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Recent findings reveal that disease progression is fuelled by early aberrant neuroinflammation and the loss of oligodendrocytes with neuroprotective and remyelinating properties. On this basis, pharmacological interventions capable of restoring a pro\u2010regenerative local milieu and re\u2010establish proper oligodendrocyte functions may be beneficial.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>Here, we evaluated the in vivo therapeutic effects of montelukast (MTK), an antagonist of the oligodendroglial G protein\u2010coupled receptor 17 (GPR17) and of cysteinyl\u2010leukotriene receptor 1 (CysLT<jats:sub>1<\/jats:sub>R) receptors on microglia and astrocytes, in the SOD1<jats:sup>G93A<\/jats:sup> ALS mouse model. We chronically treated SOD1<jats:sup>G93A<\/jats:sup> mice with MTK, starting from the early symptomatic disease stage. Disease progression was assessed by behavioural and immunohistochemical approaches.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Oral MTK treatment significantly extended survival probability, delayed body weight loss and ameliorated motor functionalityonly in female SOD1<jats:sup>G93A<\/jats:sup> mice. Noteworthy, MTK significantly restored oligodendrocyte maturation and induced significant changes in the reactive phenotype and morphological features of microglia\/macrophages and astrocytes in the spinal cord of female SOD1<jats:sup>G93A<\/jats:sup> mice, suggesting enhanced pro\u2010regenerative functions. Importantly, concomitant MN preservation has been detected after MTK administration. No beneficial effects were observed in male mice, highlighting a sex\u2010based difference in the protective activity of MTK.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>Our results provide the first preclinical evidence indicating that repurposing of MTK, a safe and marketed anti\u2010asthmatic drug, may be a promising sex\u2010specific strategy for personalized ALS treatment.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.16408","type":"journal-article","created":{"date-parts":[[2024,5,16]],"date-time":"2024-05-16T05:54:53Z","timestamp":1715838893000},"page":"3303-3326","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Montelukast improves disease outcome in SOD1<sup>G93A<\/sup> female mice by counteracting oligodendrocyte dysfunction and aberrant glial 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