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The role of steroid biosynthesis in the protective actions of ligands for the translocator protein (TSPO).
https://repo.qst.go.jp/records/71769
https://repo.qst.go.jp/records/71769f0b5ac1a-ba21-4668-9d16-b3a6759ff0da
| Item type | 会議発表用資料 / Presentation(1) | |||||
|---|---|---|---|---|---|---|
| 公開日 | 2014-11-27 | |||||
| タイトル | ||||||
| タイトル | The role of steroid biosynthesis in the protective actions of ligands for the translocator protein (TSPO). | |||||
| 言語 | ||||||
| 言語 | eng | |||||
| 資源タイプ | ||||||
| 資源タイプ識別子 | http://purl.org/coar/resource_type/c_c94f | |||||
| 資源タイプ | conference object | |||||
| アクセス権 | ||||||
| アクセス権 | metadata only access | |||||
| アクセス権URI | http://purl.org/coar/access_right/c_14cb | |||||
| 著者 |
Barron, Anna
× Barron, Anna× Amy, Christensen× Ji, Bin× Suhara, Tetsuya× Higuchi, Makoto× Christian, Pike× Barron, Anna× Ji, Bin× Suhara, Tetsuya× Higuchi, Makoto |
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| 抄録 | ||||||
| 内容記述タイプ | Abstract | |||||
| 内容記述 | Background: Translocator protein (TSPO), previously known as the peripheral benzodiazepine receptor, is a multi-functional mitochondrial transmembrane protein primarily localised in steroid-producing tissues, including the brain. TSPO ligands elicit pleiotropic neuroprotective and cognitive benefits, mechanistically linked to the regulation of steroid synthesis. Our recent findings demonstrate that TSPO ligands promote neurosteroidogenesis, reduce Aβ neuropathology and neuroinflammation, and improve functional outcomes in the 3xTgAD mouse model. Here we investigated the role of steroid biosynthesis in the mechanism(s) by which the TSPO ligand, Ro5-4864, improves AD-related neuropathological and behavioural outcomes in non-Tg and 3xTgAD mice. Methods: Male non-tg mice (3 mo old C57BL/J6) were treated with the TSPO ligand Ro5-4864, combined with pre-administration of the steroid biosynthesis inhibitor, aminoglutethimide (AG). AG is a well characterized pharmacological inhibitor of the side-chain cleaving enzyme, P450scc, which is responsible for the conversion of cholesterol to pregnenolone, the precursor to all other neurosteroids. Soluble A β was measured in brain extracts by ELISA; a nxiety-related behavior was assessed in the elevated plus maze; and learning and memory performance was assessed by object recognition performance. Experiments were repeated in senescent 3xTg-AD mice (16mo old) as a model of amyloid-induced gliosis and behavioral impairments. Microgliosis was assessed based on morphological classification and quantification of Iba-1 immunoreactivity in 3xTgAD mice. Results: Ro5-4864 reduced anxiety and improved learning and memory performance in both non-tg and 3xTgAD mice. The anxiolytic and recognition memory benefits of Ro5-4864 were completely ablated by inhibition of steroid biosynthesis with AG. In contrast, the anti-amyloidogenic and anti-inflammatory effects of Ro5-4864 were not blocked by co-administration of AG, suggesting TSPO-mediated reductions in AD-related neuropathology are largely independent of neurosteroidogenesis. Conclusions: These findings suggest the pleiotropic neuroprotective benefits of TSPO ligands may be mediated by separate mechanisms, with the rapid behavioral benefits attributable to TSPO-stimulated steroid biosynthesis, while potential disease-modifying effects on AD-related pathology may be mediated by direct effects on glial function, altered mitochondrial function or cholesterol homeostasis. Determination of the key mechanism(s) of TSPO action is critical to identifying the most efficacious TSPO ligands, optimally translating preclinical findings into clinical use, and rationally developing TSPO ligands for therapeutic use. |
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| 会議概要（会議名, 開催地, 会期, 主催者等） | ||||||
| 内容記述タイプ | Other | |||||
| 内容記述 | Alzheimer`s Association International Conference | |||||
| 発表年月日 | ||||||
| 日付 | 2014-07-15 | |||||
| 日付タイプ | Issued | |||||
