Clopidogrel modulate deregulated metabolic pathways in cuprizone fed mice model of Multiple Sclerosis

Multiple sclerosis is a debilitating demyelinating progressive neurodegenerative disease, that eventually leads to the death of patients. Transcriptomic patient dataset analysis revealed marked alterations in P₂Y₁₂ expression in microglia from individuals with Multiple Sclerosis. Absorption, Distribution, Metabolism, and Excretion (ADME) profiling highlighted clopidogrel, a P₂Y₁₂ inhibitor, as a potentially promising treatment option for advanced stages of the disease. Our previous invitro studies using N9 microglial cells showed that, clopidogrel effectively mitigated TNF-α mediated inflammatory response and chemotaxis. We employed targeted metabolomic analysis of healthy, cuprizone-fed, clopidogrel-treated, and clopidogrel-treated cuprizone-fed mice to understand the metabolic modulation associated with clopidogrel treatment. Our analysis reveals that cuprizone-fed mice show deregulation of metabolic pathways important for lipid, oxidative stress, and biotin metabolism. Notably, clopidogrel modulates metabolic pathways in cuprizone-fed mice particularly involved in lipid, biotin and myelin biosynthesis. Taken together, our earlier findings with N9 microglial cells and current results from the cuprizone-fed mice model suggest clopidogrel as a potential therapeutic agent in Multiple Sclerosis.

The online version contains supplementary material available at 10.1007/s13205-026-04715-0.