关键词: GPR17 receptor SOD1G93A amyotrophic lateral sclerosis montelukast neuroinflammation oligodendrocytes

Mesh : Animals Female Cyclopropanes / pharmacology Quinolines / pharmacology Acetates / pharmacology therapeutic use Oligodendroglia / drug effects metabolism pathology Sulfides / pharmacology Amyotrophic Lateral Sclerosis / drug therapy genetics pathology Mice, Transgenic Mice Male Receptors, Leukotriene / metabolism genetics Receptors, G-Protein-Coupled / metabolism genetics Superoxide Dismutase-1 / genetics metabolism Mice, Inbred C57BL Disease Models, Animal Spinal Cord / drug effects metabolism pathology Microglia / drug effects metabolism pathology Nerve Tissue Proteins

来  源:   DOI:10.1111/bph.16408

Abstract:
OBJECTIVE: 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.
METHODS: 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 (CysLT1R) receptors on microglia and astrocytes, in the SOD1G93A ALS mouse model. We chronically treated SOD1G93A mice with MTK, starting from the early symptomatic disease stage. Disease progression was assessed by behavioural and immunohistochemical approaches.
RESULTS: Oral MTK treatment significantly extended survival probability, delayed body weight loss and ameliorated motor functionalityonly in female SOD1G93A 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 SOD1G93A 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: 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.
摘要:
目的:肌萎缩侧索硬化症(ALS)是一种致命的神经退行性疾病,其特征是进行性运动神经元(MN)丢失和随之而来的肌肉萎缩,没有有效的治疗方法。最近的发现表明,早期异常神经炎症和具有神经保护和髓鞘再生特性的少突胶质细胞的丧失促进了疾病的进展。在此基础上,能够恢复促再生局部环境和重建适当少突胶质细胞功能的药物干预可能是有益的.
方法:这里,我们评估了孟鲁司特(MTK)的体内治疗效果,少突胶质细胞G蛋白偶联受体17(GPR17)和小胶质细胞和星形胶质细胞上半胱氨酰-白三烯受体1(CysLT1R)受体的拮抗剂,在SOD1G93AALS小鼠模型中。我们用MTK长期治疗SOD1G93A小鼠,从早期有症状的疾病阶段开始。通过行为和免疫组织化学方法评估疾病进展。
结果:口服MTK治疗显著延长生存概率,仅在雌性SOD1G93A小鼠中延迟体重减轻和改善运动功能。值得注意的是,MTK显著恢复少突胶质细胞成熟,诱导雌性SOD1G93A小鼠脊髓小胶质细胞/巨噬细胞和星形胶质细胞的反应表型和形态特征发生显著改变,表明增强的促再生功能。重要的是,MTK给药后检测到伴随的MN保存。在雄性小鼠中没有观察到有益效果,突出了MTK保护活性的性别差异。
结论:我们的结果提供了第一个临床前证据,表明MTK的再利用,一种安全且上市的抗哮喘药物,可能是个性化ALS治疗的有希望的性别特异性策略。
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