title: Treatment with the MAO-A inhibitor clorgyline elevates monoamine neurotransmitter levels and improves affective phenotypes in a mouse model of Huntington disease.
abstract: Abnormal monoamine oxidase A and B (MAO-A/B) activity and an imbalance in monoamine neurotransmitters have been suggested to underlie the pathobiology of depression, a major psychiatric symptom observed in patients with neurodegenerative diseases, such as Huntington disease (HD). Increased MAO-A/B activity has been observed in brain tissue from patients with HD and in human and rodent HD neural cells. Using the YAC128 mouse model of HD, we studied the effect of an irreversible MAO-A inhibitor, clorgyline, on the levels of select monoamine neurotransmitters associated with affective function. We observed a decrease in striatal levels of the MAO-A/B substrates, dopamine and norepinephrine, in YAC128 HD mice compared with wild-type mice, which was accompanied by increased anxiety- and depressive-like behaviour at five months of age. Treatment for 26 days with clorgyline restored dopamine, serotonin, and norepinephrine neurotransmitter levels in the striatum and reduced anxiety- and depressive-like behaviour in YAC128 HD mice. This study supports a potential therapeutic use for MAO-A inhibitors in the treatment of depression and anxiety in patients with HD.
authors.affiliation: Translational Laboratory in Genetic Medicine (TLGM), Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, Immunos, Level 5, Singapore 138648.
authors.forename: Marta
authors.initials: M
authors.lastname: Garcia-Miralles
authors.affiliation: Translational Laboratory in Genetic Medicine (TLGM), Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, Immunos, Level 5, Singapore 138648.
authors.forename: Jolene
authors.initials: J
authors.lastname: Ooi
authors.affiliation: Translational Laboratory in Genetic Medicine (TLGM), Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, Immunos, Level 5, Singapore 138648.
authors.forename: Costanza
authors.initials: C
authors.lastname: Ferrari Bardile
authors.affiliation: Translational Laboratory in Genetic Medicine (TLGM), Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, Immunos, Level 5, Singapore 138648.
authors.forename: Liang Juin
authors.initials: LJ
authors.lastname: Tan
authors.affiliation: Cardiovascular Research Institute, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Maya
authors.initials: M
authors.lastname: George
authors.affiliation: Translational Laboratory in Genetic Medicine (TLGM), Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, Immunos, Level 5, Singapore 138648; Cardiovascular Research Institute, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Chester L
authors.initials: CL
authors.lastname: Drum
authors.affiliation: Translational Laboratory in Genetic Medicine (TLGM), Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, Immunos, Level 5, Singapore 138648.
authors.forename: Rachel Yanping
authors.initials: RY
authors.lastname: Lin
authors.affiliation: Translational Laboratory in Genetic Medicine (TLGM), Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, Immunos, Level 5, Singapore 138648; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, 117597, Singapore; Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, University of British Columbia, Vancouver, BC V5Z 4H4, Canada.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Hayden
authors.affiliation: Translational Laboratory in Genetic Medicine (TLGM), Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, Immunos, Level 5, Singapore 138648; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, 117597, Singapore. Electronic address: pouladi@tlgm.a-star.edu.sg.
authors.forename: Mahmoud A
authors.initials: MA
authors.lastname: Pouladi
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003010:Clorgyline / Q000627:therapeutic use*; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000187:drug effects; D019417:Hindlimb Suspension; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000150:complications* / Q000235:genetics / Q000378:metabolism; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D008995:Monoamine Oxidase / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000627:therapeutic use*; D019964:Mood Disorders / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics; D018377:Neurotransmitter Agents / Q000378:metabolism*; D010641:Phenotype; D013550:Swimming
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D008996:Monoamine Oxidase Inhibitors; D009419:Nerve Tissue Proteins; D018377:Neurotransmitter Agents; D008995:Monoamine Oxidase; D003010:Clorgyline
keywords: Anxiety; Depression; Huntington's disease; Monoamine oxidase; Monoamine oxidase inhibitors; Monoamines; Mouse model; Psychiatric features