Department of Clinical Neurosciences, Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
Department of Medicine, Division of Neurology, Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Alberta T6G 2R7, Canada.
J Neurosci. 2020 Oct 28;40(44):8587-8600. doi: 10.1523/JNEUROSCI.1098-20.2020. Epub 2020 Oct 15.
Age is a critical risk factor for many neurologic conditions, including progressive multiple sclerosis. Yet the mechanisms underlying the relationship are unknown. Using lysolecithin-induced demyelinating injury to the mouse spinal cord, we characterized the acute lesion and investigated the mechanisms of increased myelin and axon damage with age. We report exacerbated myelin and axon loss in middle-aged (8-10 months of age) compared with young (6 weeks of age) female C57BL/6 mice by 1-3 d of lesion evolution in the white matter. Transcriptomic analysis linked elevated injury to increased expression of , the gene encoding the catalytic subunit of NADPH oxidase gp91phox. Immunohistochemistry in male and female mice for gp91phox revealed that the upregulation in middle-aged animals occurred primarily in microglia and not infiltrated monocyte-derived macrophages. Activated NADPH oxidase generates reactive oxygen species and elevated oxidative damage was corroborated by higher malondialdehyde immunoreactivity in lesions from middle-aged compared with young mice. From a previously conducted screen for generic drugs with antioxidant properties, we selected the antihypertensive CNS-penetrant medication indapamide for investigation. We report that indapamide reduced superoxide derived from microglia cultures and that treatment of middle-aged mice with indapamide was associated with a decrease in age-exacerbated lipid peroxidation, demyelination and axon loss. In summary, age-exacerbated acute injury following lysolecithin administration is mediated in part by microglia NADPH oxidase activation, and this is alleviated by the CNS-penetrant antioxidant, indapamide. Age is associated with an increased risk for the development of several neurologic conditions including progressive multiple sclerosis, which is represented by substantial microglia activation. We demonstrate that in the lysolecithin demyelination model in young and middle-aged mice, the latter group developed greater acute axonal and myelin loss attributed to elevated oxidative stress through NADPH oxidase in lineage-traced microglia. We thus used a CNS-penetrant generic medication used in hypertension, indapamide, as we found it to have antioxidant properties in a previous drug screen. Following lysolecithin demyelination in middle-aged mice, indapamide treatment was associated with decreased oxidative stress and axon/myelin loss. We propose indapamide as a potential adjunctive therapy in aging-associated neurodegenerative conditions such as Alzheimer's disease and progressive multiple sclerosis.
年龄是许多神经疾病的关键风险因素，包括进行性多发性硬化症。然而，其潜在机制尚不清楚。我们使用溶血卵磷脂诱导的小鼠脊髓脱髓鞘损伤，对急性病变进行了特征描述，并研究了年龄相关髓鞘和轴突损伤增加的机制。我们报告称，与年轻（6 周龄）雌性 C57BL/6 小鼠相比，中年（8-10 月龄）雌性小鼠的白质急性病变中，髓鞘和轴突丢失更为严重，在病变发生后 1-3 天即可观察到。转录组分析将损伤程度与编码 NADPH 氧化酶 gp91phox 催化亚基的 基因的表达上调联系起来。我们对雄性和雌性 小鼠进行的 gp91phox 免疫组织化学分析表明，中年动物的上调主要发生在小胶质细胞中，而不是浸润的单核细胞来源的巨噬细胞中。激活的 NADPH 氧化酶产生活性氧，并且在来自中年小鼠的病变中证实了更高的丙二醛免疫反应性，这表明氧化损伤增加。从之前进行的具有抗氧化特性的通用药物筛选中，我们选择了具有中枢神经系统渗透性的降压药物吲达帕胺进行研究。我们报告称，吲达帕胺可减少小胶质细胞培养物中产生的超氧化物，并且吲达帕胺治疗中年小鼠可降低与年龄相关的脂质过氧化、脱髓鞘和轴突丢失。总之，溶血卵磷脂给药后年龄加剧的急性损伤部分由小胶质细胞 NADPH 氧化酶激活介导，而中枢神经系统渗透性抗氧化剂吲达帕胺可缓解这种损伤。年龄与几种神经疾病的发展风险增加有关，包括进行性多发性硬化症，其特点是小胶质细胞大量激活。我们证明，在年轻和中年小鼠的溶血卵磷脂脱髓鞘模型中，后者发展为更大的急性轴突和髓鞘丢失，归因于通过谱系追踪的小胶质细胞中的 NADPH 氧化酶升高的氧化应激。因此，我们使用了一种在之前的药物筛选中具有抗氧化特性的中枢神经系统渗透性通用药物吲达帕胺。在中年小鼠的溶血卵磷脂脱髓鞘后，吲达帕胺治疗与氧化应激和轴突/髓鞘丢失减少相关。我们提出吲达帕胺作为阿尔茨海默病和进行性多发性硬化症等与衰老相关的神经退行性疾病的潜在辅助治疗方法。
