Presti-Silva Sarah Martins, Rodrigues-Ribeiro Lucas, Gorshkov Vladimir, Kjeldsen Frank, Verano-Braga Thiago, Pires Rita Gomes Wanderley
Postgraduate Program in Biochemistry and Immunology, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
Department of Physiological Science, Federal University of Espirito Santo, Vitoria, Espirito Santo, Brazil.
Proteomics Clin Appl. 2025 May;19(3):e70006. doi: 10.1002/prca.70006. Epub 2025 Apr 4.
Parkinson's disease (PD) is neuropathologically characterized by the progressive degeneration of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc), affecting 10 million people worldwide. Rosmarinic acid (RA), a polyphenol found in plants like rosemary (Rosmarinus officinalis), is known for its intriguing biological properties and potential antioxidant and neuroprotective effects. In a previous study we showed that RA treatment prevented hyperlocomotion in mice with MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-induced parkinsonism and improved the monoaminergic system in healthy animals. However, the molecular mechanisms underlying RA's action in PD remain unclear.
In this study, we treated MPTP-induced PD animals (C57BL/6 male mice) with RA orally at a dose of 100 mg/kg for 15 days and examined the proteome of substantia nigra (SN) to identify possible regulatory targets of RA treatment to shed some lights into its neuroprotective effects.
Quantitative proteomics revealed that RA treatment regulated proteins associated with oxidative phosphorylation (OXPHOS), glutamatergic synapse, and vesicular cycle signaling pathway. We identified 371 proteins significantly regulated in response to RA administration (255 upregulated and 116 downregulated). Notably, some cellular targets of RA treatment reported here, including mGluR2/mGluR3/EAAT-proteins from the glutamatergic system-and proteins from the Complex I of the electron transport chain are promising targets for therapeutic intervention.
These findings highlight the molecular differences between MPTP-induced PD mice and those treated with RA, providing insights on the molecular basis behind the neuroprotective effects of RA and revealing potential PD signatures that warrant further investigation.
帕金森病（PD）的神经病理学特征是黑质致密部（SNpc）中多巴胺能（DA）神经元的进行性退化，全球有1000万人受其影响。迷迭香酸（RA）是一种存在于迷迭香（Rosmarinus officinalis）等植物中的多酚，以其有趣的生物学特性以及潜在的抗氧化和神经保护作用而闻名。在先前的一项研究中，我们表明RA治疗可预防MPTP（1-甲基-4-苯基-1,2,3,6-四氢吡啶）诱导的帕金森病小鼠的运动亢进，并改善健康动物的单胺能系统。然而，RA在PD中作用的分子机制仍不清楚。
在本研究中，我们以100mg/kg的剂量对MPTP诱导的PD动物（C57BL/6雄性小鼠）进行为期15天的口服RA治疗，并检测黑质（SN）的蛋白质组，以确定RA治疗可能的调控靶点，从而深入了解其神经保护作用。
定量蛋白质组学显示，RA治疗调节了与氧化磷酸化（OXPHOS）、谷氨酸能突触和囊泡循环信号通路相关的蛋白质。我们鉴定出371种因RA给药而受到显著调节的蛋白质（255种上调和116种下调）。值得注意的是，本文报道的RA治疗的一些细胞靶点，包括来自谷氨酸能系统的mGluR2/mGluR3/EAAT蛋白以及电子传递链复合体I中的蛋白，是有前景的治疗干预靶点。
这些发现突出了MPTP诱导的PD小鼠与接受RA治疗的小鼠之间的分子差异，为RA神经保护作用背后的分子基础提供了见解，并揭示了值得进一步研究的潜在PD特征。
