M30 Antagonizes Indoleamine 2,3-Dioxygenase Activation and Neurodegeneration Induced by Corticosterone in the Hippocampus

Abstract

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.

Influence of Xiaoyaosan on depressive-like behaviors in chronic stress-depressed rats through regulating tryptophan metabolism in hippocampus

“…Hippocampus is also a target of stress hormones, and stress and high glucocorticoids can affect the hippocampal neuroplasticity 12. It is reported that TPH2 gene is expressed in the hippocampus and raphe nuclei,13 and IDO1 has a certain effect on the function and structure of hippocampal neurons 14. Therefore, hippocampus may be a key region to observe the stress-induced changes in TPH2 and IDO1 in the 5-HT system.…”

Potential Roles of microRNAs in the Regulation of Monoamine Oxidase A in the Brain

“…For example, an MAO inhibitor, phenelzine, better prevents the recurrence of depressive symptoms, compared to tricyclic antidepressants, nortriptyline (Georgotas et al, 1989 ). In addition to changing neurotransmitter levels in the brain, inhibition of MAO leads to a neuroprotective effect against glucocorticoid (GC)-induced apoptosis (Johnson et al, 2010 ; Lam et al, 2016 ). M30, an MAO inhibitor with iron-chelating antioxidant properties, prevents corticosterone-induced alteration in the hippocampus, such as activation of indoleamine 2,3-dioxygenase, hippocampal apoptosis, loss of synaptic proteins and neurodegeneration and neuroinflammation (Lam et al, 2016 ).…”

“…In addition to changing neurotransmitter levels in the brain, inhibition of MAO leads to a neuroprotective effect against glucocorticoid (GC)-induced apoptosis (Johnson et al, 2010 ; Lam et al, 2016 ). M30, an MAO inhibitor with iron-chelating antioxidant properties, prevents corticosterone-induced alteration in the hippocampus, such as activation of indoleamine 2,3-dioxygenase, hippocampal apoptosis, loss of synaptic proteins and neurodegeneration and neuroinflammation (Lam et al, 2016 ). Selective MAO-A inhibition with pirlindole abolishes the alteration induced by chronic mild stress, such as behavioral changes in forced swimming test and the dendritic atrophy of granule neurons, but promotes adult neurogenesis in the hippocampus of rats exposed to chronic mild stress (Morais et al, 2014 ), indicating the effectiveness of MAO-A inhibition for stress-induced neurobiological alterations in the brain.…”