Lam Chun-Sing, Tipoe George Lim, Wong Johnny Kong-Ching, Youdim Moussa B H, Fung Man-Lung
School of Biomedical Sciences, The University of Hong Kong, Hong Kong, Hong Kong SAR.
Research Centre of Heart, Brain, Hormone & Healthy Aging, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR.
PLoS One. 2016 Nov 21;11(11):e0166966. doi: 10.1371/journal.pone.0166966. eCollection 2016.
Monoamine oxidases (MAO), downstream targets of glucocorticoid, maintain the turnover and homeostasis of monoamine neurotransmitters; yet, its pathophysiological role in monoamine deficiency, oxidative stress and neuroinflammation remains controversial. Protective effects of M30, a brain selective MAO inhibitor with iron-chelating antioxidant properties, have been shown in models of neurodegenerative diseases. This study aims to examine the neuroprotective mechanism of M30 against depressive-like behavior induced by corticosterone (CORT). Sprague-Dawley rats were given CORT subcutaneous injections with or without concomitant M30 administration for two weeks. CORT-treated rats exhibited depressive-like behavior with significant elevated levels of MAO activities, serotonin turnover, oxidative stress, neuroinflammation and apoptosis in the hippocampus with significant losses of synaptic proteins when compared to the control. The expression and activity of cytokine-responsive indoleamine 2,3-dioxygenase (IDO-1), a catabolic enzyme of serotonin and tryptophan, was significantly increased in the CORT-treated group with lowered levels of serotonin. Besides, CORT markedly reduced dendritic length and spine density. Remarkably, M30 administration neutralized the aberrant changes in the hippocampus and prevented the induction of depressive-like behavior induced by CORT. Our results suggest that M30 is neuroprotective against CORT-induced depression targeting elevated MAO activities that cause oxidative stress and neuroinflammation, resulting in IDO-1 activation, serotonin deficiency and neurodegeneration.
单胺氧化酶（MAO）是糖皮质激素的下游靶点，维持单胺类神经递质的更新和稳态；然而，其在单胺缺乏、氧化应激和神经炎症中的病理生理作用仍存在争议。M30是一种具有铁螯合抗氧化特性的脑选择性MAO抑制剂，已在神经退行性疾病模型中显示出保护作用。本研究旨在探讨M30对皮质酮（CORT）诱导的抑郁样行为的神经保护机制。将Sprague-Dawley大鼠皮下注射CORT，同时或不同时给予M30，持续两周。与对照组相比，CORT处理的大鼠表现出抑郁样行为，海马中MAO活性、5-羟色胺更新、氧化应激、神经炎症和细胞凋亡水平显著升高，突触蛋白显著丢失。5-羟色胺和色氨酸的分解代谢酶细胞因子反应性吲哚胺2,3-双加氧酶（IDO-1）的表达和活性在CORT处理组中显著增加，5-羟色胺水平降低。此外，CORT显著降低了树突长度和棘密度。值得注意的是，给予M30可中和海马中的异常变化，并预防CORT诱导的抑郁样行为。我们的结果表明，M30对CORT诱导的抑郁症具有神经保护作用，其靶点是升高的MAO活性，MAO活性会导致氧化应激和神经炎症，从而导致IDO-1激活、5-羟色胺缺乏和神经退行性变。
