背景:抑郁症是最常见的精神疾病。最近,阿立哌唑,一种新型的抗精神病药物,已被批准作为治疗难治性抑郁症(TRD)的辅助疗法。然而,阿立哌唑抗抑郁作用的潜在机制尚不完全清楚.除了钙信号失调参与抑郁症的病理生理学,有一些证据表明CACNA1C(编码Cav1.2通道的基因)在脑区慢性应激后过度表达,涉及情感和应激反应。根据表明阿立哌唑对细胞内钙水平的影响的数据,本研究旨在探讨阿立哌唑的治疗作用机制,通过关注CACNA1C表达的调节,在大鼠应激诱导的抑郁症模型中。
方法:使用慢性不可预测的轻度压力(CUMS)抑郁症模型,我们检查了阿立哌唑对抑郁和焦虑样行为的影响(通过强迫游泳测试和高架迷宫),血清IL-6(Elisa),和细胞存活(Nissl染色)。此外,CACNA1C,BDNF,和TrkB在PFC和海马中的表达(RT-qPCR),以及海马中的BDNF和GAP-43蛋白水平(免疫组织荧光),已经被分析过了.
结果:我们的数据表明,阿立哌唑可以改善焦虑和抑郁样行为,CUMS后降低血清IL-6水平和海马细胞死亡。此外,我们显示了对过表达的CACNA1C的显着调节,以及下调的BDNF和GAP-43表达讨论:这些结果表明,阿立哌唑可以通过改善BDNF和gap-43的表达来促进突触可塑性。此外,炎症减轻和CACNA1C表达下调可能是阿立哌唑减轻慢性应激诱导的海马细胞死亡并发挥其关键抗抑郁作用的一些机制。
Depression is the most common psychiatric disorder. Recently, aripiprazole, a novel antipsychotic drug, has been approved as the adjunctive therapy for the Treatment-Resistant Depression (TRD). However, the mechanisms underlying the antidepressant effects of aripiprazole are not fully known. Besides the involvement of calcium signaling dysregulations in the pathophysiology of depression, there is some evidence of overexpressed CACNA1C (the gene encoding the Cav1.2 channels) following chronic stress in the brain regions, which involved in emotional and stress responses. Based on the data indicating the aripiprazole\'s effects on intracellular calcium levels, this study aimed to investigate the mechanisms of therapeutic effects of aripiprazole, by a focus on the modulation of CACNA1C expression, in the rat stress-induced model of depression.
Using Chronic Unpredictable Mild Stress (CUMS) model of depression, we examined the effects of aripiprazole on depressive and anxiety-like behaviors (by forced swimming test and elevated plus maze), serum IL-6 (Elisa), and cell survival (Nissl staining). In addition, CACNA1C, BDNF, and TrkB expression in the PFC and hippocampus (RT-qPCR), as well as BDNF and GAP-43 protein levels in the hippocampus (Immunohistofluorescence), have been assayed.
Our data indicated that aripiprazole could improve anxiety and depressive-like behaviors, decrease the serum levels of IL-6 and hippocampal cell death following CUMS. In addition, we showed the significant modulation on overexpressed CACNA1C, as well as downregulated BDNF and GAP-43 expression DISCUSSION: These results demonstrate that aripiprazole may promote synaptic plasticity by improving the expression of BDNF and gap-43. In addition, inflammation reduction and CACNA1C expression downregulation may be some of mechanisms by which aripiprazole alleviates chronic stress-induced hippocampal cell death and play its pivotal antidepressant role.