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Aging-Exacerbated Acute Axon and Myelin Injury Is Associated with Microglia-Derived Reactive Oxygen Species and Is Alleviated by the Generic Medication Indapamide.
Michaels, Nathan J; Lemmon, Kennedy; Plemel, Jason R; Jensen, Samuel K; Mishra, Manoj K; Brown, Dennis; Rawji, Khalil S; Koch, Marcus; Yong, V Wee.
Afiliação
  • Michaels NJ; Department of Clinical Neurosciences, Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
  • Lemmon K; Department of Clinical Neurosciences, Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
  • Plemel JR; Department of Medicine, Division of Neurology, Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Alberta T6G 2R7, Canada.
  • Jensen SK; Department of Clinical Neurosciences, Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
  • Mishra MK; Department of Clinical Neurosciences, Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
  • Brown D; Department of Clinical Neurosciences, Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
  • Rawji KS; Department of Clinical Neurosciences, Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
  • Koch M; Department of Clinical Neurosciences, Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
  • Yong VW; Department of Clinical Neurosciences, Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta T2N 4N1, Canada vyong@ucalgary.ca.
J Neurosci ; 40(44): 8587-8600, 2020 10 28.
Article em En | MEDLINE | ID: mdl-33060175
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 Cybb, the gene encoding the catalytic subunit of NADPH oxidase gp91phox. Immunohistochemistry in male and female Cx3cr1CreER/+:Rosa26tdTom/+ 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.SIGNIFICANCE STATEMENT 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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Axônios / Envelhecimento / Espécies Reativas de Oxigênio / Microglia / Indapamida / Bainha de Mielina / Anti-Hipertensivos Tipo de estudo: Prognostic_studies / Risk_factors_studies Limite: Animals Idioma: En Ano de publicação: 2020 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Axônios / Envelhecimento / Espécies Reativas de Oxigênio / Microglia / Indapamida / Bainha de Mielina / Anti-Hipertensivos Tipo de estudo: Prognostic_studies / Risk_factors_studies Limite: Animals Idioma: En Ano de publicação: 2020 Tipo de documento: Article