title: Role of monoamine oxidase, nitric oxide synthase and regional brain monoamines in the antidepressant-like effects of methylene blue and selected structural analogues.
abstract: Dual action antidepressants have important therapeutic implications. Methylene blue (MB), a charged compound structurally related to tricyclic antidepressants, acts on both monoamine oxidase (MAO) and the nitric oxide (NO)-cGMP pathway, and has demonstrated antidepressant activity in rodents. We investigated the antidepressant properties of MB and selected structural analogues and whether their actions involve MAO, NO synthase (NOS) and regional brain monoamines. Acute imipramine (IMI, 15 mg/kg), saline, MB, acriflavine (ACR), methylene green (MG), methylene violet (MV), thionine (THI) and tacrine (TAC) (1-60 mg/kg i.p.) were tested for antidepressant activity in the forced swim test (FST), as well as MAO-A/B inhibitory activity. Active antidepressant compounds were subsequently studied at their most effective dose during sub-chronic treatment, followed by behavioural sampling in the FST and assay of cortico-limbic monoamines and hippocampal nitrate (for NOS activity). Only IMI, MB (15, 30, 60 mg/kg) and MG (7.5, 25, 40 mg/kg) reduced immobility in the acute FST. MB, MG and ACR were potent inhibitors of especially MAO-A. Following sub-chronic treatment, IMI (15 mg/kg) increased noradrenergic behaviour in the FST, while MB (15 mg/kg) and MG (15 mg/kg) enhanced serotonergic behaviour. MB and MG bolstered cortico-limbic serotonin (5HT) levels and to a lesser extent l-norepinephrine (l-NE), but did not significantly alter regional dopamine (DA) levels. MB, and to lesser degree MG, reduced hippocampal nitrate levels. MB and MG present with structure-specific antidepressant-like effects following acute and sub-chronic treatment, possibly involving NOS and MAO-A inhibition and cortico-limbic 5HT and l-NE release. A role for MAO-B and DA appears minimal.
authors.affiliation: Division of Pharmacology, Unit for Drug Research and Development, School of Pharmacy, North-West University (Potchefstroom campus), Hofman street, Private Bag X6001, Potchefstroom 2520, South Africa. Brian.Harvey@nwu.ac.za
authors.forename: Brian H
authors.initials: BH
authors.lastname: Harvey
authors.forename: Ingrid
authors.initials: I
authors.lastname: Duvenhage
authors.forename: Francois
authors.initials: F
authors.lastname: Viljoen
authors.forename: Nellie
authors.initials: N
authors.lastname: Scheepers
authors.forename: Sarel F
authors.initials: SF
authors.lastname: Malan
authors.forename: Gregers
authors.initials: G
authors.lastname: Wegener
authors.forename: Christiaan B
authors.initials: CB
authors.lastname: Brink
authors.forename: Jacobus P
authors.initials: JP
authors.lastname: Petzer
mesh_terms: D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000737:chemistry / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D015306:Biogenic Monoamines / Q000378:metabolism / Q000502:physiology*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D008751:Methylene Blue / Q000031:analogs & derivatives / Q000494:pharmacology*; D015394:Molecular Structure; D008995:Monoamine Oxidase / Q000378:metabolism / Q000502:physiology*; D009043:Motor Activity / Q000187:drug effects; D019001:Nitric Oxide Synthase / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins; D013329:Structure-Activity Relationship; D013550:Swimming
chemical_list: D000929:Antidepressive Agents, Tricyclic; D015306:Biogenic Monoamines; D011994:Recombinant Proteins; D019001:Nitric Oxide Synthase; D008995:Monoamine Oxidase; D008751:Methylene Blue