Age-Related Histone Modification Effect on Antipsychotic Action

年龄相关的组蛋白修饰对抗精神病作用的影响

• 批准号: 9281089
• 负责人: Hongxin Dong
• 金额: $ 38.63万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-26 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9281089
• 关键词: Acetylation; Adverse drug effect; Adverse effects; Affect; Age; Aging; Alzheimer' s disease model; Animal Model; Antipsychotic Agents; Anxiety; Behavior; Behavioral Model; Behavioral Symptoms; Brain region; Chronic; Cognitive; Complex; Corpus striatum structure; DRD2 gene; Data; Dementia; Development; Dopamine; Dose; Drug Kinetics; Drug Targeting; Drug effect disorder; Elderly; Epigenetic Process; FOS gene; Gene Transfer; Genes; Geriatrics; HTR2A gene; Haloperidol; Histone Deacetylase; Histone Deacetylase Inhibitor; Histones; Incidence; Intervention; MS-275; Measures; Mediating; Memory; Mental disorders; Methylation; Motor; Mus; Neurologic; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Pharmacotherapy; Play; Population; Psychiatric therapeutic procedure; Psychopathology; Receptor Gene; Regulation; Serotonin; Severities; Symptoms; Testing; Tg2576; Therapeutic; Valproic Acid; Viral; Vulnerable Populations; Work; age related; aged; aging population; alternative treatment; base; behavioral outcome; experience; histone modification; improved; interest; motor symptom; mouse model; neuropsychiatric disorder; neuropsychiatry; novel; novel strategies; older patient; promoter; psychological symptom; public health relevance; receptor; receptor binding; receptor expression; receptor function; response; risk benefit ratio; treatment strategy

 DESCRIPTION (provided by applicant): a common class of medication prescribed to the elderly for the treatment of psychiatric disorders and behavioral and psychological symptoms of dementia (BPSD). However, in aged patients, the incidence and severity of the side effects such as experiencing extrapyramidal motor symptoms induced by APDs is increased. Although aged-induced changes in pharmacokinetics may contribute to the increased sensitivity to the side effects of APDs in the elderly, age-related pharmacodynamic changes at the target receptor level likely play a key role in the increased sensitivity to the side effects of APDs. However, the mechanisms underlying these age-related declines in receptor function are not well understood. Recently, we identified that histone modifications alter the therapeutic actions of a typical APD, haloperidol, in aged mice. In addition, our preliminary data in this application demonstrates that increases in the severity of extrapyramidal symptom-like side effects (motor side effects) in aged mice can be related to histone hypoacetylation of the dopamine 2 receptor (D2R) gene (Drd2) promoter that in turn decreases the expression of striatal D2Rs. Co- treatment with histone deacetylase inhibitors (HDACis) valproic acid (VPA) or entinostat (MS-275) restored the expression of striatal D2Rs and reduced age-related increases in the motor side effects of haloperidol. Our findings and preliminary results suggest that age-related histone modifications at the gene promoters of target receptors could affect APD action. In this proposal, we seek to confirm the novel epigenetic mechanisms underlying the regulation of APD action during aging and determine whether HDACis could be a candidate to improve APD treatment in the elderly. Our central hypothesis is that age-related increases in the motor side effects of APDs are due to histone hypoacetylation on their targeted receptor genes and that these epigenetic changes and their functional consequences can be reversed by co-treatment with HDACis. To test our hypotheses, first, we will verify that age-related histone modifications are one of the mechanisms underlying increased sensitivity to side effects induced by APDs. Then, we will identify the HDAC subtype(s) that contribute to histone modification and increase in the severity of APD-induced side effects in aged mice. Finally, we will evaluate the therapeutic benefits of HDACi and APD co-treatment that could reduce the severity of APD-induced side effects in aged mice and in Tg2576 mice, an animal model of Alzheimer's disease also being considered as a model of BPSD. The proposed study will advance our understanding of the mechanisms of age-related epigenetic alterations and their effects on APD action. This mechanistic concept will have implications not only for neuropsychiatric medication but also for other medications in geriatrics. Our study will serve as a guide to investigate epigenetic mechanisms on drug action with ultimate benefiting for the aged population.

 描述（由申请人提供）：为老年人开出的一类常见药物，用于治疗精神疾病以及痴呆症的行为和心理症状（BPSD）。然而，在老年患者中，APD 引起的锥体外系运动症状等副作用的发生率和严重程度会增加。尽管年龄引起的药代动力学变化可能导致老年人对 APD 副作用的敏感性增加，但目标受体水平的年龄相关药效学变化可能在对 APD 副作用敏感性增加中发挥关键作用。然而， 这些与年龄相关的受体功能下降的机制尚不清楚。最近，我们发现组蛋白修饰改变了典型 APD 氟哌啶醇对老年小鼠的治疗作用。此外，我们在本申请中的初步数据表明，老年小鼠锥体外系症状样副作用（运动副作用）严重程度的增加可能与多巴胺 2 受体 (D2R) 基因 (Drd2) 启动子的组蛋白低乙酰化有关，进而降低纹状体 D2R 的表达。与组蛋白脱乙酰酶抑制剂 (HDACis)、丙戊酸 (VPA) 或恩替司他 (MS-275) 共同治疗可恢复纹状体 D2R 的表达，并减少氟哌啶醇与年龄相关的运动副作用的增加。我们的发现和初步结果表明，目标受体基因启动子上与年龄相关的组蛋白修饰可能会影响 APD 作用。在本提案中，我们试图确认衰老过程中 APD 作用调节的新表观遗传机制，并确定 HDACis 是否可以成为改善老年人 APD 治疗的候选者。我们的中心假设是，APD 运动副作用与年龄相关的增加是由于其靶受体基因上的组蛋白低乙酰化所致，并且这些表观遗传变化及其功能后果可以通过与 HDACis 联合治疗来逆转。为了检验我们的假设，首先，我们将验证与年龄相关的组蛋白修饰是对 APD 引起的副作用敏感性增加的机制之一。然后，我们将确定有助于组蛋白修饰并增加老年小鼠 APD 诱导副作用严重程度的 HDAC 亚型。最后，我们将评估 HDACi 和 APD 联合治疗的治疗效果，可以降低老年小鼠和 Tg2576 小鼠 APD 引起的副作用的严重程度，Tg2576 小鼠是阿尔茨海默病的动物模型，也被认为是 BPSD 的模型。这项研究将增进我们对与年龄相关的表观遗传改变的机制及其对 APD 作用的影响的理解。这种机械概念不仅对神经精神药物有影响，而且对老年病学的其他药物也有影响。我们的研究将作为研究药物作用的表观遗传机制的指南，最终造福于老年人群。