Shenzhen Key Laboratory of Modern Toxicology, Shenzhen Medical Key Discipline of Health Toxicology (2020-2024), Shenzhen Center for Disease Control and Prevention, Shenzhen, China.
Department of Neurology, The First Affiliated Hospital of Bengbu Medical University, Bengbu, China.
CNS Neurosci Ther. 2024 Jun;30(6):e14692. doi: 10.1111/cns.14692.
Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease characterized by progressive death of upper and lower motor neurons, leading to generalized muscle atrophy, paralysis, and even death. Mitochondrial damage and neuroinflammation play key roles in the pathogenesis of ALS. In the present study, the efficacy of A-1, a derivative of arctigenin with AMP-activated protein kinase (AMPK) and silent information regulator 1 (SIRT1) activation for ALS, was investigated.
A-1 at 33.3 mg/kg was administrated in SOD1 transgenic mice orally from the 13th week for a 6-week treatment period. Motor ability was assessed before terminal anesthesia. Muscle atrophy and fibrosis, motor neurons, astrocytes, and microglia in the spinal cord were evaluated by H&E, Masson, Sirius Red, Nissl, and immunohistochemistry staining. Protein expression was detected with proteomics analysis, Western blotting, and ELISA. Mitochondrial adenosine triphosphate (ATP) and malondialdehyde (MDA) levels were measured using an assay kit.
A-1 administration in SOD1 mice enhanced mobility, decreased skeletal muscle atrophy and fibrosis, mitigated loss of spinal motor neurons, and reduced glial activation. Additionally, A-1 treatment improved mitochondrial function, evidenced by elevated ATP levels and increased expression of key mitochondrial-related proteins. The A-1 treatment group showed decreased levels of IL-1β, pIκBα/IκBα, and pNF-κB/NF-κB.
A-1 treatment reduced motor neuron loss, improved gastrocnemius atrophy, and delayed ALS progression through the AMPK/SIRT1/PGC-1α pathway, which promotes mitochondrial biogenesis. Furthermore, the AMPK/SIRT1/IL-1β/NF-κB pathway exerted neuroprotective effects by reducing neuroinflammation. These findings suggest A-1 as a promising therapeutic approach for ALS.
肌萎缩侧索硬化症（ALS）是一种严重的神经退行性疾病，其特征是上下运动神经元进行性死亡，导致广泛的肌肉萎缩、瘫痪，甚至死亡。线粒体损伤和神经炎症在 ALS 的发病机制中起关键作用。在本研究中，研究了具有 AMP 激活的蛋白激酶（AMPK）和沉默信息调节因子 1（SIRT1）激活作用的牛蒡子苷元衍生物 A-1 治疗 ALS 的疗效。
SOD1 转基因小鼠从第 13 周开始口服给予 A-1（33.3mg/kg），为期 6 周的治疗期。在终末麻醉前评估运动能力。通过 H&E、Masson、天狼猩红、尼氏染色和免疫组织化学染色评估脊髓中的肌肉萎缩和纤维化、运动神经元、星形胶质细胞和小胶质细胞。通过蛋白质组学分析、Western blot 和 ELISA 检测蛋白表达。使用试剂盒测定线粒体三磷酸腺苷（ATP）和丙二醛（MDA）水平。
A-1 治疗 SOD1 小鼠可增强运动能力，减少骨骼肌萎缩和纤维化，减轻脊髓运动神经元丢失，并减少神经胶质细胞激活。此外，A-1 治疗可改善线粒体功能，表现为 ATP 水平升高和关键线粒体相关蛋白表达增加。A-1 治疗组的 IL-1β、pIκBα/IκBα 和 pNF-κB/NF-κB 水平降低。
A-1 治疗可通过 AMPK/SIRT1/PGC-1α 途径减少运动神经元丢失、改善腓肠肌萎缩并延缓 ALS 进展，从而促进线粒体生物发生。此外，AMPK/SIRT1/IL-1β/NF-κB 途径通过减少神经炎症发挥神经保护作用。这些发现表明 A-1 可能是治疗 ALS 的一种有前途的方法。
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