Abstract
Thioridazine as an antipsychotic agent was extensively used to treat various psychotic disorders, e.g. schizophrenia. However, the therapy with this drug can induce serious side effects such as extrapyramidal symptoms or ocular and skin disorders, which mechanisms are still not fully established. To gain inside the molecular mechanisms underlying thioridazine toxicity, we examined the effect of this drug on cell viability, antioxidant defence system as well as melanogenesis in normal human melanocytes. It was demonstrated that thioridazine induces concentration-dependent loss in cell viability. The value of EC50 was calculated to be 2.24 μM. To study the effect of thioridazine on antioxidant defence system in melanocytes, the level of hydrogen peroxide and the activities of antioxidant enzymes superoxide dismutase, catalase and glutathione peroxidase were determined. The drug in concentrations of 0.1, 0.25, 1.0 and 2.5 μM caused changes in cellular antioxidant defence system indicating the induction of oxidative stress. It was also shown that the analysed neuroleptic in concentrations of 1.0 and 2.5 μM significantly inhibited melanogenesis. The observed changes in cell viability, antioxidant defence system and melanization in normal human melanocytes after thioridazine treatment may explain an important role of reactive oxygen species as well as melanin in mechanisms involved in this drug side effects directed on pigmented tissues.
Highlights
Thioridazine is a typical antipsychotic drug belonging to phenothiazine neuroleptics of the piperidine type
It is of interest that accumulation of H2O2 in melanocytes in millimolar concentrations may lead to disruption of many proteins and peptides leading to deactivation of important antioxidant enzymes including catalase, thioredoxin reductase and methionine sulphoxide reductases A and B (Schallreuter et al 2008; Kim and Lee 2013)
The micromolar concentrations of H2O2 cause an increase in the activity of many proteins and peptides such as tyrosinase, transcription factors (e.g. microphthalmia-associated transcription factor (MITF), p53) as well as antioxidant enzymes (Schallreuter et al 2008)
Summary
Thioridazine is a typical antipsychotic drug belonging to phenothiazine neuroleptics of the piperidine type. It is a mild neuroleptic, displaying sedative and antidepressant effects, which was used in the treatment of positive and negative symptoms of schizophrenia (Wójcikowski et al 2006). Thioridazine exhibits anticancer, antibacterial, antiviral, antiprotozoic as well as multidrug resistance reversal activity (Morak-Młodawska and Jeleń 2007; Rho et al 2011). Anticancer activity of this drug results from its antiproliferative and antisurvival effects (Min et al 2014).
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