Chakkittukandiyil Amritha, Sajini Deepak Vasudevan, Rymbai Emdormi, Sugumar Deepa, Mathew Jinu, Arumugam Suresh, Ramachandran Vadivelan, Selvaraj Divakar
Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty, Nilgiris, Tamil Nadu, India.
Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty, Nilgiris, Tamil Nadu, India.
Toxicol Appl Pharmacol. 2025 Jan;494:117172. doi: 10.1016/j.taap.2024.117172. Epub 2024 Nov 26.
The Kelch-like ECH-associated protein 1/Nuclear factor erythroid 2 related factor 2/Antioxidant Response Elements (Keap1/Nrf2/ARE) pathway is essential for neuronal resilience against the complex pathogenesis of Parkinson's disease (PD). Activating this pathway by covalently modifying Keap1 cysteine residues is a promising strategy for regulating neuroprotective gene expression. Our study aimed to identify phytochemicals that could irreversibly inhibit Keap1. A preliminary docking analysis revealed that ethyl ferulate could covalently bind with Cys151 of Keap1 by Michael's addition reaction. Further, we designed several ethyl ferulate derivatives with improved lipophilicity and assessed their binding affinity with Keap1. The molecules with good binding scores were synthesized and structures were confirmed through H NMR, C NMR, FT-IR, and mass spectroscopy. Neuroprotection screening was conducted in all-trans retinoic acid differentiated SH-SY5Y cells using rotenone as a disease-inducing agent. Pre-treatment with compounds C2 and C4 significantly mitigated rotenone toxicity. Additionally, C2 and C4 decreased rotenone-induced ROS production and mitochondrial membrane potential loss. C2 and C4 also induced Nrf2 nuclear translocation in SH-SY5Y cells and increased mRNA expression of heme oxygenase-1, an Nrf2-regulated antioxidant response element. In vivo, pretreatment with C2 (50, 100 mg/kg, p.o.) and C4 (50, 100 mg/kg, p.o.) protected against neurodegenerative phenotypes associated with rotenone (1.5 mg/kg, s.c.) induction in Wistar rats. Results indicate, C2 and C4 dose-dependently improved muscle rigidity, catalepsy, and cognitive deficits in rotenone-induced Wistar rats, and mitigated dopaminergic neurodegeneration in the substantia nigra. These findings highlight the potential of ethyl ferulate derivatives in modulating oxidative stress and neurodegeneration in PD via activation of Nrf2.
kelch样ECH相关蛋白1/核因子红细胞2相关因子2/抗氧化反应元件（Keap1/Nrf2/ARE）通路对于神经元抵抗帕金森病（PD）复杂发病机制的复原力至关重要。通过共价修饰Keap1半胱氨酸残基来激活该通路是调节神经保护基因表达的一种有前景的策略。我们的研究旨在鉴定能够不可逆抑制Keap1的植物化学物质。初步对接分析表明，阿魏酸乙酯可通过迈克尔加成反应与Keap1的Cys151共价结合。此外，我们设计了几种亲脂性得到改善的阿魏酸乙酯衍生物，并评估了它们与Keap1的结合亲和力。合成了具有良好结合分数的分子，并通过氢核磁共振、碳核磁共振、傅里叶变换红外光谱和质谱对结构进行了确认。使用鱼藤酮作为疾病诱导剂，在全反式维甲酸分化的SH-SY5Y细胞中进行神经保护筛选。用化合物C2和C4预处理可显著减轻鱼藤酮毒性。此外，C2和C4降低了鱼藤酮诱导的活性氧产生和线粒体膜电位丧失。C2和C4还诱导了SH-SY5Y细胞中Nrf2的核转位，并增加了血红素加氧酶-1（一种Nrf2调节的抗氧化反应元件）的mRNA表达。在体内，用C2（50、100mg/kg，口服）和C4（50、100mg/kg，口服）预处理可预防Wistar大鼠中与鱼藤酮（1.5mg/kg，皮下注射）诱导相关的神经退行性表型。结果表明，C2和C4剂量依赖性地改善了鱼藤酮诱导的Wistar大鼠的肌肉僵硬、僵住症和认知缺陷，并减轻了黑质中的多巴胺能神经变性。这些发现突出了阿魏酸乙酯衍生物通过激活Nrf2调节PD中氧化应激和神经变性的潜力。
