Repurposing the memory-promoting meclofenoxate hydrochloride as a treatment for Parkinson’s disease through integrative multi-omics analysis
Parkinson's disease (PD) is a devastating neurodegenerative disorder with growing prevalence worldwide and, as yet, no effective treatment. Drug repurposing is invaluable for detecting novel PD therapeutics. Here, we compiled gene expression data from 1231 healthy human brain samples and 357 samples across tissues, ethnicities, brain regions, Braak stages, and disease status. By integrating them with multiple-source genomic data, we found a PD-associated gene co-expression module, and its alignment with the CMAP database successfully identified drug candidates. Among these, meclofenoxate hydrochloride (MH) and sodium phenylbutyrate (SP) are indicated to be able to prevent mitochondrial destruction, reduce lipid peroxidation, and protect dopamine synthesis. MH was validated to prevent neuronal death and synaptic damage, improve motor function, and reduce anhedonic and depressive-like behaviors of PD mice. The interaction of MH with a PD-related protein, sigma1, was confirmed experimentally. Thus, our findings support that MH potentially ameliorates PD by interacting with sigma1.
Authors
- Huasong Zhang (ORCID: https://orcid.org/0000-0003-4514-6313)
- Yuedong Yang (ORCID: https://orcid.org/0000-0002-6782-2813)
- D.N. Cooper (ORCID: https://orcid.org/0000-0002-8943-8484)
- Linyun Ma
- Yuanhao Yang (ORCID: https://orcid.org/0000-0002-5857-0124)
- Cong Fan (ORCID: https://orcid.org/0000-0001-5668-6361)
- Ling Li (ORCID: https://orcid.org/0000-0003-0663-3784)
- Feiyi Liu
- Shaoying Li (ORCID: https://orcid.org/0000-0002-4703-5660)
- Huiying Zhao
- Ronggui Hu (ORCID: https://orcid.org/0000-0002-3939-6087)
Institutions
- Translational Research Institute (AU)
- Sun Yat-sen University (CN)
- The University of Queensland (AU)
- Chinese Academy of Sciences (CN)
- Third Affiliated Hospital of Guangzhou Medical University (CN)
- Mater Research (AU)
- Longgang Central Hospital (CN)
- Sun Yat-sen Memorial Hospital (CN)
- Key Laboratory of Guangdong Province (CN)
- Center for Excellence in Molecular Cell Science (CN)
- University of Chinese Academy of Sciences (CN)
- Cardiff University (GB)
- Guangzhou Medical University (CN)
Publication Details
- Journal
- npj Parkinson s Disease
- Published
- 2025-06-13
- DOI
- https://doi.org/10.1038/s41531-025-01027-7
- Primary Topic
- Parkinson's Disease Mechanisms and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Natural Science Foundation of China
- Sun Yat-sen University
- Natural Science Foundation of Guangdong Province
- National Key Research and Development Program of China