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: 8445889
• 负责人: Hongxin Dong
• 金额: $ 23.18万
• 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 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8445889
• 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）：抗精神病药物广泛用于老年患者治疗各种精神病理疾病，包括精神病和与认知障碍相关的行为障碍。然而，目前针对老年人的治疗策略往往无效，副作用发生率增加。导致老年人抗精神病药疗效降低的因素尚未完全清楚。已证明 c-fos 等立即早期基因的诱导会影响中枢神经系统中的抗精神病药物活性。典型和非典型抗精神病药都会诱导特定大脑区域（包括纹状体和前额皮质）c Fos 的表达。我们的初步数据显示，抗精神病药物诱导的老年小鼠伏核中的 c-Fos 表达水平较低，并且 c-fos 启动子上组蛋白 H3 赖氨酸残基 27 (H3K27) 的乙酰化水平降低。与丙戊酸（VPA）（一种组蛋白脱乙酰酶 HDAC 抑制剂）共同治疗可恢复抗精神病药物诱导的 c-Fos 诱导并改善老年小鼠的行为表现。我们的初步数据表明，表观遗传机制可能在老年人药物疗效降低的过程中发挥关键作用。在这项研究中，我们假设与年龄相关的抗精神病药疗效下降是大脑表观遗传变化的结果，可以通过抗精神病药和 HDAC 抑制剂联合治疗来改善这种变化。为了检验我们的假设，年轻（3 个月大）和老年（24 个月大）小鼠将单独接受氟哌啶醇（HAL，典型）或氯氮平（CLZ，非典型）治疗或与 HDAC1 特异性抑制剂联合治疗恩替司他 (MS-275) 或泛 HDAC 抑制剂 VPA 14 天。首先，我们将使用染色质免疫沉淀 (ChIP) 分析和实时 PCR 研究老年小鼠大脑中 c-fos 启动子上组蛋白 H3 赖氨酸残基 27 (H3K27) 的乙酰化与抗精神病药物诱导的 c-Fos 诱导之间的关系。然后，我们将使用免疫荧光双标记检查 HDAC 抑制剂/抗精神病药联合治疗后 c-Fos 表达的增加是否对多巴胺能或血清素能神经元具有特异性。然后，我们将使用与记忆和运动功能相关的行为测试，研究 MS-275 治疗是否能带来与 VPA 治疗类似的认知改善。这项研究将揭示衰老、抗精神病药物疗效和表观遗传调控之间的相互作用。通过加深我们对药物疗效的表观遗传机制的理解，将有可能开发出新的精神治疗策略，以最大限度地提高效益，同时最大限度地减少副作用。