Repurposing the antiplatelet drug prasugrel for Parkinson's disease: evidence of neuroprotective effects and proteomic profiles.

Chronic neuroinflammation is a hallmark pathological feature of Parkinson's disease (PD) that contributes to progressive neuronal death. Current medications are largely palliative, underscoring the need for alternative therapeutic strategies. Drug repurposing offers a cost-effective and time-efficient approach by leveraging established safety profiles. Here, we screened the U.S. Food and Drug Administration-approved drug library using two in vitro PD models: 1-methyl-4-phenylpyridinium (MPP+)-induced primary cortical neurons and lipopolysaccharide (LPS)-induced BV2 microglial cells. Proteomic alterations following prasugrel treatment were profiled using Ingenuity Pathway Analysis. Neuroprotective effects were validated by biochemical assays and further confirmed in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model. We found that prasugrel, an antiplatelet drug used for acute coronary syndrome, exhibited significant neuroprotective and anti-inflammatory effects. It reduced the expression of apoptosis- and inflammation-related proteins, inhibited mitogen-activated protein kinase (MAPK)-mediated neuronal death and suppressed nuclear factor kappa B (NF-κB)-dependent inflammatory signaling. In vivo, prasugrel administration preserved dopaminergic neurons and improved motor performance in MPTP-treated mice. These findings demonstrate that prasugrel mitigates neuronal apoptosis and microglial activation through modulation of MAPK and NF-κB signaling pathways, supporting its development as a repurposed therapeutic candidate for PD.