Chlorpromazine belongs to the first antipsychotics generation widely used in treatment of mental diseases. A multifaceted influence of chlorpomazine on intracellular processes has been revealed. Earlier we have shown that chlorpromazine increases intracellular Ca2+ concentration, causing Ca2+ mobilization from intracellular Ca2+-stores and subsequent Ca2+-entry from external medium, in rat peritoneal macrophages. However, the mechanisms by which chlorpomazine 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 cyclooxygenase pathway of arachidonic acid metabolism in the effect of phenothiazine neuroleptic chlorpromazine on intracellular Ca2+-concentration in macrophages. Using Fura-2AM microfluorimetry it was shown for the first time that two structurally distinct cyclooxygenase inhibitors acetylsalicylic acid (aspirin) and indomethacin attenuate Ca2+-responses, induced by chlorpromazine in rat peritoneal macrophages. The data obtained suggest the involvement of cyclooxygenases and (or) cyclooxygenase pathway products in the chlorpromazine effect on intracellular Ca2+-concentration in macrophages. The participation of arachidonic acid cascade enzymes in the influence of chlorpromazine on intracellular Ca2+ concentration 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 chlorpromazine-induced Ca2+ responses.
chlorpromazine, cyclooxygenases, intracellular Ca2+-concentration, peritoneal macrophages
1. Dilsaver S.C. Antipsychotic agents: a review. Am. Fam. Phys., 1993, vol. 47, pp. 199-204.
2. Sudeshna G., Parimal K. Multiple non-psychiatric effects of phenothiazines: a review. Europ. J. Pharmacol., 2010, vol. 648, pp. 6-14.
3. Oruch R., Lund A., Pryme I.F., Holmsen H. An intercalation mechanism as a mode of action exerted by psychotropic drugs: results of altered phospholipid substrate availabilities in membranes? J. Chem. Biol., 2010, vol. 3, pp. 67-88.
4. Kruteckaya Z.I., Milenina L.S., Naumova A.A., Butov S.N., Antonov V.G., Nozdrachev A.D. Vliyanie hlorpromazina na vnutrikletochnuyu koncentraciyu Sa2+ v makrofagah. Dokl. Akad. Nauk, 2017, t. 474, № 1, s. 116-118. [Krutetskaya Z.I., Milenina L.S., Naumova A.A., Butov S.N., Antonov V.G., Nozdrachev A.D. The effect of chlorpromazine on intracellular Ca2+ concentration in macrophages. Dokl. Bioch. Biophys., 2017, vol. 474, pp. 162-164.]
5. Milenina L.S., Kruteckaya Z.I., Naumova A.A., Butov S.N., Kruteckaya N.I., Antonov V.G. Ingibitory metabolizma arahidonovoy kisloty podavlyayut Sa2+otvety, vyzyvaemye trifluoperazinom, v makrofagah. Citologiya, 2018, t. 60, № 2, s. 116-121. [Milenina L.S., Krutetskaya Z.I., Naumova A.A., Butov S.N., Krutetskaya N.I., Antonov V.G. Arachidonic acid metabolism inhibitors attenuate Ca2+ responses induced by trifluoperazine in macrophages. Cell Tissue Biol., 2018, vol. 12, № 4, pp. 315-322.]
6. Needleman P., Turk J., Jacksick B.A., Morrison A.R., Lefkowith J.B. Arachidonic acid metabolism. Annu. Rev. Biochem., 1986, vol. 55, pp. 69-102.
7. Brown G.P., Monick M. M., Hunninghake G.W. Human alveolar macrophage arachidonic acid metabolism. Am. J. Physiol. Cell Physiol., 1988, vol. 254, pp. C809-C815.
8. Walenga R.W., Opas E. E., Feinstein M.B. Differential effects of calmodulin antagonists on phospholipases A2 and C in thrombin-stimulated platelets. J. Biol. Chem., 1981, vol. 256, pp. 12523-12528.
9. Oruch R., Pryme I. F., Holmsen H. Effects of psychotropic drugs on the thrombin-induced liberation of arachidonate in human platelets. Saudi Med. J., 2008, vol. 29, pp. 1397-1407.
10. Grynkiewicz G., Poenie M., Tsien R.Y. A new generation of Ca2+ indicators with greatly improved fluorescence properties. J. Biol. Chem., 1985, vol. 260, pp. 3440-3450.
11. Xie Q., Zhang Y., Zhai C., Bonanno J. A. Calcium influx factor from cytochrome P-450 metabolism and secretion-like coupling mechanisms for capacitative calcium entry in corneal endothelial cells. J. Biol. Chem., 2002, vol. 277, pp. 16559- 16566.
12. De Witt D.L., El Harish E.A., Kraemer S.A., Andrews M.J., Yao E.F., Armstrong R.L., Smith W.L. The aspirin and heme-binding sites of ovine and murine prostaglandin endoperoxide synthases. J. Biol Chem., 1990, vol. 265, pp. 5192- 5198.
13. Mitchell J.A., Akarasereenont P., Thiemermann C., Flower R.J., Vane J.R. Selectivity of nonsteroidal anti-inflammatory drugs as inhibitors of constitutive and inducible cyclooxygenases. Proc. Natl. Acad. Sci., 1994, vol. 90, pp. 11693-11697.
14. Dubois R. N., Abramson S.B., Crofford L., Gupta R.A., Simon L.S., Van de Putte L.B.A., Lipsky P.E. Cyclooxygenase in biology and disease. FASEB J., 1998, vol. 12, pp. 1063-1073.
15. Jaszczyszyn A., Gasiorowski K., Swiatek P., Malinka W., Cieslik-Boczula K., Petrus J., Czarnik-Matusewicz B. Chemical structure of phenothiazines and their biological activity. Pharmacol. Rep., 2012, vol. 64, pp. 16-23.
