title: 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.
authors.affiliation: School of Biomedical Sciences, The University of Hong Kong, Hong Kong, Hong Kong SAR.
authors.forename: Chun-Sing
authors.initials: CS
authors.lastname: Lam
authors.affiliation: 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.
authors.forename: George Lim
authors.initials: GL
authors.lastname: Tipoe
authors.affiliation: Department of Pharmacology & Pharmacy, The University of Hong Kong, Hong Kong, Hong Kong SAR.
authors.forename: Johnny Kong-Ching
authors.initials: JK
authors.lastname: Wong
authors.affiliation: Eve Topf Center for Neurodegenerative Diseases Research, Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, 31096, Israel.
authors.forename: Moussa B H
authors.initials: MB
authors.lastname: Youdim
authors.affiliation: 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.
authors.forename: Man-Lung
authors.initials: ML
authors.lastname: Fung
mesh_terms: D000818:Animals; D003345:Corticosterone / Q000009:adverse effects* / Q000494:pharmacology; D049229:Dendritic Spines / Q000201:enzymology / Q000473:pathology; D003863:Depression / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology; D004789:Enzyme Activation / Q000187:drug effects; D006624:Hippocampus / Q000201:enzymology* / Q000473:pathology; D006912:Hydroxyquinolines / Q000494:pharmacology*; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology; D008297:Male; D019636:Neurodegenerative Diseases / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism
chemical_list: C517687:5-(N-methyl-N-propargylaminomethyl)-8-hydroxyquinoline; D006912:Hydroxyquinolines; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D012701:Serotonin; D003345:Corticosterone