Aging and Antipsychotic Efficacy - Epigenetic Mechanisms

描述(申请人提供)：抗精神病药物被广泛地开给老年患者，用于治疗各种精神病理疾病，包括与认知障碍相关的精神病和行为障碍。然而，目前针对老年人的治疗策略往往是无效的，副作用的发生率增加。导致老年人群抗精神病药物疗效降低的因素尚不完全清楚。C-fos等即刻早期基因的诱导已被证明影响中枢神经系统抗精神病药物的活性。典型和非典型抗精神病药物均可诱导特定脑区c-Fos的表达，包括纹状体和前额叶皮质。我们的初步数据显示，抗精神病药物诱导的c-Fos在老年小鼠伏隔核中的表达水平较低，以及组蛋白H3赖氨酸残基27(H3K27)在c-fos启动子上的乙酰化程度降低。组蛋白去乙酰化酶HDAC抑制剂丙戊酸(VPA)能恢复抗精神病药诱导的c-Fos诱导，改善老龄小鼠的行为行为。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下降中发挥关键作用。在这项研究中，我们假设与年龄相关的抗精神病药物疗效下降是大脑表观遗传学变化的结果，这种变化可以通过与抗精神病药物和HDAC抑制剂共同治疗来改善。为了验证我们的假设，年轻的(3个月大的)和老年的(24个月大的)小鼠将接受氟哌啶醇(HAL，典型的)或氯氮平(CLZ，非典型的)单独或与HDAC1特异性抑制剂Eninostat(MS-275)或PAN-HDAC抑制剂VPA联合治疗14天。首先，我们将利用染色质免疫沉淀法(ChIP)和实时定量聚合酶链式反应(Real-time PCR)研究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老年小鼠脑内c-fos诱导的关系。然后，我们将使用免疫荧光双标记技术检查HDAC抑制剂/抗精神病药物联合治疗后c-Fos表达增加是否是多巴胺或5-羟色胺能神经元所特有的。使用与记忆和运动功能相关的行为测试，然后我们将调查MS-275治疗是否产生与VPA治疗类似的认知改善。这项研究将阐明衰老、抗精神病药物疗效和表观遗传调控之间的相互作用。通过推进我们对药物疗效表观遗传机制的理解，将有可能开发出新的精神药物治疗策略，在最大限度地提高疗效的同时将副作用降至最低。

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.