Computational drug repurposing in Parkinson’s disease: Omaveloxolone and cyproheptadine as promising therapeutic candidates

作者：Xin Guo, Jie Wang, Hongyang Fan, Wanying Tao, Zijing Ren, Xingyue Li, Suyu Liu, Peiyang Zhou, Yingzhu Chen · 发表于：Frontiers in Pharmacology · 年份：2025 · DOI：10.3389/fphar.2025.1539032 · 被引用次数：5 · 研究领域：Parkinson's Disease Mechanisms and Treatments、Nuclear Receptors and Signaling、Cholinesterase and Neurodegenerative Diseases

Background: Parkinson's disease (PD), a prevalent and progressive neurodegenerative disorder, currently lacks effective and satisfactory pharmacological treatments. Computational drug repurposing represents a promising and efficient strategy for drug discovery, aiming to identify new therapeutic indications for existing pharmaceuticals. Methods: We employed a drug-target network approach to computationally repurpose FDA-approved drugs from databases such as DrugBank. A literature review was conducted to select candidates not previously reported as pharmacoprotective against PD. Subsequent in vitro evaluation utilized Cell Counting Kit-8 (CCK8) assays to assess the neuroprotective effects of the selected compounds in the SH-SY5Y cell model of Parkinson's disease induced by 1-methyl-4-phenylpyridinium (MPP+). Furthermore, an in vivo mouse model of Parkinson's disease induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was developed to investigate the mechanisms of action and therapeutic potential of the identified drug candidates. Results: Our approach identified 176 drug candidates, with 28 selected for their potential anti-Parkinsonian effects and lack of prior PD-related reporting. CCK8 assays showed significant neuroprotection in SH-SY5Y cells for Omaveloxolone and Cyproheptadine. In the MPTP-induced mouse model, Cyproheptadine inhibited interleukin-6 (IL-6) expression and prevented Tyrosine Hydroxylase (TH) downregulation via the MAPK/NFκB pathway, while Omavelo...