Montelukast Modulates MPTP-induced Ferroptosis and Neuroinflammation Linked To the GPX4/ACSL4/5-LOX Pathway

Ferroptosis, an iron-dependent form of regulated cell death, has been increasingly linked to neurodegeneration in Parkinson's disease (PD). The lipid-peroxidizing enzyme 5-lipoxygenase (5-LOX) contributes to ferroptotic stress, while montelukast, a leukotriene receptor antagonist widely used for asthma, indirectly interferes with this pathway. Here, we investigated whether montelukast protects against dopaminergic injury in a mouse model of PD induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Mice were evaluated for behavioral deficits and underwent histological and biochemical analyses to assess iron burden, oxidative stress, ferroptosis markers, and neuroinflammation. Montelukast administration alleviated MPTP-induced motor dysfunction, preserved tyrosine hydroxylase-positive neurons, and reduced α-synuclein accumulation. Treatment also decreased iron deposition and malondialdehyde production while restoring glutathione and superoxide dismutase activity. At the molecular level, montelukast upregulated xCT/GPX4 while downregulating ACSL4/5-LOX, indicating suppression of ferroptosis. Moreover, montelukast attenuated microglial activation and pro-inflammatory cytokine expression. Collectively, our results suggest that prophylactic administration of montelukast mitigates dopaminergic neurodegeneration by modulating markers of ferroptosis and inflammatory signaling. These findings indicate the GPX4/ACSL4/5-LOX axis as a potential neuroprotective target for PD.