Haloperidol Reduces the Activity of Complement and Induces the Anti-Inflammatory Transformation of Peritoneal Macrophages in Rats

  • E. G. Cheremnykh
  • P. A. Ivanov
  • Oleg Yu SokolovEmail author
  • T. A. Prokhorova
  • E. B. Tereshkina
  • N. V. Baymeeva
  • I. I. Miroshnichenko
  • N. V. Kost
Letter to the Editor


It is known that psychotropic substances affect the immune system. Unfortunately, chronic antipsychotic administration causes side toxicological effects, associated with oxidative stress. The mechanisms of these effects are still unclear. We investigated the impact of sub-chronic administration of haloperidol (Hal) on parameters of innate immunity and related systems in healthy rats and compared them with Hal content. Hal administration (0.5 mg/kg, 3 weeks) resulted in two-fold decrease of the activity of the complement system and hemostasis. Hal content correlated with the activity of the complement (r = −0.71), phagocytic activity of peritoneal macrophages (r = 0.78), leukocyte elastase (r = −0.71) and glutathione-S-transferase activity (r = −0.67). Hal fully blocked in vitro PMA-induced iNOS expression in macrophages and changed their morphology to “anti-inflammatory” phenotype. The comparison of in vivo and in vitro data showed that Hal has a direct effect on phagocytic component of innate immunity and an indirect effect on leukocyte elastase and antioxidant enzymes. The results obtained in the present study indicated that Hal significantly affects homeostasis and causes a number of complex biological transformations.

Graphical Abstract


Haloperidol Innate immunity Complement system Macrophages Hemostasis Antioxidant system Rats 



The authors thank A.A.Shmakova for her kind assistance in translating the article into English.


  1. Anderson G, Berk M, Dodd S, Bechter K, Altamura AC, Dell'osso B, Kanba S, Monji A, Fatemi SH, Buckley P, Debnath M, Das UN, Meyer U, Müller N, Kanchanatawan B, Maes M (2013) Immuno-inflammatory, oxidative and nitrosative stress, and neuroprogressive pathways in the etiology, course and treatment of schizophrenia. Prog Neuro-Psychopharmacol Biol Psychiatry 42:1–4. CrossRefGoogle Scholar
  2. Bogdan M, Popescu F, Bogdan F (2011) Contributions to the study of morphofunctional interrelations in the liver of the rats treated with certain antipsychotic drugs. Romanian J Morphol Embryol 52(1 Suppl):465–469Google Scholar
  3. Gumulec J, Raudenska M, Hlavna M, Stracina T, Sztalmachova M, Tanhauserova V, Pacal L, Ruttkay-Nedecky B, Sochor J, Zitka O, Babula P, Adam V, Kizek R, Novakova M, Masarik M (2013) Determination of oxidative stress and activities of antioxidant enzymes in Guinea pigs treated with haloperidol. Exp Ther Med 5(2):479–484. CrossRefGoogle Scholar
  4. Ivanov PA, Faktor MI, Karpova NS, Cheremnykh EG, Brusov OS (2016) Complement-mediated death of ciliate Tetrahymena pyriformis caused by human blood serum. Bull Exp Biol Med 160(6):775–778. CrossRefGoogle Scholar
  5. Kaminska T, Wysocka A, Marmurowska-Michalowska H, Dubas-Slemp H, Kandefer-Szerszen M (2001) Investigation of serum cytokine levels and cytokine production in whole blood cultures of paranoid schizophrenic patients. Arch Immunol Ther Exp 49:439–445Google Scholar
  6. Kehinde AJ (2017) Functional oil from black seed differentially inhibits aldose-reductase and Ectonucleotidase activities by up-regulating cellular energy in haloperidol-induced hepatic toxicity in rat liver. J Oleo Sci Sep1;66(9):1051–1060. CrossRefGoogle Scholar
  7. Kropp S, Kern V, Lange K, Degner D, Hajak G, Kornhuber J, Ruther E, Emrich HM, Schneider U, Bleich S (2005) Oxidative stress during treatment with first- and second-generation antipsychotics. J Neuropsychiatry Clin Neurosci 17(2):227–231. CrossRefGoogle Scholar
  8. Lourenço GA, Dorce VA, Palermo-Neto J (2005 May) Haloperidol treatments increased macrophage activity in male and female rats: influence of corticosterone and prolactin serum levels. Eur Neuropsychopharmacol 15(3):271–277. CrossRefGoogle Scholar
  9. Markiewski MM, Nilsson B, Ekdahl KN, Mollnes TE, Lambris JD.. Complement and coagulation:strangers or partners in crime? Trends Immunol, 2007; Vol.28(4):184–192. doi:
  10. McWhorter FY, Wang T, Nguyen P, Chung T, Liu WF (2013) Modulation of macrophage phenotype by cell shape. PNAS 110(43):17253–17258. CrossRefGoogle Scholar
  11. Miroshnichenko II, Baymeeva NV (2018) Simultaneous determination of antipsychotic drugs and their active metabolites by LC–MS-MS and its application to therapeutic drug monitoring. J Chromatogr Sci 56(6):510–517. CrossRefGoogle Scholar
  12. Müller N, Weidinger E, Leitner B, Schwarz MJ (2015) The role of inflammation in schizophrenia. Front Neurosci 9:372. CrossRefGoogle Scholar
  13. Murray M (2006) Role of CYP pharmacogenetics and drug-drug interactions in the efficacy and safety of atypical and other antipsychotic agents. J Pharm Pharmacol 58(7):871–885. CrossRefGoogle Scholar
  14. Polydoro M, Schroder N, Lima MNM, Caldana F, Laranja DC, Bromberg E, Roesler R, Quevedo J, Moreira JCF, Dal-Pizzol F (2004) Haloperidol- and clozapine-induced oxidative stress in the rat brain. Pharmacol Biochem Behav 78(4):751–756. CrossRefGoogle Scholar
  15. Schmidt AJ, Hemmeter UM, Krieg JC, Vedder H, Heiser P (2009) Impact of haloperidol and quetiapine on the expression of genes encoding antioxidant enzymes in human neuroblastoma SH-SY5Y cells. J Psychiatr Res 43(8):818–823. CrossRefGoogle Scholar
  16. Takahide O (2018) Grl1 protein is a candidate K antigen in Tetrahymena thermophila. Protist 169(3):321–332. CrossRefGoogle Scholar
  17. Tarique AA, Logan J, Thomas E, Holt PG, Sly P, Fantino E (2015) Phenotypic, functional, and plasticity features of classical and alternatively activated human macrophages. Am J Respir Cell Mol Biol 53(5):676–688. CrossRefGoogle Scholar
  18. Wolfe J (1986) Analysis of tetrahymena mucocyst material with lectins and alcian blue. J Eukaryot Microbiol 35(1):46–51 February 1988. Google Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Mental Health Research CenterMoscowRussia

Personalised recommendations