Yu Xiaorong, Yang Yunpeng, Zhang Bo, Han Guangyu, Yu Junxing, Yu Qi, Zhang Lei
Department of Anesthesiology, Xi'an People's Hospital (Xi'an No.4 Hospital), Xi'an 710004, Shaanxi Province, PR China.
Department of Neurology, Xi'an People's Hospital (Xi'an No.4 Hospital), Xi'an 710004, Shaanxi Province, PR China.
Neuroscience. 2023 Jan 15;509:157-172. doi: 10.1016/j.neuroscience.2022.11.018. Epub 2022 Nov 23.
β-hydroxybutyrate (BHB) is one of main component of ketone body, which plays an important protective role in various tissues and organs. Whereas, its exact regulatory roles and mechanisms in Parkinson's disease (PD) have not been full elucidated. In this study, SN4741 cells and C57BL/6 mice were treated with 1-methyl-4-phenylpyridinium ion (MPP)/1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to establish the PD model in vitro and in vivo. Cell viability and damage to dopaminergic neurons were measured by cell counting kit 8, Calcein-AM/PI staining, terminal dexynucleotidyl transferase (TdT)-mediated dUTP nick end labeling and hematoxylin & eosin staining. Corresponding assay kits and BODIPY 581/591 C11 probe evaluated oxidative stress and intracellular iron levels. Western blot examined the ferroptosis-related proteins. MPTP/MPP-treatment reduced cell viability but triggered oxidative stress and ferroptosis in SNA4741 cells and brain tissues of mice. However, these effects were dramatically reversed by BHB and Fer-1 treatment. Mechanistically, Zinc finger protein 36 (ZFP36) was a target of BHB, and its depletion could reverse the anti-oxidative stress and anti-ferroptosis roles of BHB. Moreover, ZFP36 could directly bound to acyl-CoA synthetase long-chain family member 4 (ACSL4) mRNA to decay its expression, thus negatively modulating ACSL4-mediated oxidative stress and ferroptosis. Summary, BHB alleviated oxidative stress and ferroptosis of dopaminergic neurons in PD via modulating ZFP36/ACSL4 axis, which provided some new understanding for PD prevention and treatment.
β-羟基丁酸（BHB）是酮体的主要成分之一，在各种组织和器官中发挥着重要的保护作用。然而，其在帕金森病（PD）中的确切调节作用和机制尚未完全阐明。在本研究中，用1-甲基-4-苯基吡啶离子（MPP）/1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）处理SN4741细胞和C57BL/6小鼠，以建立体外和体内的PD模型。通过细胞计数试剂盒8、钙黄绿素-AM/PI染色、末端脱氧核苷酸转移酶（TdT）介导的dUTP缺口末端标记和苏木精-伊红染色来测量细胞活力和对多巴胺能神经元的损伤。相应的检测试剂盒和BODIPY 581/591 C11探针评估氧化应激和细胞内铁水平。蛋白质免疫印迹法检测铁死亡相关蛋白。MPTP/MPP处理降低了细胞活力，但在SNA4741细胞和小鼠脑组织中引发了氧化应激和铁死亡。然而，BHB和Fer-1处理显著逆转了这些作用。机制上，锌指蛋白36（ZFP36）是BHB的靶点，其缺失可逆转BHB的抗氧化应激和抗铁死亡作用。此外，ZFP36可直接结合到酰基辅酶A合成酶长链家族成员4（ACSL4）的mRNA上，使其表达衰减，从而负向调节ACSL4介导的氧化应激和铁死亡。总之，BHB通过调节ZFP36/ACSL4轴减轻了PD中多巴胺能神经元的氧化应激和铁死亡，这为PD的预防和治疗提供了一些新的认识。
