Attenuation of the effects of oxidative stress by the MAO-inhibiting antidepressant and carbonyl scavenger phenelzine
Attenuation of the effects of oxidative stress by the MAO-inhibiting antidepressant and carbonyl scavenger phenelzine
复制标题
DOI：
10.1016/j.cbi.2019.03.003
复制
发表时间：
2019-05-01
影响因子：
5.1
通讯作者：
Kar, Satyabrata
中科院分区：
文献类型：
--
作者：
Baker, Glen;Matveychuk, Dmitriy;Kar, Satyabrata
苯乙肼（β-苯乙胺）是一种单胺氧化酶（MAO）抑制抗抑郁药，具有抗焦虑特性。它具有许多重要的药理学特性，可能会改变氧化应激的影响。在进行了全面的文献检索后，这篇综述论文的作者旨在提供苯乙肼可能减轻氧化应激的机制的概述和讨论。它抑制γ-氨基丁酸（GABA）转氨酶，导致脑GABA水平升高，抑制MAO和伯胺氧化酶，并且由于其含肼结构，化学反应以螯合许多反应性醛（例如丙烯醛和4-羟基-2-壬烯醛），这些醛被认为与许多神经退行性疾病中的氧化应激有关。苯乙肼的特殊性在于它既是单胺氧化酶的抑制剂又是其底物，后者至少产生一种活性代谢物β-苯乙叉肼（PEH）。该代谢物抑制GABA转氨酶，是一种非常弱的MAO抑制剂，但是一种强的伯胺氧化酶抑制剂，并螯合醛。苯乙肼可通过减少由MAO与生物胺的相互作用产生的反应性代谢物（醛、过氧化氢、氨/氨衍生物）的形成、通过螯合各种其他反应性醛和通过抑制伯胺氧化酶来改善氧化应激的影响。在用神经毒素MPP+处理的PC 12细胞中，已报道苯乙肼减少MPP+的几种不良反应。据报道，它还可以减少过氧亚硝酸盐在血浆和血小板蛋白中诱导的脂质过氧化损伤。在动物模型中，苯乙肼在全脑缺血和皮质撞击创伤性脑损伤中具有神经保护作用。最近的研究报告在文献中丙烯醛在脊髓损伤和多发性硬化症的可能参与表明，苯乙肼可以减轻丙烯醛在这些模型中的不良反应。在我们的实验室的苯乙肼和PEH对伯胺氧化酶（催化形成有毒的醛和过度表达的阿尔茨海默氏病），螯合的有毒醛丙烯醛，并减少丙烯醛诱导的毒性在小鼠皮层神经元的影响的研究结果也报道。
Phenelzine (beta-phenylethylhydrazine) is a monoamine oxidase (MAO)-inhibiting antidepressant with anxiolytic properties. It possesses a number of important pharmacological properties which may alter the effects of oxidative stress. After conducting a comprehensive literature search, the authors of this review paper aim to provide an overview and discussion of the mechanisms by which phenelzine may attenuate oxidative stress. It inhibits gamma-aminobutyric acid (GABA) transaminase, resulting in elevated brain GABA levels, inhibits both MAO and primary amine oxidase and, due to its hydrazine-containing structure, reacts chemically to sequester a number of reactive aldehydes (e.g. acrolein and 4-hydroxy-2-nonenal) proposed to be implicated in oxidative stress in a number of neurodegenerative disorders. Phenelzine is unusual in that it is both an inhibitor of and a substrate for MAO, the latter action producing at least one active metabolite, beta-phenylethylidenehydrazine (PEH). This metabolite inhibits GABA transaminase, is a very weak inhibitor of MAO but a strong inhibitor of primary amine oxidase, and sequesters aldehydes. Phenelzine may ameliorate the effects of oxidative stress by reducing formation of reactive metabolites (aldehydes, hydrogen peroxide, ammonia/ammonia derivatives) produced by the interaction of MAO with biogenic amines, by sequestering various other reactive aldehydes and by inhibiting primary amine oxidase. In PC12 cells treated with the neurotoxin MPP+, phenelzine has been reported to reduce several adverse effects of MPP+. It has also been reported to reduce lipid peroxidative damage induced in plasma and platelet proteins by peroxynitrite. In animal models, phenelzine has a neuroprotective effect in global ischemia and in cortical impact traumatic brain injury. Recent studies reported in the literature on the possible involvement of acrolein in spinal cord injury and multiple sclerosis indicate that phenelzine can attenuate adverse effects of acrolein in these models. Results from studies in our laboratories on effects of phenelzine and PEH on primary amine oxidase (which catalyzes formation of toxic aldehydes and is overexpressed in Alzheimer's disease), on sequestration of the toxic aldehyde acrolein, and on reduction of acrolein-induced toxicity in mouse cortical neurons are also reported.