Pharmaceutical Chemistry, School of Pharmacy , North-West University , Private Bag X6001 , Potchefstroom 2520 , South Africa.
Centre of Excellence for Pharmaceutical Sciences , North-West University , Private Bag X6001 , Potchefstroom 2520 , South Africa.
ACS Chem Neurosci. 2018 Dec 19;9(12):2917-2928. doi: 10.1021/acschemneuro.8b00042. Epub 2018 Jul 25.
Methylene blue (MB) possesses diverse medical applications. Among these, MB presents with antidepressant-like effects in animals and has shown promise in clinical trials for the treatment of mood disorders. As an antidepressant, MB may act via various mechanisms which include modulation of the nitric oxide cyclic guanosine monophosphate (NO-cGMP) cascade, enhancement of mitochondrial respiration and antioxidant effects. MB is also, however, a high potency inhibitor of monoamine oxidase (MAO) A, which most likely contributes to its antidepressant effect, but also to its adverse effects profile (e.g., serotonin toxicity). The latter has raised the question whether it is possible to design out the MAO inhibition properties of MB yet retaining its clinically useful attributes. This study explores this idea further by characterizing five newly synthesized low MAO-A active MB analogues and examining their antidepressant-like properties in the acute forced swim test (FST) in rats, with comparison to imipramine and MB. The results show that all five analogues exhibit antidepressant-like properties in the FST without confounding effects on locomotor activity. The magnitude of these effects is comparable to those of imipramine and MB. Moreover, these newly synthesized MB analogues are markedly less potent MAO-A inhibitors (IC = 0.518-4.73 μM) than MB (IC = 0.07 μM). We postulate that such lower potency MAO-A inhibitors may present with a reduced risk of adverse effects associated with MAO-A inhibition. While low level MAO-A inhibition still may produce an antidepressant effect, we posit that other MB-related mechanisms may underlie their antidepressant effects, thereby representing a novel group of antidepressant compounds.
亚甲蓝（MB）具有多种医学应用。其中，MB 在动物中具有抗抑郁作用，并在治疗情绪障碍的临床试验中显示出前景。作为一种抗抑郁药，MB 可能通过多种机制发挥作用，包括调节一氧化氮环鸟苷酸（NO-cGMP）级联、增强线粒体呼吸和抗氧化作用。然而，MB 也是一种高活性的单胺氧化酶（MAO）A 抑制剂，这很可能有助于其抗抑郁作用，但也会导致其不良反应谱（例如，血清素毒性）。后者提出了一个问题，即是否有可能设计出 MB 的 MAO 抑制特性，同时保留其临床有用的特性。本研究通过对五种新合成的低 MAO-A 活性 MB 类似物进行表征，并在大鼠急性强迫游泳试验（FST）中检查其抗抑郁样特性，与丙咪嗪和 MB 进行比较，进一步探讨了这一想法。结果表明，所有五种类似物在 FST 中均表现出抗抑郁样特性，而对运动活性没有混杂影响。这些作用的幅度与丙咪嗪和 MB 的相当。此外，这些新合成的 MB 类似物作为 MAO-A 抑制剂的效力明显低于 MB（IC = 0.518-4.73 μM）（IC = 0.07 μM）。我们推测，这种低效力的 MAO-A 抑制剂可能与 MAO-A 抑制相关的不良反应风险降低有关。虽然低水平的 MAO-A 抑制仍可能产生抗抑郁作用，但我们认为，MB 相关的其他机制可能是其抗抑郁作用的基础，从而代表了一类新的抗抑郁化合物。
