The Protective Effects of Small-Molecule Compound 0242 Against LPS-Induced Neuroinflammation and in P301S Tau Transgenic Mice

IF 4.5 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemical Research Pub Date : 2026-07-07 DOI:10.1007/s11064-026-04834-3

Xinyuan Suo, Peifeng Wan, Jie Yu, Xinyu Zhu, Chenggang Tian, Shuyu Li, Guangqiang Sun, Hongchun Liu, Simin Liu, Meiyu Geng, Jingwei Tian, Weibo Yang, Yu Zhang

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Abstract

Neuroinflammation and tau pathology are central drivers of Alzheimer’s disease (AD) progression, necessitating multi-target therapeutic strategies. Here, we evaluated the efficacy and mechanisms of 0242, a novel small-molecule derivative optimized from the berberine scaffold. In lipopolysaccharide (LPS)-stimulated BV-2 microglia, 0242 treatment significantly inhibited cell activation and nitric oxide release without cytotoxicity, while downregulating the mRNA levels of pro-inflammatory cytokines IL-1β and TNF-α. Transcriptomic profiling revealed that 0242 modulated LPS-induced inflammatory gene signatures by enriched core signaling cascades, including NF-κB, TLR, and JAK-STAT and upregulating cytoprotective genes such as ceruloplasmin (Cp) and Bcl2a1b. In vivo, oral administration of 0242 attenuated hippocampal astrocyte and microglial activation in an LPS-induced acute neuroinflammatory mouse model. Furthermore, in female P301S tau transgenic mice, 0242 treatment significantly improved spontaneous locomotor activity and recognition memory. Histological and biochemical analyses confirmed that 0242 suppressed hippocampal glial activation and reduced total tau protein levels in the prefrontal cortex. Collectively, these findings suggest that 0242 may exert potent anti-neuroinflammatory effects by modulating multiple immune signaling cascades and uniquely alleviates tau pathology in AD.

Graphical abstract

Created with BioGDP.com [1]

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小分子化合物0242对lps诱导的神经炎症及P301S Tau转基因小鼠的保护作用

神经炎症和tau病理是阿尔茨海默病（AD）进展的主要驱动因素，需要多靶点治疗策略。在这里，我们评估了0242的功效和机制，0242是一种由小檗碱支架优化而成的新型小分子衍生物。在脂多糖（LPS）刺激的BV-2小胶质细胞中，0242处理显著抑制细胞活化和一氧化氮释放，无细胞毒性，同时下调促炎细胞因子IL-1β和TNF-α的mRNA水平。转录组学分析显示，0242通过丰富的核心信号级联，包括NF-κB、TLR和JAK-STAT，以及上调铜蓝蛋白（Cp）和Bcl2a1b等细胞保护基因，调节lps诱导的炎症基因特征。在体内，口服0242可减弱lps诱导的急性神经炎症小鼠模型海马星形胶质细胞和小胶质细胞的激活。此外，在雌性P301S tau转基因小鼠中，0242治疗显著改善了自发运动活动和识别记忆。组织学和生化分析证实，0242抑制海马胶质细胞激活，降低前额皮质总tau蛋白水平。总的来说，这些发现表明0242可能通过调节多种免疫信号级联发挥有效的抗神经炎症作用，并独特地缓解AD中的tau病理。

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来源期刊

Neurochemical Research 医学-神经科学

CiteScore

7.70

自引率

2.30%

发文量

320

审稿时长

6 months

期刊介绍： Neurochemical Research is devoted to the rapid publication of studies that use neurochemical methodology in research on nervous system structure and function. The journal publishes original reports of experimental and clinical research results, perceptive reviews of significant problem areas in the neurosciences, brief comments of a methodological or interpretive nature, and research summaries conducted by leading scientists whose works are not readily available in English.