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

Xin Guo ¹ Jie Wang ² Hongyang Fan ¹ Wanying Tao ³ Zijing Ren ² Xingyue Li ² Suyu Liu ⁴ Peiyang Zhou ² YingZhu Chen ^1*

• ¹ Medical College, Yangzhou University, Yangzhou, Jiangsu Province, China
• ² The First People's Hospital of Xiangyang City, Xiangyang, Hebei Province, China
• ³ Xiangyang Central Hospital, Xiangyang, China
• ⁴ Nanjing University, Nanjing, Jiangsu Province, China

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.In this study, we employed a drug-target network approach to identify potential therapeutic candidates for Parkinson's disease by computationally repurposing FDAapproved drugs from databases such as DrugBank. This approach yielded a total of 176 drug candidates. A comprehensive review of existing literature was conducted to identify drug candidates, resulting in the selection of 28 compounds not previously reported as pharmacoprotective against Parkinson's disease, yet possessing potential anti-Parkinsonian properties. Subsequent evaluation using Cell Counting Kit-8 (CCK8) assays conclusively demonstrated that Omaveloxolone and Cyproheptadine exerted significant neuroprotective effects in the SH-SY5Y cell model of Parkinson's disease induced by 1-Methyl-4-phenylpyridinium (MPP+). Through the development of a mouse model of Parkinson's disease induced by 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine (MPTP), our study demonstrated that Cyproheptadine effectively inhibited interleukin-6 (IL-6) expression and prevented the downregulation of Tyrosine Hydroxylase (TH) via the MAPK/NFκB signaling pathway. Concurrently, Omaveloxolone alleviates the downregulation of TH, which may be mediated by the activation of the Kelch-like ECH-associated protein 1 (KEAP1)-NF-E2-related factor 2 (Nrf2)/antioxidant response element (ARE) signaling pathway. Both pharmacological agents contributed to the preservation of dopaminergic neurons and amelioration of neurological deficits within the Parkinson's disease model. In conclusion, this study elucidates potential drug candidates for the treatment of Parkinson's disease through the application of computational repurposing, thereby underscoring its efficacy as a drug discovery strategy.