Montelukast improves disease outcome in SOD1G93A female mice by counteracting oligodendrocyte dysfunction and aberrant glial reactivity

Abstract Background and Purpose Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron (MN) loss and consequent muscle atrophy, for which no effective therapies are available. 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‐regenerative local milieu and re‐establish proper oligodendrocyte functions may be beneficial. Experimental Approach Here, we evaluated the in vivo therapeutic effects of montelukast (MTK), an antagonist of the oligodendroglial G protein‐coupled receptor 17 (GPR17) and of cysteinyl‐leukotriene receptor 1 (CysLT 1 R) receptors on microglia and astrocytes, in the SOD1 G93A ALS mouse model. We chronically treated SOD1 G93A mice with MTK, starting from the early symptomatic disease stage. Disease progression was assessed by behavioural and immunohistochemical approaches. Key Results Oral MTK treatment significantly extended survival probability, delayed body weight loss and ameliorated motor functionalityonly in female SOD1 G93A 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 G93A mice, suggesting enhanced pro‐regenerative functions. Importantly, concomitant MN preservation has been detected after MTK administration. No beneficial effects were observed in male mice, highlighting a sex‐based difference in the protective activity of MTK. Conclusions and Implications Our results provide the first preclinical evidence indicating that repurposing of MTK, a safe and marketed anti‐asthmatic drug, may be a promising sex‐specific strategy for personalized ALS treatment.