Development of epigenetic drugs for neurodevelopmental disorders

2017 Fiscal Year Final Research Report

• Project/Area Number: 15K09592
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: University of Yamanashi
• Principal Investigator: MIYAKE Kunio 山梨大学, 大学院総合研究部, 准教授 (60550712)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Keywords: エピジェネティクス / 抗精神病薬 / ヒストン修飾 / 神経変性疾患 / 神経細胞死

Outline of Final Research Achievements

Antidepressants are known to alter gene expression patterns by inducing changes in the epigenetic status of neuronal cells. We examined whether antidepressants exert an anti-apoptotic effect via epigenetic mechanisms. We analyzed global gene expression in mouse primary cortical neurons after treatment with antidepressants. The neuroprotection-associated genes, activating transcription factor 3 (Atf3) and heme oxygenase 1 (Hmox1), were up-regulated by treatment with amitriptyline. Quantitative chromatin immunoprecipitation assay revealed that amitriptyline increased enrichments of trimethylation of histone H3 lysine 4 in the promoter regions of Atf3 and Hmox1, which indicate an active epigenetic status. Amitriptyline pre-treatment attenuated 1-methyl-4-phenylpyridinium ion- or amyloid beta 1-42-induced neuronal cell death and inhibited the activation of extracellular signal-regulated kinase 1 and 2. These findings suggest preconditioning and neuroprotective effects of amitriptyline.

Free Research Field

エピジェネティクス