Fouché Belinda, Turner Stephanie, Gorham Rebecca, Stephenson Eloise J, Gutbier Simon, Elson Joanna L, García-Beltrán Olimpo, Van Der Westhuizen Francois H, Pienaar Ilse S
Centre for Human Metabolomics, North-West University, Potchefstroom, South Africa.
School of Life Sciences, University of Sussex, Falmer, Brighton, UK.
Mol Neurobiol. 2023 Feb;60(2):749-767. doi: 10.1007/s12035-022-03107-8. Epub 2022 Nov 11.
Coumarins are plant-derived polyphenolic compounds belonging to the benzopyrones family, possessing wide-ranging pharmaceutical applications including cytoprotection, which may translate into therapeutic potential for multiple diseases, including Parkinson's disease (PD). Here we demonstrate the neuroprotective potential of a new polyhydroxyl coumarin, N-(1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)-2-(7-hydroxy-2-oxo-2H-chromen-4-yl)acetamide (CT51), against the mitochondrial toxin 1-methyl-4-phenylpyridinium (MPP). MPP+'s mechanism of toxicity relates to its ability to inhibit complex I of the mitochondrial electron transport chain (METC), leading to adenosine triphosphate (ATP) depletion, increased reactive oxygen species (ROS) production, and apoptotic cell death, hence mimicking PD-related neuropathology. Dopaminergic differentiated human neuroblastoma cells were briefly pretreated with CT51, followed by toxin exposure. CT51 significantly restored somatic cell viability and neurite processes; hence, the drug targets cell bodies and axons thereby preserving neural function and circuitry against PD-related damage. Moreover, MPP+ emulates the iron dyshomeostasis affecting dopaminergic neurons in PD-affected brains, whilst CT51 was previously revealed as an effective iron chelator that preferentially partitions to mitochondria. We extend these findings by characterising the drug's interactive effects at the METC level. CT51 did not improve mitochondrial coupling efficiency. However, voltammetric measurements and high-resolution respirometry analysis revealed that CT51 acts as an antioxidant agent. Also, the neuronal protection afforded by CT51 associated with downregulating MPP+-induced upregulated expression of hypoxia-inducible factor 1 alpha (HIF-1α), a protein which regulates iron homeostasis and protects against certain forms of oxidative stress after translocating to mitochondria. Our findings support the further development of CT51 as a dual functioning iron chelator and antioxidant antiparkinsonian agent.
香豆素是植物来源的多酚类化合物，属于苯并吡喃酮家族，具有广泛的药物应用，包括细胞保护作用，这可能转化为对多种疾病（包括帕金森病（PD））的治疗潜力。在此，我们展示了一种新型多羟基香豆素N-(1,3-二羟基-2-(羟甲基)丙烷-2-基)-2-(7-羟基-2-氧代-2H-色烯-4-基)乙酰胺（CT51）对线粒体毒素1-甲基-4-苯基吡啶鎓（MPP）的神经保护潜力。MPP+的毒性机制与其抑制线粒体电子传递链（METC）复合体I的能力有关，导致三磷酸腺苷（ATP）耗竭、活性氧（ROS）生成增加和细胞凋亡性死亡，从而模拟了与PD相关的神经病理学。多巴胺能分化的人神经母细胞瘤细胞先用CT51进行短暂预处理，然后暴露于毒素。CT51显著恢复了体细胞活力和神经突过程；因此，该药物靶向细胞体和轴突，从而保护神经功能和神经回路免受与PD相关的损伤。此外，MPP+模拟了影响PD患者大脑中多巴胺能神经元的铁稳态失调，而CT51先前被揭示为一种有效的铁螯合剂，优先分布于线粒体。我们通过表征该药物在METC水平的相互作用效应来扩展这些发现。CT51并未提高线粒体偶联效率。然而，伏安测量和高分辨率呼吸测定分析表明CT51作为一种抗氧化剂起作用。此外，CT51提供的神经元保护作用与下调MPP+诱导的缺氧诱导因子1α（HIF-1α）上调表达有关，HIF-1α是一种在转位到线粒体后调节铁稳态并抵御某些形式氧化应激的蛋白质。我们的研究结果支持将CT51进一步开发为一种具有双重功能的铁螯合剂和抗氧化抗帕金森病药物。
