Azure B and a synthetic structural analogue of methylene blue, ethylthioninium chloride, present with antidepressant-like properties

Abstract

Aims: 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, ethylthioniniumchloride (ETC), and to evaluate the effects of the structural changes on theMAO 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. Main 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. Key findings: 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. Conclusion: Azure B may therefore be a contributor to the antidepressant effect of MB. Small structural changes made to MBretain its antidepressant effect, even though the resulting phenothiaziniumcompound possesses reduced MAO-A inhibitory potency