Targeting the BH3-interacting domain death agonist to develop mechanistically unique antidepressants.
Targeting the BH3-interacting domain death agonist to develop mechanistically unique antidepressants.
复制标题
以 BH3 相互作用域死亡激动剂为目标，开发机制独特的抗抑郁药。
DOI：
10.1038/mp.2011.77
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发表时间：
2012
影响因子：
11
通讯作者：
Manji,HK
中科院分区：
文献类型：
--
作者：
Malkesman,O;Austin,DR;Tragon,T;Henter,ID;Reed,JC;Pellecchia,M;Chen,G;Manji,HK
BH3 相互作用结构域死亡激动剂 (Bid) 是 B 细胞淋巴瘤 2 (Bcl-2) 蛋白家族的促凋亡成员。先前的研究表明，压力会降低与情绪障碍病理生理学相关的大脑区域中的 Bcl-2 水平，而抗抑郁药和情绪稳定剂会增加 Bcl-2 水平。 Bcl-2 蛋白家族在细胞弹性以及突触和神经元可塑性中发挥重要作用，并可能影响情绪和情感行为。本研究使用两种药理学拮抗剂（BI-11A7 和 BI-2A7）抑制小鼠体内的 Bid；选择性血清素再摄取抑制剂西酞普兰用作阳性对照。这些药物在几种著名的抑郁症啮齿动物模型中进行了研究——强迫游泳测试（FST）、悬尾测试（TST）和习得性无助（LH）范式——以及女性尿液嗅探测试（FUST），这是一种与性相关的奖励寻求行为的测量方法。西酞普兰和 BI-11A7 均显着减少了 FST 和 TST 中的不动时间，并减弱了接受 LH 范式的小鼠的逃避潜伏期。在 FUST 中，两种药物均显着延长了已出现无助的小鼠嗅嗅尿液的持续时间。 LH 诱导增加了凋亡诱导因子 (AIF) 的激活，这是一种由 Bid 激活的不依赖半胱天冬酶的细胞死亡成分，并且慢性 BI-11A7 输注可减弱线粒体 AIF 的表达。综上所述，结果表明，Bid 等凋亡蛋白的功能扰动以及 Bcl-2 功能的增强，是开发治疗情绪障碍的新疗法的假定策略。
The BH3-interacting domain death agonist (Bid) is a pro-apoptotic member of the B-cell lymphoma-2 (Bcl-2) protein family. Previous studies have shown that stress reduces levels of Bcl-2 in brain regions implicated in the pathophysiology of mood disorders, whereas antidepressants and mood stabilizers increase Bcl-2 levels. The Bcl-2 protein family has an essential role in cellular resilience as well as synaptic and neuronal plasticity and may influence mood and affective behaviors. This study inhibited Bid in mice using two pharmacological antagonists (BI-11A7 and BI-2A7); the selective serotonin reuptake inhibitor citalopram was used as a positive control. These agents were studied in several well-known rodent models of depression—the forced swim test (FST), the tail suspension test (TST), and the learned helplessness (LH) paradigm—as well as in the female urine sniffing test (FUST), a measure of sex-related reward-seeking behavior. Citalopram and BI-11A7 both significantly reduced immobility time in the FST and TST and attenuated escape latencies in mice that underwent the LH paradigm. In the FUST, both agents significantly improved duration of female urine sniffing in mice that had developed helplessness. LH induction increased the activation of apoptosis-inducing factor (AIF), a caspase-independent cell death constituent activated by Bid, and mitochondrial AIF expression was attenuated by chronic BI-11A7 infusion. Taken together, the results suggest that functional perturbation of apoptotic proteins such as Bid and, alternatively, enhancement of Bcl-2 function, is a putative strategy for developing novel therapeutics for mood disorders.