Arthur Richmond, Navik Umashanker, Kumar Puneet
Department of Pharmacology, Central University of Punjab, Bathinda, India.
Mol Neurobiol. 2025 Mar;62(3):3583-3600. doi: 10.1007/s12035-024-04487-9. Epub 2024 Sep 23.
Neurodegenerative disorders like Huntington's disease (HD) are a major threat to human health, with severe gait abnormalities and pathological changes (oxidative stress, neuroinflammation, and apoptosis) playing important roles in their development. The effects of artemisinin (ART) alone and in combination with the ERK antagonist PD98059 against 3-nitropropionic acid (3-NPA)-induced cell death and oxidative stress in SH-SY5Y cells were determined using the MTT and DCFH-DA assays, as well as RT-qPCR assays. In vivo, possible neuroprotective effects of ART (10, 20, and 40 mg/kg i.p.) against the neurotoxicity generated by 21-day 3-NPA (10 mg/kg i.p.) treatment was evaluated in rats by assessing behavioral parameters on days 1, 14, and 21. Further, various biochemical, inflammatory, apoptotic markers, histopathological changes, and protein expression were assessed using brain striatal samples. ART significantly mitigated the neurotoxic effect of 3-NPA in SH-SY5Y cells by regulating the mRNA expression of ERK, Bax, Bcl2, and cytochrome C. However, ART's neuroprotective activity was reduced in the presence of PD98059. Also, ART treatment for 21 days substantially alleviated the behavioral impairments associated with 3-NPA toxicity. It reduced the oxidative stress induced by 3-NPA, as evidenced by the lower levels of MDA, nitrite, and improved catalase, SOD activity, and GSH levels. ART treatment restored 3-NPA-induced histopathological alterations in the striatal area. ART effectively suppressed neuroinflammatory (IL-6) and apoptotic markers (caspase 3 and 9), increasing BDNF levels and restoring the p-ERK1/2, Nrf2, and HO-1 expression. ART could exert its neuroprotective effect via antioxidant, anti-inflammatory, and antiapoptotic properties with a possible involvement of the ERK/BDNF/Nrf2/HO-1 pathway.
像亨廷顿舞蹈病（HD）这样的神经退行性疾病是对人类健康的重大威胁，严重的步态异常和病理变化（氧化应激、神经炎症和细胞凋亡）在其发展过程中起着重要作用。使用MTT和DCFH-DA测定法以及RT-qPCR测定法，确定了青蒿素（ART）单独使用以及与ERK拮抗剂PD98059联合使用对3-硝基丙酸（3-NPA）诱导的SH-SY5Y细胞死亡和氧化应激的影响。在体内，通过评估第1、14和21天的行为参数，评估了ART（10、20和40mg/kg腹腔注射）对21天3-NPA（10mg/kg腹腔注射）治疗产生的神经毒性的可能神经保护作用。此外，使用脑纹状体样本评估了各种生化、炎症、凋亡标志物、组织病理学变化和蛋白质表达。ART通过调节ERK、Bax、Bcl2和细胞色素C的mRNA表达，显著减轻了3-NPA对SH-SY5Y细胞的神经毒性作用。然而，在存在PD98059的情况下，ART的神经保护活性降低。此外，ART治疗21天显著减轻了与3-NPA毒性相关的行为障碍。它降低了3-NPA诱导的氧化应激，这表现为MDA、亚硝酸盐水平降低以及过氧化氢酶、超氧化物歧化酶活性提高和谷胱甘肽水平改善。ART治疗恢复了3-NPA诱导的纹状体区域组织病理学改变。ART有效抑制了神经炎症（IL-6）和凋亡标志物（caspase 3和9），增加了脑源性神经营养因子（BDNF）水平，并恢复了p-ERK1/2、核因子E2相关因子2（Nrf2）和血红素加氧酶-1（HO-1）的表达。ART可能通过抗氧化、抗炎和抗凋亡特性发挥其神经保护作用，可能涉及ERK/BDNF/Nrf2/HO-1途径。
