Abstract
Neuroinflammation mediated by microglial activation plays a critical role in Parkinson's disease (PD), with the NLRP3 inflammasome contributing to dopaminergic neurodegeneration. Varlitinib, a clinically developed pan-human epidermal growth factor receptor inhibitor, has been investigated as an anticancer agent; however, its therapeutic potential in PD remains unknown. Here, we evaluated the neuroprotective effects of varlitinib in in vitro and in vivo PD models. BV2 microglial cells were stimulated with α-synuclein and 1-methyl-4-phenylpyridinium and treated with varlitinib. Varlitinib significantly improved cell viability, reduced lactate dehydrogenase release, and suppressed IL-1β and IL-18 production. Co-treatment with the selective NLRP3 inhibitor MCC950 produced no additional anti-inflammatory effects, suggesting that NLRP3 inflammasome signaling contributes, at least in part, to varlitinib's actions. In a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse model of PD, varlitinib significantly improved motor performance, reduced microglial activation in the substantia nigra and striatum, and preserved tyrosine hydroxylase-positive dopaminergic neurons. Collectively, these findings support varlitinib as a potential drug-repurposing candidate for PD.