3β-Methoxy-pregnenolone (MAP4343) as an innovative therapeutic approach for depressive disorders
3β-Methoxy-pregnenolone (MAP4343) as an innovative therapeutic approach for depressive disorders
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DOI：
10.1073/pnas.1121485109
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发表时间：
2012-01-31
影响因子：
11.1
通讯作者：
Baulieu, Etienne-Emile
中科院分区：
文献类型：
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作者：
Bianchi, Massimiliano;Baulieu, Etienne-Emile
新出现的证据表明，抑郁症（DDs）的发病机制与脑微管功能的神经元异常有关，包括α-微管蛋白亚型的变化。目前可用的抗抑郁药物可能通过挽救这些改变而起作用，但只有在长期治疗后才能解释其延迟的治疗效果。微管相关蛋白2（MAP-2）调节神经元微管动力学。我们的假设是MAP-2代表了治疗DD的创新靶点。合成的阿替诺龙衍生物MAP 4343（3 β-甲氧基阿替诺龙）在体外结合MAP-2，并增加其刺激微管蛋白组装的能力。在这里，我们表明，MAP 4343在大鼠中具有抗抑郁疗效，并且与选择性5-羟色胺再摄取抑制剂（SSRI）氟西汀相比具有优势。单次注射MAP 4343改变了α-微管蛋白同种型的表达，表明未处理的Sprague-Dawley大鼠海马中微管动力学增加，而氟西汀没有影响。MAP 4343在大鼠强迫游泳试验（FST）中具有积极疗效，FST是通过减少不动行为筛选潜在抗抑郁药物的最常用试验。在抑郁症的大鼠隔离饲养模型中，与氟西汀相比，给予MAP 4343在恢复“抑郁样”行为方面显示出更快和更持久的疗效。这些作用伴随着海马体、杏仁核和前额皮质中α-微管蛋白同种型的改变。我们的研究结果表明，基于独特的作用机制，MAP 4343在治疗DD方面具有潜在的治疗用途。
Emerging evidence suggests that the pathogenesis of depressive disorders (DDs) is associated with neuronal abnormalities in brain microtubule function, including changes in a-tubulin isoforms. Currently available antidepressant drugs may act by rescuing these alterations, but only after long-term treatment explaining their delayed therapeutic efficacy. The microtubule associated protein type-2 (MAP-2) modulates neuronal microtubule dynamics. Our hypothesis is that MAP-2 represents an innovative target for the treatment of DDs. The synthetic pregnenolone-derivative MAP4343 (3 beta-methoxy-pregnenolone) binds MAP-2 in vitro and increases its ability to stimulate tubulin assembly. Here, we show that MAP4343 has antidepressant efficacy in rats and advantages compared with the selective serotonin reuptake inhibitor (SSRI) fluoxetine. A single injection of MAP4343 changes the expression of alpha-tubulin isoforms indicative of increased microtubule dynamics in the hippocampus of naive Sprague-Dawley rats, whereas fluoxetine had no effects. MAP4343 has positive efficacy in the rat forced swimming test (FST), the most used assay to screen potential antidepressant drugs by decreasing immobility behavior. In the rat isolation-rearing model of depression, administration of MAP4343 showed more rapid and more persistent efficacy compared with fluoxetine in recovering "depressive-like" behaviors. These effects were accompanied by modifications of a-tubulin isoforms in the hippocampus, amygdala, and prefrontal cortex. Our findings suggest the potential therapeutic use of MAP4343 for the treatment of DDs, based on a unique mechanism of action.