Epigenetic modulation of antipsychotic-induced side effects in aged mice

抗精神病药引起的老年小鼠副作用的表观遗传调节

• 批准号: 8655436
• 负责人: Janitza Liz Montalvo-Ortiz
• 金额: $ 4万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8655436
• 关键词: Address; Adult; Adverse effects; Affect; Age; Age-Months; Aging; Agitation; Antipsychotic Agents; Autopsy; Behavior; Behavioral; Biochemical; Biological Assay; Bradykinesia; Catalepsy; Chronic; Corpus striatum structure; Coupled; DRD2 gene; Data; Deterioration; Disease; Dopamine; Dopamine Receptor; Dose; Drug effect disorder; Drug usage; Elderly; Epigenetic Process; Female; Frequencies; Gene Expression; Genes; Haloperidol; Histone Acetylation; Histone Deacetylase; Histone Deacetylase Inhibitor; Histones; Hypermethylation; Individual; Injection of therapeutic agent; Lead; Link; Liquid substance; MS-275; Measures; Mediating; Mental disorders; Messenger RNA; Methylation; Molecular; Mus; Pharmaceutical Preparations; Physiological; Play; Population; Prefrontal Cortex; Promoter Regions; Property; Proteins; Psychotic Disorders; Raclopride; Radioactivity; Regulation; Reporting; Reverse Transcriptase Polymerase Chain Reaction; Severities; Symptoms; System; Tardive Dyskinesia; Testing; Therapeutic; Therapeutic Intervention; Time; Tissues; Valproic Acid; Vorinostat; Western Blotting; age related; aged; aging brain; base; behavior test; chromatin immunoprecipitation; epigenetic marker; functional status; histone modification; improved; mRNA Expression; male; neurochemistry; neuropsychiatry; novel therapeutics; older patient; prevent; promoter; protein expression; receptor; receptor expression; receptor function; scintillation spectrometry; treatment duration; young adult

The use of psychotropic medications in the elderly population is always challenging due to decreased efficacy and an exacerbated side effects. Thus, there is an urgent need to find new and efficient ways to increase efficacy and to decrease side effects of antipsychotics for aged individuals. Age-related changes epigenetic modulation may contribute to the deterioration of appropriate gene expression induced by antipsychotics. Previous studies have suggested that disruption in receptor functions of dopamine during aging, the primary target of antipsychotic drugs, may be due to changes in gene expression. Age-related changes in the homeostatic tone of the dopaminergic system may be mediated by epigenetic mechanisms, thus revealing a potential reversibility of these effects by pharmacological therapeutic intervention. For this study, we will investigate (1) if age-related decrease of striatal and cortical dopamine 2 (D2) receptor (mRNA and protein levels) are due to histone hypoacetylation and hypermethylation; (2) if increased physiological and behavioral sensitivity to antipsychotic drugs in aged mice is due to decreased D2 gene and protein expression and decreased D2 receptor occupancy and (3) if co-treatment of HDAC inhibitors (valproic acid (VPA) and vorinostat (SAHA)) will decrease haloperidol (HAL)-induced extrapyramidal side effects (EPS) in aged mice by reversing age-related epigenetic effects. Our preliminary findings revealed that co-treatment of HAL with VPA reverses age-related hypoacetylation at the striatal Drd2 promoter region that correlates with decreased D2 receptor protein expression. These changes are associated with decreased HAL-induced EPS behavior. These findings, together with the dissertation proposal, will indicate whether aging reduces histone acetylation and increases histone tri-methylation levels in the striatum and prefrontal cortex that subsequently interfere with the regulation of D2 receptor which is relevant for reduction of EPS. Our study will provide molecular, cellular, pharmacological and behavioral evidence showing that age-related histone modifications affect antipsychotic properties, uncovering the links between aging, epigenetic modulation and antipsychotic drug action. This proposal will help to develop novel therapeutic strategy for aged people, particularly those that suffer from psychiatric disorders.

在老年人群中使用精神药物一直是具有挑战性的，因为疗效下降，副作用加剧。因此，迫切需要寻找新的、有效的方法来提高老年人抗精神病药物的疗效，减少其副作用。年龄相关的变化，表观遗传调节可能有助于抗精神病药物引起的适当基因表达的恶化。先前的研究表明，抗精神病药物的主要靶点——衰老过程中多巴胺受体功能的破坏可能是由于基因表达的改变。与年龄相关的多巴胺能系统稳态张力的变化可能是由表观遗传机制介导的，因此揭示了通过药物治疗干预这些影响的潜在可逆性。在这项研究中，我们将探讨(1)纹状体和皮层多巴胺2 （D2）受体（mRNA和蛋白水平）的年龄相关性下降是否与组蛋白低乙酰化和高甲基化有关；(2)老年小鼠对抗精神病药物的生理和行为敏感性是否增加是由于D2基因和蛋白表达的减少以及D2受体占据的减少；(3)HDAC抑制剂（丙戊酸（VPA）和vorinostat (SAHA)）的联合治疗是否会通过逆转年龄相关的表观遗传效应来减少氟哌啶醇（HAL）诱导的老年小鼠锥体外系副作用（EPS）。我们的初步研究结果显示，HAL与VPA的联合治疗逆转了纹状体Drd2启动子区域与年龄相关的低乙酰化，该区域与D2受体蛋白表达降低相关。这些变化与hal诱导的EPS行为减少有关。这些发现和论文提案将表明，衰老是否会降低纹状体和前额皮质的组蛋白乙酰化和组蛋白三甲基化水平，从而干扰与EPS减少相关的D2受体的调节。我们的研究将提供分子、细胞、药理学和行为证据，表明年龄相关的组蛋白修饰影响抗精神病药物的特性，揭示衰老、表观遗传调节和抗精神病药物作用之间的联系。这一建议将有助于为老年人，特别是那些患有精神疾病的老年人开发新的治疗策略。