Lorlatinib protects dopaminergic neurons by inhibiting ALK-mediated neuroinflammation in a mouse model of Parkinson's disease.

Research overview

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Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra (SN), where neuroinflammation plays a critical pathogenic role. Anaplastic lymphoma kinase (ALK) has recently emerged as a therapeutic target for inflammatory and immune disorders; however, its role in neuroinflammation and PD remains unclear. In this study, we investigated the role of ALK using the ALK-specific inhibitor lorlatinib (LOR) in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD. LOR significantly improved motor function, attenuated dopaminergic neuronal loss, and restored neurotrophic factor expression. LOR also suppressed ALK phosphorylation and inhibited activation of the downstream STING-TBK1-IRF3/NF-κB signaling pathway in the SN. Notably, MPTP-induced p-ALK expression was predominantly colocalized with microglia, suggesting a potential role for microglial ALK in PD-related neuroinflammation. LOR consistently reduced microglial and astrocytic activation, decreased pro-inflammatory cytokine expression, and attenuated oxidative stress by activating the Nrf2 antioxidant signaling pathway. Additionally, LOR restored the blood-brain barrier integrity and suppressed T lymphocyte infiltration into the SN region. Finally, LOR attenuated the MPTP-induced apoptosis and necroptotic cell death in dopaminergic neurons. Collectively, these findings demonstrate that ALK inhibition confers neuroprotection by modulating microglia-mediated neuroinflammation. Given that LOR is a clinically approved anticancer drug with blood-brain barrier permeability, this study provides experimental evidence supporting its repositioning for the treatment of neuroinflammatory disorders, such as PD.

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