognition in tBCCAO model mice. ISOA alleviated the neuronal damages by increasing the number of NeuN-positive cells, decreasing the TUNEL-positive cells density, up-regulating MAP-2 expression, lighting the damage of neuronal nucleus and synapse. Mechanistically, we found that ISOA reduced the oxidative stress in neurons, which manifested by reduction on the expressions of superoxide, H2O2, intercellular reactive oxygen species (ROS) and malondialdehyde (MDA) level, and up-regulations on the expressions of anti-oxidant enzymes superoxide dismutase, heme oxygenase-1, glutathione peroxidase 4, glutathione, and NAD(P)H: quinone oxidoreductase 1. Further investigation showed that ISOA activated nuclear factor erythroid 2-related factor 2 (Nrf2) pathway by downregulating the expression of kelch-like ECH-associated protein 1, upregulating the nuclear translocation and expression of Nrf2, and augmenting antioxidant response elements (ARE) promotor activity. The ISOA-mediated promotion on ARE promotor activity and anti-oxidant enzymes expressions, and suppression on superoxide and ROS expressions and MDA levels were weakened by pharmacological inhibition or genetic knockdown of Nrf2. These effects were enhanced after knockdown Keap1 in H2O2-treated cells. Our study demonstrates that ISOA alleviates the cognitive impairments and neuronal loss in VCI by attenuating oxidative stress through promoting the activation of Nrf2 pathway.

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异美加豆素 A 通过激活 Nrf2 途径抑制氧化应激,从而改善神经元损伤并减轻血管性认知障碍。
氧化应激与血管性认知障碍(VCI)中的认知功能障碍和神经元进行性退化密切相关。含有多个羟基的天然木质素分子异美利坚素 A(ISOA)在抑制血管性认知障碍中的氧化应激方面具有巨大潜力。本研究的主要目的是深入研究 ISOA 对抗 VCI 的药理特性,并从抗氧化压力的角度阐明产生这种效应的机制。研究分别在体内和体外采用了瞬时双侧颈总动脉闭塞(tBCCAO)小鼠模型和过氧化氢(H2O2)处理的N2a细胞。行为测试表明,ISOA(5、10 毫克/千克)可减轻 tBCCAO 模型小鼠的学习、记忆和识别能力。ISOA通过增加NeuN阳性细胞数量、降低TUNEL阳性细胞密度、上调MAP-2表达、减轻神经元核和突触的损伤来缓解神经元损伤。从机理上讲,我们发现 ISOA 可降低神经元的氧化应激,表现为降低超氧化物、H2O2、细胞间活性氧(ROS)和丙二醛(MDA)的表达,上调抗氧化酶超氧化物歧化酶、血红素加氧酶-1、谷胱甘肽过氧化物酶 4、谷胱甘肽和 NAD(P)H:醌氧化还原酶 1 的表达。进一步的研究表明,ISOA 通过下调 kelch-like ECH-associated protein 1 的表达、上调 Nrf2 的核转位和表达以及增强抗氧化反应元件(ARE)启动子的活性,激活了核因子红细胞 2 相关因子 2(Nrf2)通路。药物抑制或基因敲除Nrf2会削弱ISOA介导的对ARE启动子活性和抗氧化酶表达的促进作用,以及对超氧化物和ROS表达及MDA水平的抑制作用。在 H2O2 处理的细胞中敲除 Keap1 后,这些效应增强。我们的研究表明,ISOA可通过促进Nrf2通路的活化来减轻氧化应激,从而缓解VCI患者的认知障碍和神经元缺失。
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来源期刊
CiteScore
8.40
自引率
3.60%
发文量
935
审稿时长
53 days
期刊介绍: International Immunopharmacology is the primary vehicle for the publication of original research papers pertinent to the overlapping areas of immunology, pharmacology, cytokine biology, immunotherapy, immunopathology and immunotoxicology. Review articles that encompass these subjects are also welcome. The subject material appropriate for submission includes: • Clinical studies employing immunotherapy of any type including the use of: bacterial and chemical agents; thymic hormones, interferon, lymphokines, etc., in transplantation and diseases such as cancer, immunodeficiency, chronic infection and allergic, inflammatory or autoimmune disorders. • Studies on the mechanisms of action of these agents for specific parameters of immune competence as well as the overall clinical state. • Pre-clinical animal studies and in vitro studies on mechanisms of action with immunopotentiators, immunomodulators, immunoadjuvants and other pharmacological agents active on cells participating in immune or allergic responses. • Pharmacological compounds, microbial products and toxicological agents that affect the lymphoid system, and their mechanisms of action. • Agents that activate genes or modify transcription and translation within the immune response. • Substances activated, generated, or released through immunologic or related pathways that are pharmacologically active. • Production, function and regulation of cytokines and their receptors. • Classical pharmacological studies on the effects of chemokines and bioactive factors released during immunological reactions.
期刊最新文献
Corrigendum to "mTOR aggravated CD4+ T cell pyroptosis by regulating the PPARγ-Nrf2 pathway in sepsis" [Int. Immunopharmacol. 140 (2024) 112822]. Corrigendum to "Role of glucose metabolism reprogramming in keratinocytes in the link between psoriasis and metabolic syndrome" [Int. Immunopharmacol. 139 (2024) 112704]. Isoamericanin A ameliorates neuronal damage and alleviates vascular cognitive impairments by inhibiting oxidative stress through activation of the Nrf2 pathway. Neuroprotective effects of gypenosides on LPS-induced anxiety and depression-like behaviors. Corrigendum to "Artesunate ameliorates ligature-induced periodontitis by attenuating NLRP3 inflammasome-mediated osteoclastogenesis and enhancing osteogenic differentiation" [Int. Immunopharmacol. 123 (2023) 110749].
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