Coniferaldehyde reverses 3-nitropropionic acid-induced Huntington's disease pathologies via PKM2 restoration and JAK2/STAT3 inhibition.

IF 6.4 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular Medicine Pub Date : 2025-07-31 DOI:10.1186/s10020-025-01308-0

Ayooluwa Gabriel Ibiayo, Peeraporn Varinthra, Mukundan Nagarajan, Ingrid Y Liu

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引用次数: 0

Abstract

Background: Huntington's disease (HD) is a fatal neurodegenerative disorder characterized by progressive motor decline and neuronal loss, with no curative disease-modifying therapies available. The mitochondrial toxin 3-nitropropionic acid (3-NP) is widely used to model HD-like pathologies. We investigated the therapeutic potential of coniferaldehyde (CFA), a natural phenolic compound with anti-inflammatory, antioxidant, and anti-radical properties, against 3-NP-induced neurodegeneration. Given the roles of oxidative stress, metabolic dysfunction, and neuroinflammation in HD, we hypothesize that CFA exerts neuroprotection by attenuating these processes via the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway - a novel target for CFA in HD.

Methods: Neurological and behavioral deficits were assessed via neurological assessment scaling, rotarod, and open field tests. Nissl staining was performed to evaluate neuronal damage in the motor cortex and striatum. Dihydroethidium staining (DHE) was used to measure reactive oxygen species (ROS) levels, and the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay was conducted to detect apoptosis. Western blot assay and immunofluorescence staining were used to examine CFA's effect. Additionally, molecular docking was performed to analyze CFA's interaction with STAT3.

Results: CFA treatment significantly improved motor function, preserved neuronal architecture, and reduced apoptosis, as confirmed by Nissl and TUNEL staining. CFA also decreased ROS levels and restored pyruvate kinase M2 (PKM2) expression, a key regulator of metabolic homeostasis. Consistently, CFA attenuated neuroinflammation by suppressing Glial Fibrillary Acidic Protein (GFAP) expression and proinflammatory cytokines Interleukin-6 (IL-6) and Interleukin-1 beta (IL-1β). Molecular docking studies revealed a strong binding affinity between CFA and STAT3, and western blot analysis showed reduced phosphorylation of STAT3, indicating modulation of the JAK2/STAT3 signaling pathway.

Conclusion: These findings demonstrate that CFA modulates oxidative, PKM2-mediated metabolic, and inflammatory pathways through the JAK2/STAT3 axis, enhancing motor function and neuronal survival in a 3-NP model of HD. This multi-targeted mechanism highlights its potential as a disease-modifying therapy for advancing therapeutic strategies in HD and related neurodegenerative disorders.

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针叶醛通过恢复PKM2和抑制JAK2/STAT3逆转3-硝基丙酸诱导的亨廷顿病病理。

背景：亨廷顿舞蹈病（HD）是一种致命的神经退行性疾病，以进行性运动能力下降和神经元丧失为特征，目前尚无可治愈的疾病改善疗法。线粒体毒素3-硝基丙酸（3-NP）被广泛用于模拟hd样病理。我们研究了松柏醛（CFA），一种具有抗炎、抗氧化和抗自由基特性的天然酚类化合物，对3- np诱导的神经变性的治疗潜力。考虑到氧化应激、代谢功能障碍和神经炎症在HD中的作用，我们假设CFA通过Janus kinase 2/signal transducer and activator of transcription 3 （JAK2/STAT3）通路（CFA在HD中的一个新靶点）减弱这些过程来发挥神经保护作用。方法：通过神经学评估量表、旋转棒和野外测试对神经学和行为缺陷进行评估。尼氏染色观察运动皮层和纹状体神经元损伤情况。采用双氢乙啶染色法（DHE）检测活性氧（ROS）水平，采用末端脱氧核苷酸转移酶介导的dUTP缺口末端标记法（TUNEL）检测细胞凋亡。Western blot法和免疫荧光染色法检测CFA的作用。此外，我们还进行了分子对接，分析了CFA与STAT3的相互作用。结果：Nissl和TUNEL染色证实，CFA治疗显著改善运动功能，保留神经元结构，减少细胞凋亡。CFA还能降低ROS水平，恢复代谢稳态关键调节因子丙酮酸激酶M2 （PKM2）的表达。一致地，CFA通过抑制胶质纤维酸性蛋白（GFAP）表达和促炎细胞因子白介素-6 （IL-6）和白介素-1β (IL-1β)来减轻神经炎症。分子对接研究显示，CFA与STAT3之间具有较强的结合亲和力，western blot分析显示，STAT3磷酸化水平降低，表明调控了JAK2/STAT3信号通路。结论：这些发现表明，CFA通过JAK2/STAT3轴调节氧化、pkm2介导的代谢和炎症途径，增强HD 3-NP模型的运动功能和神经元存活。这种多靶点机制突出了其作为一种疾病修饰疗法的潜力，可以推进HD和相关神经退行性疾病的治疗策略。

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来源期刊

Molecular Medicine 医学-生化与分子生物学

CiteScore

8.60

自引率

0.00%

发文量

137

审稿时长

1 months

期刊介绍： Molecular Medicine is an open access journal that focuses on publishing recent findings related to disease pathogenesis at the molecular or physiological level. These insights can potentially contribute to the development of specific tools for disease diagnosis, treatment, or prevention. The journal considers manuscripts that present material pertinent to the genetic, molecular, or cellular underpinnings of critical physiological or disease processes. Submissions to Molecular Medicine are expected to elucidate the broader implications of the research findings for human disease and medicine in a manner that is accessible to a wide audience.