Saint Petersburg, St. Petersburg, Russian Federation
Trifluoperazine (TFP) belongs to the first antipsychotics generation widely used in treatment of mental diseases. A multifaceted influence of TFP on intracellular processes has been revealed. Earlier we have shown that TFP increases intracellular Ca2+ concentration, [Ca2+]i, causing Ca2+ mobilization from intracellular Ca2+ stores and subsequent store-dependent Ca2+ entry from external medium, in rat peritoneal macrophages. However, the mechanisms by which TFP causes Ca2+ responses are not fully understood. In activation and functioning of immune cells, including macrophages, the arachidonic acid metabolism cascade plays an important role. In macrophages arachidonic acid is oxidized predominantly by cyclooxygenases and lipoxygenases. Therefore, it was useful to investigate the involvement of lipoxygenase pathway of arachidonic acid metabolism in TFP effect on [Ca2+]i in macrophages. Using Fura-2AM microfluorimetry, we have found that selective blockers of 5-lipoxygenases (caffeic acid and zileuton) and 12-lipoxygenases (baicalein) significantly suppress TFP-induced Ca2+ responses in rat peritoneal macrophages. Nordihydroguaretic acid, which inhibits all isoforms of lipoxygenases, almost completely suppresses TFP-induced Ca2+ responses. The data obtained suggest the involvement of lipoxygenases and (or) lipoxygenase pathway products in TFP effect on [Ca2+]i in macrophages. The participation of arachidonic acid cascade enzymes in TFP effect on [Ca2+]i can be explained by the model of embedding of amphiphilic antipsychotic agents, including phenothiazine neuroleptics, in the membrane inner monolayer. This can lead to a change in membrane fluidity and functioning of membrane-bound enzymes, such as phospholipase A2, which triggers arachidonic acid cascade. In turn, the enzymes and/or products of arachidonic acid metabolism are involved in the formation of TFP-induced Ca2+ responses.
trifluoperazine, lipoxygenases, intracellular Ca2+ concentration, peritoneal macrophages
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