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Novel translocator protein (TSPO) ligands for the potential treatment of Alzheimer's disease: A next generation alternative to conventional hormone therapy
https://repo.qst.go.jp/records/71551
https://repo.qst.go.jp/records/7155188648f0d-d2fa-4908-8480-4c340aa6e70c
| 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 | Novel translocator protein (TSPO) ligands for the potential treatment of Alzheimer's disease: A next generation alternative to conventional hormone therapy | |||||
| 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 |
Prita, Asih
× Prita, Asih× Anna, Barron× Bin, Ji× Andrew, Katsifis× Filomena, Mattner× Giuseppe, Verdile× Veer, Gupta× R, Trengrove× Ralph, Martins× アッシュ プリタ× Ｂａｒｒｏｎ Ａｎｎａ× 季 斌 |
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| 抄録 | ||||||
| 内容記述タイプ | Abstract | |||||
| 内容記述 | Background: Reductions in sex steroids and neurosteroid production have been reported in AD brain. Hormonal supplementation has shown benefits in offering neuroprotection and reducing cerebral amyloid load in animal studies. Although requiring further investigation in clinical trials, concerns have been raised with long-term therapeutic application due to potential side-effects. Ligands of the translocator protein (TSPO) can stimulate synthesis of these protective hormones directly in the brain, therefore are promising candidates for the development of a targeted alternative to conventional hormone therapy for use in AD. Classic TSPO ligands have been previously shown to increase neurosteroid levels and reduce cerebral A β i n a mouse model of AD. However, these ligands have limited clinical usefulness due to low specificity and poor blood-brain barrier penetration. We screened 14 novel TSPO ligands in vitro for safety and efficacy as potential therapeutic agents for AD. \nMethods: Fourteen novel TSPO ligands based on substituted 2'-phenyl imidazopyridine structure were prepared for evaluation. Structural variations on substituents on the 2'-phenyl ring and the acetamide side chain were made yielding compounds of varying affinity selectivity and biological function. These ligands were screened for toxicity (10 nM-100μM) by MTS and LDH release assay in the M17 human neuroblastoma cell line. Their neurosteroidogenic potency were assessed by measuring pregnenolone levels (the precursor to all other neurosteroids) by ELISA in M17, N2a (human and mouse neuroblastoma, respectively) and C6 (mouse glioma) cell lines. MA-10 Leydig cells were used t o identify ligands specific for inducing steroidogenesis in the brain and not the testes. \nResults: No toxicity was observed at the steroidogenic dose range (nm) for any of the ligands, although toxicity was observed in 6 out of the 14 ligands at high doses (100 uM). Three novel ligands were selected based on favourable toxicity and neurosteroidogenic potency profiles for assessment of anti-amyloidogenic efficacy. TSPO expression was confirmed by western blot. And finally, Aβ and neurosteroid levels were measured by LC-MS/MS. \nConclusions: New generation TSPO l igands are promising candidates for the development of a targeted alternative to conventional hormone therapy in AD. Our results represent an innovative model to identify novel TSPO ligands that specifically target neurosteroid production. |
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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 | |||||
