Neuroprotective Role of Transchalcone in Parkinson's Disease through AMP-activated Protein Kinase-mediated Signaling Pathway.

Journal of physiological investigation Pub Date : 2024-11-01 Epub Date: 2024-12-06 DOI:10.4103/ejpi.EJPI-D-24-00083
Yao Cheng, Shaik Althaf Hussain, Turki Mayudh Alrubie, Xiaomin Zhang
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Abstract

Abstract: Parkinson's disease (PD) is a gradually worsening neurodegenerative condition marked by the deterioration of dopaminergic neurons, motor dysfunction, and mitochondrial dysfunction. Trans-chalcone, a natural flavonoid, has shown promise in various disease models because of its antioxidant and anti-inflammatory features. This study investigates the neuroprotective effects of transchalcone in a rat model of PD, focusing on its impact on the activation levels of AMP-activated protein kinase (AMPK) signaling pathway, sirtuin1 (SIRT1) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) proteins, and mitochondrial-inflammatory responses. Male Sprague Dawley rats were allocated into five groups Control, Control plus transchalcone, PD, PD plus transchalcone, PD plus compound-C, and PD plus Compound-C and trans-chalcone. PD was induced using intranigral 6-hydroxydopamine injection. Trans-chalcone (100 μg/kg) and compound-C (20 mg/kg) were intraperitoneally administered daily for 4 weeks in PD rats. Motor function was assessed using rota-rod and grid tests. Striatal dopamine and cytokines (interleukin 1-beta [IL-1 β], IL-10) and p65-nuclear factor kappa-B (NF-κB) levels were measured with enzyme-linked immunosorbent assay. Mitochondrial function was evaluated by fluorometric techniques. The expression of phosphorylated AMPK, PGC-1α, and SIRT1 was analyzed by Western blotting. Trans-chalcone treatment significantly improved motor function, evidenced by increased latency to fall in the rota-rod test and recovered traversal time in the grid test. It also restored dopamine levels, enhanced mitochondrial function (reduced reactive oxygen species levels, increased membrane potential, and adenosine triphosphate production), normalized cytokines (IL-1 β, IL-10) and p65-NF-κB, and upregulated the proteins expression in rats with PD. Inhibition of AMPK activity with compound-C suppressed the neuroprotective impacts of trans-chalcone, highlighting the contribution of AMPK signaling pathway in its mechanism of action. Neuroprotective and mitoprotective impacts of trans-chalcone were mostly mediated through the activation of AMPK-SIRT1-PGC1α pathway. These results indicate that trans-chalcone could be a promising therapeutic agent for PD, warranting further investigation to assess its efficacy and safety in human patients.

通过amp激活的蛋白激酶介导的信号通路,转沙耳酮在帕金森病中的神经保护作用。
摘要:帕金森病(PD)是一种以多巴胺能神经元退化、运动功能障碍和线粒体功能障碍为特征的逐渐加重的神经退行性疾病。反式查尔酮是一种天然类黄酮,由于其抗氧化和抗炎特性,在多种疾病模型中显示出前景。本研究探讨了经沙尔康酮在帕金森病大鼠模型中的神经保护作用,重点研究了其对amp激活的蛋白激酶(AMPK)信号通路、sirtuin1 (SIRT1)和过氧化物酶体增殖体激活受体γ辅助激活因子1- α (PGC1α)蛋白激活水平以及线粒体炎症反应的影响。将雄性sd大鼠分为对照组、对照组加转查尔酮组、PD组、PD组加转查尔酮组、PD组加化合物-c组、PD组加化合物-c和反式查尔酮组。采用黑质内6-羟多巴胺注射诱导PD。PD大鼠每天腹腔注射反式查尔酮(100 μg/kg)和化合物c (20 mg/kg),连续4周。采用旋转棒和网格测试评估运动功能。采用酶联免疫吸附法检测纹状体多巴胺、细胞因子(白细胞介素1- β [IL-1 β]、IL-10)和p65核因子κ b (NF-κB)水平。用荧光技术评价线粒体功能。Western blotting分析磷酸化AMPK、PGC-1α、SIRT1的表达。反式查尔酮治疗显著改善了运动功能,在旋转杆测试中增加了跌倒潜伏期,在网格测试中恢复了穿越时间。它还能恢复多巴胺水平,增强线粒体功能(降低活性氧水平,增加膜电位和三磷酸腺苷的产生),使细胞因子(IL-1 β, IL-10)和p65-NF-κB正常化,并上调PD大鼠的蛋白质表达。化合物c抑制AMPK活性抑制了反式查尔酮的神经保护作用,突出了AMPK信号通路在其作用机制中的作用。反式查尔酮的神经保护和有丝分裂保护作用主要通过激活AMPK-SIRT1-PGC1α途径介导。这些结果表明,反式查尔酮可能是一种有前景的PD治疗剂,值得进一步研究以评估其在人类患者中的有效性和安全性。
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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