title: Azure B and a synthetic structural analogue of methylene blue,  ethylthioninium chloride, present with antidepressant-like properties.
abstract: OBJECTIVE
  The phenothiazinium compound, methylene blue (MB), possesses diverse pharmacological actions and is attracting attention for the treatment of bipolar disorder and Alzheimer's disease. MB acts on both monoamine oxidase (MAO) and the nitric oxide (NO)-cGMP pathway, and possesses antidepressant activity in rodents. The goal of this study was to synthesise a structural analogue of MB, ethylthioninium chloride (ETC), and to evaluate the effects of the structural changes on the MAO inhibitory and antidepressant properties of MB. This study also investigated the antidepressant properties of azure B, the major metabolite of MB, versus MB and imipramine as active comparators.
  
  
  METHODS
  ETC and azure B were firstly evaluated as inhibitors of human MAO, and secondly for antidepressant-like activity in the acute forced swim test (FST) in rats, and compared to saline, imipramine and MB.
  
  
  RESULTS
  The results document that ETC is a reversible inhibitor of MAO-A and MAO-B with IC50 values of 0.510 μM and 0.592 μM, respectively, and that it is a weaker MAO-A inhibitor than MB and azure B. ETC and azure B were more effective than imipramine and MB in reversing immobility in the FST without inducing locomotor effects, with evidence supporting a serotonergic action. Of interest is the finding that ETC is more toxic for cultured cells than MB.
  
  
  CONCLUSIONS
  Azure B may therefore be a contributor to the antidepressant effect of MB. Small structural changes made to MB retain its antidepressant effect, even though the resulting phenothiazinium compound possesses reduced MAO-A inhibitory potency.
authors.forename: Anzelle
authors.initials: A
authors.lastname: Delport
authors.forename: Brian H
authors.initials: BH
authors.lastname: Harvey
authors.forename: Anél
authors.initials: A
authors.lastname: Petzer
authors.forename: Jacobus P
authors.initials: JP
authors.lastname: Petzer
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000928:Antidepressive Agents / Q000737:chemistry / Q000494:pharmacology*; D001399:Azure Stains / Q000737:chemistry* / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003863:Depression / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D020128:Inhibitory Concentration 50; D008124:Locomotion / Q000187:drug effects; D008297:Male; D008751:Methylene Blue / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D015394:Molecular Structure; D008996:Monoamine Oxidase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D009042:Motivation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000928:Antidepressive Agents; D001399:Azure Stains; D008996:Monoamine Oxidase Inhibitors; C000594839:ethylthioninium; C025819:Azure B; D008751:Methylene Blue