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（应用程序提供）：一种普通的药物类药物，以治疗精神疾病以及痴呆症的行为和心理症状（BPSD）。但是，在老年患者中，增加了副作用的事件和严重程度，例如经历了APDS引起的锥体外运动症状。尽管老化诱导的药代动力学变化可能会导致对APD的副作用的提高，而在目标接收器水平的老年，与年龄相关的药效学变化可能在提高APD副作用的敏感性方面起关键作用。但是， 这些与年龄相关的受体功能下降的机制尚不清楚。最近，我们确定了组蛋白的修饰改变了老年小鼠中典型的APD，氟哌啶醇的治疗作用。此外，我们在本应用程序中的初步数据表明，年龄小鼠中类似锥体外症状的副作用（运动副作用）的严重程度与多巴胺2受体（D2R）基因（DRD2）启动子的组蛋白低乙酰化有关，从而降低了纹状体D2R的表达。与组蛋白脱乙酰基酶抑制剂（HDACIS）丙戊酸（VPA）或Entinostat（MS-275）共同治疗恢复了纹状体D2RS的表达，并降低了氟哌啶醇的运动副作用中与年龄相关的增长。我们的发现和初步结果表明，目标受体基因启动子的年龄相关组蛋白修饰可能会影响APD作用。在此提案中，我们试图确认在衰老过程中调节APD作用的新型表观遗传机制，并确定HDACIS是否可以在先前改善APD治疗。我们的中心假设是，APD的运动副作用与年龄相关的增加是由于组蛋白对靶向受体基因的脱乙酰基化引起的，并且这些表观遗传变化及其功能后果可以通过与HDACIS共同处理来逆转。首先，为了检验我们的假设，我们将验证与年龄相关的组蛋白修饰是对APD引起的副作用的敏感性增加的基础机制之一。然后，我们将确定HDAC亚型有助于组蛋白修饰并增加APD诱导的老年小鼠的严重程度。最后，我们将评估HDACI和APD共同治疗的治疗益处，这些益处可以降低APD诱导的老年小鼠和TG2576小鼠的严重程度，TG2576小鼠是阿尔茨海默氏病的动物模型也被认为是BPSD的模型。拟议的研究将提高我们对与年龄相关的表观遗传改变机制及其对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，而且对老年医学药物的其他药物有影响。我们的研究将作为研究药物作用的表观遗传机制的指南，最终受益于老年人群。