Curcumin analogue C66 ameliorates the pathology of Alzheimer's disease through suppression of JNK signaling pathway

IF 4.7 2区医学 Q2 IMMUNOLOGY

International immunopharmacology Pub Date : 2025-07-03 DOI:10.1016/j.intimp.2025.115156

Li Xiong , Qin Yu , Linjie Chen , Yu Deng , Qi Ai , Xiaoxia Xu , Ziyao Meng , Fan Chen , Xia Zhao , Jurui Wei , Houming Yu

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Abstract

Oxidative stress and neuroinflammation are two key pathological features in the early stage of Alzheimer's disease (AD), and they promote each other to further drive the progression of AD. Therefore, the development of therapeutic agents with dual anti-inflammatory and antioxidant properties represents a promising strategy for AD treatment. C66, a synthetic derivative of curcumin, protected PC12 cells and primary neurons from oxidative damage caused by Aβ. In addition, C66 alleviated Aβ-induced excessive inflammatory response in BV2 cells. Further results showed that C66 reduced neuroinflammation and neuronal apoptosis, ultimately improved cognitive decline in APPswe/PSEN1dE9 (APP/PS1) double transgenic AD mice. Importantly, C66 exhibited superior improved properties in APP/PS1 mice compared with the clinical control drug donepezil. Mechanistically, we indicated that C66 conferred its neuroprotective effects by inhibiting c-Jun N-terminal kinase (JNK) pathway. The result was further confirmed by using SP600125, a specific JNK inhibitor. Together, our findings suggest that C66 is expected to be further developed as a drug candidate for AD therapy.

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姜黄素类似物C66通过抑制JNK信号通路改善阿尔茨海默病的病理

氧化应激和神经炎症是阿尔茨海默病（Alzheimer's disease， AD）早期的两个关键病理特征，它们相互促进，进一步推动AD的进展。因此，开发具有抗炎和抗氧化双重特性的治疗剂是治疗AD的一种很有前途的策略。C66是姜黄素的合成衍生物，可以保护PC12细胞和原代神经元免受a β引起的氧化损伤。此外，C66可减轻a β诱导的BV2细胞过度炎症反应。进一步的研究结果表明，C66降低了APPswe/PSEN1dE9 （APP/PS1）双转基因AD小鼠的神经炎症和神经元凋亡，最终改善了认知能力下降。重要的是，与临床对照药物多奈哌齐相比，C66在APP/PS1小鼠中表现出更优越的改善性能。在机制上，我们发现C66通过抑制c-Jun n -末端激酶（JNK）途径发挥其神经保护作用。使用特异性JNK抑制剂SP600125进一步证实了这一结果。总之，我们的研究结果表明，C66有望作为阿尔茨海默病治疗的候选药物得到进一步开发。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

International immunopharmacology 医学-免疫学

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.