Division of Neuroscience, Department of Pharmacology, ISF College of Pharmacy (Affiliated to IK Gujral Punjab Technical University, Jalandhar, Punjab, 144603, India), Moga, Punjab, India.
Division of Neuroscience, Department of Pharmacology, ISF College of Pharmacy (Affiliated to IK Gujral Punjab Technical University, Jalandhar, Punjab, 144603, India), Moga, Punjab, India.
Neurochem Int. 2024 Nov;180:105876. doi: 10.1016/j.neuint.2024.105876. Epub 2024 Oct 3.
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that gradually deteriorates motor neurons, leading to demyelination, muscle weakness, and eventually respiratory failure. The disease involves several pathological processes, such as increased glutamate levels, mitochondrial dysfunction, and persistent neuroinflammation, often exacerbated by environmental toxins like mercury. This study explores the therapeutic potential of Olea europaea active phytoconstituents oleanolic acid (OLA) against ALS by targeting the overactivated PI3K/Akt/mTOR/STAT-3/GSK-3β signalling pathways. Methods involved in-silico studies, in vitro and in vivo experiments in which varying doses of methylmercury 5 mg/kg, p.o. and OLA (100 and 200 mg/kg, i.p.) were administered to rats for 42 days. Behavioural assessments, gross morphological, histopathological, and neurochemical parameters were measured in cerebrospinal fluid (CSF), blood plasma, and brain homogenates (cerebral cortex, hippocampus, striatum, midbrain, cerebellum) along with complete blood count (CBC) analysis. Results revealed OLA's significant neuroprotective properties. OLA effectively modulated targeted pathways, reducing pro-inflammatory cytokines, restoring normal levels of myelin basic protein (MBP) and neurofilament light chain (NEFL), and reducing histopathological changes. Gross pathological studies indicated less tissue damage, while CBC analysis showed improved hematology parameters. Additionally, the combination of OLA and edaravone (10 mg/kg, i.p.) demonstrated enhanced efficacy, improving motor functions and extending survival in ALS model rats. In conclusion, OLA exhibits significant therapeutic potential for ALS, acting as a potent modulator of key pathological signaling pathways. The findings suggest the feasibility of integrating OLA into existing treatment regimens, potentially improving clinical outcomes for ALS patients. However, further research must validate these findings in human clinical trials.
肌萎缩侧索硬化症（ALS）是一种进行性神经退行性疾病，逐渐损害运动神经元，导致脱髓鞘、肌肉无力，最终导致呼吸衰竭。该疾病涉及多个病理过程，如谷氨酸水平升高、线粒体功能障碍和持续的神经炎症，通常会被汞等环境毒素加剧。本研究通过靶向过度激活的 PI3K/Akt/mTOR/STAT-3/GSK-3β 信号通路，探讨了油橄榄活性植物成分齐墩果酸（OLA）治疗肌萎缩侧索硬化症的治疗潜力。方法包括计算机模拟研究、体外和体内实验，其中对大鼠用不同剂量的甲基汞（5mg/kg，口服）和 OLA（100 和 200mg/kg，腹腔注射）处理 42 天。在脑脊髓液（CSF）、血浆和脑匀浆（大脑皮层、海马体、纹状体、中脑、小脑）中测量行为评估、大体形态、组织病理学和神经化学参数，并进行全血细胞计数（CBC）分析。结果表明 OLA 具有显著的神经保护作用。OLA 有效调节了靶向通路，减少了促炎细胞因子，恢复了髓鞘碱性蛋白（MBP）和神经丝轻链（NEFL）的正常水平，并减少了组织病理学变化。大体病理研究表明组织损伤减少，而 CBC 分析显示血液学参数得到改善。此外，OLA 与依达拉奉（10mg/kg，腹腔注射）联合使用显示出增强的疗效，改善了肌萎缩侧索硬化症模型大鼠的运动功能并延长了其生存期。总之，OLA 对肌萎缩侧索硬化症具有显著的治疗潜力，是关键病理信号通路的有效调节剂。研究结果表明，将 OLA 纳入现有的治疗方案具有可行性，可能改善肌萎缩侧索硬化症患者的临床结果。然而，还需要在人体临床试验中验证这些发现。
