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Cellular mechanisms of adverse cardiotoxic effects of selected antipsychotics

Biophysics

2024

Mgr. Zuzana Ševčíková Tomášková, PhD.

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Faculty of Mathematics, Physics, and Informatics, Comenius University in Bratislava

The treatment of mental disorders, such as bipolar disorder, depression, or schizophrenia is often associated by a whole spectrum of cardiotoxic side effects that can limit effectiveness of the patient´s treatment. Elucidation of the origin of these adverse effects could lead to design of a potential compensatory therapy, ultimately aiding patients in leading normal lives. The topic is focused on the study of the mechanisms by which cardiotoxic effects occur during the treatment of these mental disorders. In our laboratory, we found that lithium, often used in therapy of bipolar disorder, causes a significant decrease in the reserve respiratory capacity of cells, but does not change their basal respiration. This condition puts the cardiac cells at a disadvantage, and their collapse may occur under higher workload. Mitochondria are involved in the cardiotoxic effects of clozapine or risperidone. The aim of the work is to examine the effect of selected drugs on the bioenergetics of the cardiomyoblast cell line and their subsequent comparison. The drugs will be selected based on the described similar effects among patients (clozapine, lamotrigine, quetiapine, olanzapine, etc.). Since cardiac rhythm disorders are among the frequent effects, in addition to bioenergetics, we will analyze the spontaneous calcium events (calcium sparks), which also occur under physiological conditions. The frequency of occurrence of calcium sparks is related to the bioenergetic state of the cell. In addition to the functional properties, the work will also focus on monitoring of the changes in the expression and/or activity of individual proteins involved in the respiratory chain, their occurrence will be tested proteomically after chronic application of the drug. From the literature several signal pathways are known that are affected by the drug, but at the functional level, the behavior of cardiac cells in the presence of antipsychotics is rarely described, in contrast to the effect on neuronal cells. Methods: work with cell cultures, confocal microscopy (detection of mitochondrial membrane potential and calcium events, monitoring the redox state of cells), measurement of oxygen consumption in cells with a Clark electrode, selected methods of molecular biology (Western blot, PCR), enzymatic reactions, work with tissues and isolation of primary cardiomyocytes.