McClarty Bryan, Rodriguez Guadalupe, Dong Hongxin
Department of Psychiatry and Behavioral Sciences, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States.
Front Neurosci. 2021 Oct 6;15:674745. doi: 10.3389/fnins.2021.674745. eCollection 2021.
Elderly patients treated with antipsychotic drugs often experience increased severity and frequency of side effects, yet the mechanisms are not well understood. Studies from our group indicate age-related histone modifications at drug targeted receptor gene promoters may contribute to the increased side effects, and histone deacetylase (HDAC) inhibitors entinostat (MS-275) and valproic acid (VPA) could reverse typical antipsychotic haloperidol (HAL) induced motor-side effects. However, whether such effects could be dose dependent and whether HDAC inhibitors could improve memory function in aged mice is unknown. We co-treated selective class 1 HDAC inhibitor tacedinaline (CI-994) at different doses (10, 20, and 30 mg/kg) with HAL (0.05 mg/kg) in young (3 months) and aged (21 months) mice for 14 consecutive days, then motor and memory behavioral tests were conducted, followed by biochemical measurements. CI-994 at doses of 10 and 20 mg/kg could decrease HAL-induced cataleptic episodes but only 20 mg/kg was sufficient to improve motor coordination in aged mice. Additionally, CI-994 at 10 and 20 mg/kg mitigate HAL-induced memory impairment in aged mice. Biochemical analyses showed increased acetylation of histone marks H3K27ac and H3K18ac at the dopamine 2 receptor (D2R) gene () promoter and increased expression of the mRNA and D2R protein in the striatum of aged mice after administration of CI-994 at 20 mg/kg. Our results suggest CI-994 can reduce HAL-induced motor and memory side effects in aged mice. These effects may act through an increase of acetylation at the promoter, thereby restoring D2R expression and improving antipsychotic drug action.
使用抗精神病药物治疗的老年患者常常经历副作用的严重程度和频率增加，但其中的机制尚未完全清楚。我们团队的研究表明，药物靶向受体基因启动子处与年龄相关的组蛋白修饰可能导致副作用增加，并且组蛋白去乙酰化酶（HDAC）抑制剂恩替诺特（MS - 275）和丙戊酸（VPA）可以逆转典型抗精神病药物氟哌啶醇（HAL）诱导的运动副作用。然而，这种作用是否具有剂量依赖性以及HDAC抑制剂是否能改善老年小鼠的记忆功能尚不清楚。我们将不同剂量（10、20和30 mg/kg）的选择性1类HDAC抑制剂他西美坦（CI - 994）与HAL（0.05 mg/kg）共同处理年轻（3个月）和老年（21个月）小鼠，连续处理14天，然后进行运动和记忆行为测试，随后进行生化测量。剂量为10和20 mg/kg的CI - 994可以减少HAL诱导的僵住发作，但只有20 mg/kg足以改善老年小鼠的运动协调性。此外，10和20 mg/kg的CI - 994减轻了HAL诱导的老年小鼠记忆损伤。生化分析表明，在给予20 mg/kg的CI - 994后，老年小鼠纹状体中多巴胺2受体（D2R）基因启动子处组蛋白标记H3K27ac和H3K18ac的乙酰化增加，并且D2R mRNA和蛋白的表达增加。我们的结果表明CI - 994可以减少HAL诱导的老年小鼠运动和记忆副作用。这些作用可能通过增加D2R基因启动子处的乙酰化来实现，从而恢复D2R表达并改善抗精神病药物的作用。
