Abstract

Parkinson's disease (PD) is a neurodegenerative movement disorder of high global burden. Uncertainties regarding its exact etiology have been hindering the development of curative therapies. As microglia, the brain's immune cells, are suspected to contribute to neurodegeneration by instigating neuroinflammation, existing anti-inflammatory agents could potentially serve as disease-modifying treatments for PD. Here we evaluated the impact of montelukast, a leukotriene receptor antagonist and anti-inflammatory drug, on motor symptoms and neuropathology in an α-synuclein transgenic mouse model (Line 61) for early onset/genetic PD. Two -weeks -old male Line 61 mice and non-transgenic littermates received daily 10 ​mg/kg montelukast or vehicle orally for 10 weeks. Motor functions were assessed through behavioral tests. Brain tissue was analyzed via unbiased transcriptomics, biochemically, and histologically for various parameters, including microglial and inflammation mediators. Upon montelukast treatment, Line 61 mice significantly improved their beam walk performance compared to vehicle -treated mice. The striatum and cerebellum of the montelukast -treated group showed microglial changes toward a smaller but more ramified appearance. Transcriptomics analysis revealed SGK1, a serine/threonine kinase upstream of NFκB and known target in PD, as the most downregulated gene in the striatum of montelukast -treated animals. This downregulation correlated with reduced striatal protein levels of activated IκB kinase, suggesting a reduced NFκB pathway activity upon montelukast treatment. Thus, oral montelukast administration might be promising for the management of PD, with specific effects on motor coordination and balance.