| dc.description.abstract | The shortcomings of current antidepressant agents prompts the design of novel multimodal
antidepressants and the identification of new antidepressant targets, especially those
located at sub-cellular level. Such antidepressants should possess improved response rates
as well as safety profiles. Methylene blue (MB) is reported to possess diverse
pharmacological actions and is attracting increasing attention for the treatment of a variety of
disorders including Alzheimer’s disease, bipolar disorder, anxiety and depression. MB acts
on both monoamine oxidase (MAO) and the nitric oxide (NO)-cGMP pathway, and
possesses antidepressant activity in rodents. The principal goal of this study was to design a
close structural analogue of MB and to evaluate the effects of these structural changes on
MAO inhibition, a well-known antidepressant target. Furthermore, MAO inhibition is also
responsible for cardiovascular toxicity in clinically used MAOI inhibitors. For this purpose we
investigated the antidepressant properties of the synthetic MB analogue (ethyl-thioniniumchloride;
ETC) as well as azure B, the major metabolite of MB, in the forced swim test (FST).
ETC was synthesized with a high degree of purity from diethyl-p-phenylenediamine with 6%
yield. ETC was firstly evaluated as a potential inhibitor of recombinant human MAO-A and
MAO-B. Azure B and ETC were evaluated over a dosage range of 4-30 mg/kg for
antidepressant-like activity in the acute FST in rats, and the results were compared to those
obtained with saline, imipramine (15 mg/kg) and MB (15 mg/kg) treated rats. Locomotor
activity was evaluated to ensure that changes in swim motivation are based on
antidepressant response and not due to an indirect effect of the drug on locomotor activity.
The results document that ETC inhibits MAO-A and MAO-B with IC50 values of 0.51 μM and
0.592 μM, respectively. Furthermore, ETC inhibits MAO-A and MAO-B reversibly, while the
mode of inhibition is most likely competitive. In the acute FST, azure B and ETC were more
effective than imipramine and MB in reversing immobility, without inducing locomotor effects.
Azure B and ETC increased swimming behaviour during acute treatment, which is indicative
of enhanced serotonergic neurotransmission. Azure B and ETC did not affect noradrenergicmediated
climbing behaviour. These results suggest that azure B may be a contributor to the
antidepressant effect of MB, and acts via increasing serotonergic transmission. Secondly,
small structural changes made to MB do not abolish its antidepressant effect even though
ETC is a less potent MAO-A inhibitor than MB. | en_US |
