Aging and Antipsychotic Efficacy - Epigenetic Mechanisms

衰老和抗精神病药的功效——表观遗传机制

• 批准号: 8600189
• 负责人: Hongxin Dong
• 金额: $ 19.31万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-12-26 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8600189
• 关键词: Acetylation; Address; Adjuvant; Adverse effects; Affect; Age; Aging; Antipsychotic Agents; Behavioral; Biological Assay; Brain; Brain region; Clozapine; Cognitive; Corpus striatum structure; Data; Dementia; Dopamine Receptor; Drug Targeting; Elderly; Epigenetic Process; FOS gene; Gene Expression; Genomics; HDAC1 gene; HTR2A gene; Haloperidol; Histone Acetylation; Histone Deacetylase; Histone Deacetylase Inhibitor; Histone H3; Histones; Human; Immediate-Early Genes; Immunofluorescence Immunologic; Impaired cognition; Incidence; Individual; Label; Left; Light; Link; Lysine; MS-275; Mammals; Memory; Mental disorders; Motor; Mus; Neuraxis; Neurons; Nucleus Accumbens; Patients; Performance; Pharmaceutical Preparations; Play; Population; Prefrontal Cortex; Process; Promoter Regions; Psychotic Disorders; Regulation; Role; Societies; Testing; Time; Valproic Acid; Work; age related; aged; aging brain; alternative treatment; atypical antipsychotic; base; behavior test; body system; brain tissue; chromatin immunoprecipitation; drug efficacy; improved; inhibitor/antagonist; novel; older patient; promoter; public health relevance; receptor; serotonin receptor; treatment strategy

DESCRIPTION (provided by applicant): Antipsychotic drugs are widely prescribed to elderly patients for the treatment of a variety of psycho- pathological conditions, including psychosis and behavioral disturbances associated with cognitive impairment. However, the current treatment strategy for elderly individuals is often ineffective, with an increased incidence of sid effects. The factors contributing to reduced antipsychotic efficacy in the elderly population are not yet full understood. Induction of immediate-early genes such as c-fos has been shown to affect antipsychotic drug activity in the CNS. Both typical and atypical antipsychotics induce c Fos expression in specific brain regions, including the striatum and prefrontal cortex. Our preliminary data shows lower levels of antipsychotic induced c-Fos expression in the nucleus accumbens of aged mice, as well decreased acetylation of histone H3 lysine residue 27 (H3K27) on the c-fos promoter. Co-treatment with valproic acid (VPA), a histone deacetylase HDAC inhibitor, was shown to restore antipsychotic induced c-Fos induction and improve behavioral performance in aged mice. Our preliminary data suggests that an epigenetic mechanism may play a key role in the reduced drug efficacy seen in elderly individuals. In this study, we hypothesize that age-associated decreases in antipsychotic efficacy are the result of epigenetic changes in the brain that can be ameliorated by co-treatment with antipsychotics and HDAC inhibitors. To test our hypotheses, young (3-month old) and aged (24-month old) mice will be treated with haloperidol (HAL, a typical) or clozapine (CLZ, an atypical) alone or in combination with the HDAC1-specific inhibitor entinostat (MS-275) or pan-HDAC inhibitor VPA for 14 days. First, we will investigate the relationship between the acetylation of histone H3 lysine residue 27 (H3K27) on the c-fos promoter and antipsychotic induced c-Fos induction in the brains of aged mice using chromatin immunoprecipitation (ChIP) assays and real-time PCR. We will then examine whether increased c-Fos expression following HDAC inhibitor/antipsychotic co-treatment is specific to dopaminergic or serotoninergic neurons using immunofluorescence double labeling. Using behavioral tests relevant to memory and motor function, we will then investigate whether MS-275 treatment results in cognitive improvements similar to those seen with VPA treatment. This study will shed light on the interactions between aging, antipsychotic drug efficacy, and epigenetic regulation. By advancing our understanding of the epigenetic mechanisms of drug efficacy, it will be possible to develop new psychotropic treatment strategies that maximize benefits while minimizing side effects.

描述（由申请人提供）：抗精神病药被广泛规定给老年患者，以治疗各种心理病理状况，包括与认知障碍有关的精神病和行为障碍。但是，当前针对老年人的治疗策略通常无效，SID效应的发生率增加。导致老年人口抗精神病药降低的因素尚未完全理解。已显示诱导直接至上的基因（例如C-FOS）会影响中枢神经系统中的抗精神病药。典型和非典型抗精神病药都在特定的大脑区域（包括纹状体和额叶皮层）诱导C FOS表达。我们的初步数据显示，老年小鼠伏隔核中抗精神病药诱导的C-FOS表达较低，以及在C-FOS启动子上组蛋白H3赖氨酸残基27（H3K27）的乙酰化降低。与丙戊酸（VPA）（一种组蛋白脱乙酰基酶HDAC抑制剂）共同治疗可恢复抗精神病药诱导的C-FOS诱导并改善老年小鼠的行为性能。我们的初步数据表明，表观遗传机制可能在老年人中降低的药物功效中起关键作用。在这项研究中，我们假设抗精神病药疗效与年龄相关的降低是大脑表​​观遗传变化的结果，这可以通过与抗精神病药和HDAC抑制剂共同治疗来改善。为了检验我们的假设，将与Haloperidol（HAL，典型）或氯氮平（CLZ（CLZ）单独或与HDAC1特异性抑制剂Entinostat（MS-275）或Pan-HDAC Inibyitor VPA一起使用14天。首先，我们将研究使用染色体蛋白免疫沉淀（CHIP）测定和实时PCR，在老年小鼠的大脑中，组蛋白H3赖氨酸残基27（H3K27）的乙酰化与抗精神病药诱导的C-FOS诱导之间的关系。然后，我们将检查HDAC抑制剂/抗精神病药共治疗后的C-FOS表达增加是否针对多巴胺能或5-羟色胺能神经元使用免疫荧光双重标记。然后，使用与记忆和运动功能相关的行为测试，我们将研究MS-275治疗是否导致认知改善是否与VPA治疗相似。这项研究将阐明衰老，抗精神病药疗效和表观遗传调节之间的相互作用。通过促进我们对药物功效的表观遗传机制的理解，可以制定新的精神治疗策略，以最大程度地提高益处，同时最大程度地减少副作用。