Age-Related Histone Modification Effect on Antipsychotic Action

 描述（由申请人提供）：一种常见的老年人处方药，用于治疗精神疾病和痴呆症（BPSD）的行为和心理症状。然而，在老年患者中，APD引起的副作用（如锥体外系运动症状）的发生率和严重程度增加。尽管年龄诱导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，但靶受体水平的年龄相关药效学变化可能在APD副作用敏感性增加中发挥关键作用。但 这些与年龄相关的受体功能下降的潜在机制还不清楚。最近，我们发现组蛋白修饰改变了老年小鼠中典型APD氟哌啶醇的治疗作用。此外，我们在本申请中的初步数据表明，老年小鼠锥体外系神经元样副作用（运动副作用）的严重程度增加可能与多巴胺2受体（D2 R）基因（Drd 2）启动子的组蛋白低乙酰化有关，这反过来又降低了纹状体D2 R的表达。与组蛋白去乙酰化酶抑制剂（HDACis）、丙戊酸（VPA）或恩替司他（MS-275）的共同治疗恢复了纹状体D2 R的表达，并减少了氟哌啶醇的运动副作用的年龄相关性增加。我们的研究结果和初步结果表明，年龄相关的组蛋白修饰的基因启动子的靶受体可能会影响APD的行动。在这项提案中，我们试图确认在衰老过程中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治疗的候选药物。我们的中心假设是APD运动副作用的年龄相关性增加是由于其靶向受体基因上的组蛋白低乙酰化，并且这些表观遗传变化及其功能后果可以通过与HDACis共同治疗来逆转。为了验证我们的假设，首先，我们将验证年龄相关的组蛋白修饰是对APD诱导的副作用敏感性增加的机制之一。然后，我们将鉴定有助于组蛋白修饰和增加老年小鼠中APD诱导的副作用严重程度的HDAC亚型。最后，我们将评估HDACi和APD联合治疗的治疗益处，这些治疗可以降低老年小鼠和Tg 2576小鼠中APD诱导的副作用的严重程度，Tg 2576小鼠是阿尔茨海默病的动物模型，也被认为是BPSD的模型。这项研究将促进我们对年龄相关的表观遗传学改变及其对APD作用的影响的机制的理解。这一机制的概念不仅对神经精神药物，而且对老年病的其他药物也有影响。我们的研究将作为一个指导调查药物作用的表观遗传机制，最终受益于老年人群。

 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.