Veterinary Research Forum
Vet Res Forum

Pro-oxidant and degenerative effects of haloperidol under inflammatory conditions in rat; the involvement of SIRT1 and NF-κB signaling pathways

Document Type : Original Article

Authors

Saman Bahrambeigi 1
Mahsa Khatamnezhad 1
Siamak Asri-Rezaei 1
Bahram Dalir-Naghadeh 1
Shahram Javadi 1
Navideh Mirzakhani 2

1 Department of Internal Medicine and Clinical Pathology, Faculty of Veterinary Medicine, Urmia University, Urmia, Iran

2 Department of Pathobiology, Faculty of Veterinary Medicine, Amol University of Special Modern Technologies, Amol ,Iran

https://doi.org/10.30466/vrf.2019.105811.2514
Abstract
The present study was conducted to evaluate the effects of different doses of haloperidol (HP) on induction of oxidative stress in blood and liver cell degeneration in comparison with influences of HP pre-treatment on inflammatory process induced by intraperitoneal (IP) administration of lipopolysaccharide (LPS). One hundred twenty male albino Wistar rats were randomly divided into eight groups (15 in each), including: Control group, LPS group, three groups as HP administration in three divided doses (0.50, 1.00 and 2.00 mg kg-1), and three treatment groups that HP was administered in three doses (0.50, 1.00 and 2.00 mg kg-1) prior to LPS administration.Concentrations of malondialdehyde, activities of antioxidant enzymes including glutathione peroxidase, superoxide dismutase and also the levels of tumor necrosis factor-alpha and interleukin 1-beta were measured in blood and serum. In addition to liver histopathological changes evaluation, hepatic silent information regulator of transcription 1 (SIRT1) and phosphorylated-nuclear factor-κB (p-NF-κB) levels were quantitated. Our findings indicated that sole administration of HP (particularly higher doses) can induce oxidative stress in blood and cell degeneration in liver, while it can attenuate inflammatory process induced by LPS administration presumably via SIRT1 up-regulation and preventing the induction of p-NF-κB. The oxidative and degenerative effects of HP and its impact on inflammatory status were completely dose- dependent according to our results. The possible anti-inflammatory effects of HP may affect reparative mechanisms and hepatic cell degeneration. However, the influences of HP on immune system need further investigations and its higher doses should be administered cautiously especially in patients with immune system dysfunctions.

Keywords

Haloperidol
Lipopolysaccharide
NF-κB
Oxidative stress
SIRT1
  1. Singh OP, Chakraborty I, Dasgupta A, et al. A comparative study of oxidative stress and inter-relationship of important antioxidants in haloperidol and olanzapine treated patients suffering from schizophrenia. Indian J Psychiatry 2008; 50(3): 171-176.
  2. Polydoro M, Schröder N, Lima MNM, et al. Haloperidol-and clozapine-induced oxidative stress in the rat brain. Pharmacol Biochem Behav 2004; 78(4): 751-756.
  3. Perera J, Tan JH, Jeevathayaparan S, et al. Neuro-protective effects of alpha lipoic acid on haloperidol-induced oxidative stress in the rat brain. Cell Biosci 2011; 1 (1): 12. doi: 10.1186/2045-3701-1-12.
  4. Vairetti M, Ferrigno A, Canonico PL, et al. Nicergoline reverts haloperidol-induced loss of detoxifying-enzyme activity. Eur J Pharmacol 2004; 505(1-3): 121-125.
  5. Andreazza AC, Barakauskas VE, Fazeli S, et al. Effects of haloperidol and clozapine administration on oxidative stress in rat brain, liver and serum. Neurosci Lett 2015; 591: 36-40.
  6. El-Awdan SA, Abdel Jaleel GA, Saleh DO. Alleviation of haloperidol induced oxidative stress in rats: Effects of sucrose vs grape seed extract. Bull Fac Pharm Cairo Univ 2015; 53(1): 29-35.
  7. Halici Z, Dursun H, Keles ON, et al. Effect of chronic treatment of haloperidol on the rat liver: a stereological and histopathological study. Naunyn Schmiedebergs Arch Pharmacol. 2009; 379(3): 253-261
  8. Vilner BJ, Bowen WD. Sigma receptor-active neuro-leptics are cytotoxic to C6 glioma cells in culture. Eur J Pharmacol 1993; 244(2): 199-201.
  9. Sivrioglu EY, Kirli S, Sipahioglu D, et al. The impact of omega-3 fatty acids, vitamins E and C supplementation on treatment outcome and side effects in schizo-phrenia patients treated with haloperidol: an open-label pilot study. Prog Neuropsychopharmacol Biol Psychiatry 2007; 31(7): 1493-1499.
  10. Bowen WD, Moses EL, Tolentino PJ, et al. Metabolites of haloperidol display preferential activity at sigma receptors compared to dopamine D-2 receptors. Eur J Pharmacol 1990; 177(3): 111-118.
  11. Yamamoto S, Ohta N, Matsumoto A, et al. Haloperidol suppresses NF-kappaB to inhibit lipopolysaccharide-induced pro-inflammatory response in raw 264 cells. Med Sci Monit 2016; 22: 367-372.
  12. Chen ML, Tsai TC, Lin YY, et al. Antipsychotic drugs suppress the AKT/NF-κB pathway and regulate the differentiation of T-cell subsets. Immunol Lett 2011; 140(1-2): 81-91.
  13. Wahba MGF, Messiha BAS, Abo-Saif AA. Ramipril and haloperidol as promising approaches in managing rheumatoid arthritis in rats. Eur J Pharmacol 2015; 765: 307-315.
  14. Bosshart H. Supra-therapeutic plasma concentrations of haloperidol induce moderate inhibition of lipopoly-saccharide-induced interleukin-8 release in human monocytes. Ann Transl Med 2016; 4(20):396. doi: 10.21037/atm.2016.10.56
  15. Khaziakhmetova V, Baiysbekov K, Torobekov S, et al. The effects of haloperidol on acute carrageenan-induced inflammation. Bionanoscience 2017; 7: 442-445.
  16. Khaziakhmetova V, Miryakupova S, Dzhamalbekov A, et al. The effects of haloperidol on the progression of chronic autoimmune inflammation induced by Freund’s adjuvant. Bionanoscience 2017; 7: 428-430.
  17. Iacovitti L, Stull ND, Mishizen A. Neurotransmitters, KCl and antioxidants rescue striatal neurons from apoptotic cell death in culture. Brain Res 1999; 816(2): 276-285.
  18. Amano T, Ujihara H, Matsubayashi H, et al. Dopamine-induced protection of striatal neurons against kainate receptor-mediated glutamate cytotoxicity in vitro. Brain Res 1994; 655(1-2): 61-69.
  19. Cosentino M, Rasini E, Colombo C, et al. Dopaminergic modulation of oxidative stress and apoptosis in human peripheral blood lymphocytes: evidence for a D1-like receptor-dependent protective effect. Free Radic Biol Med 2004; 36(10): 1233-1240.
  20. Ruiz-Miyazawa KW, Pinho-Ribeiro FA, Zarpelon AC, et al. Vinpocetine reduces lipopolysaccharide-induced inflammatory pain and neutrophil recruitment in mice by targeting oxidative stress, cytokines and NF-κB. Chem Biol Intract 2015; 237: 9-17.
  21. Goraca A, Piechota A, Huk-Kolega H. Effect of alpha-lipoic acid on LPS-induced oxidative stress in the heart. J Physiol Pharmacol.2009; 60(1): 61-68.
  22. Hamesch K, Borkham-Kamphorst E, Strnad P, et al. Lipopolysaccharide-induced inflammatory liver injury in mice. Lab Anim 2015; 49(1 Suppl): 37-46.
  23. Wang H, Xu D-X, Lv J-W, et al. Melatonin attenuates lipopolysaccharide (LPS)-induced apoptotic liver damage in D-galactosamine-sensitized mice. Toxico-logy 2007; 237(1-3): 49-57.
  24. Daitoku H, Hatta M, Matsuzaki H, et al. Silent information regulator 2 potentiates Foxo1-mediated transcription through its deacetylase activity. Proc Natl Acad Sci U S A 2004; 101(27): 10042-10047.
  25. Tong C, Morrison A, Mattison S, et al. Impaired SIRT1 nucleocytoplasmic shuttling in the senescent heart during ischemic stress. FASEB J 2013; 27(11): 4332-4342.
  26. Kauppinen A, Suuronen T, Ojala J, et al. Antagonistic crosstalk between NF-κB and SIRT1 in the regulation of inflammation and metabolic disorders. Cell Signal 2013; 25(10): 1939-1948.
  27. Yang H, Zhang W, Pan H, et al. SIRT1 activators suppress inflammatory responses through promotion of p65 deacetylation and inhibition of NF-κB activity. PloS One 2012; 7(9): e46364. doi: 10.1371/journal. pone.0046364.
  28. Yang H, Feldser HG, Zhang W, et al. SIRT1 activators promote p65 deacetylation and suppress TNFa stimulated Nf-Kb activation. The FASEB Journal 2011:25 (S1): 945.12-945.12
  29. Telles-Correia D, Barbosa A, Cortez-Pinto H, et al. Psychotropic drugs and liver disease: A critical review of pharmacokinetics and liver toxicity. World J Gastrointest Pharmacol Ther 2017; 8(1): 26-38.
  30. Froemming JS, Lam YWF, Jann MW, et al. Pharmacokinetics of haloperidol. Clin Pharmacokinet 1989; 17(6): 396-423.
  31. Chang WH, Lin SK, Jann MW, et al. Pharmacodynamics and pharmacokinetics of haloperidol and reduced haloperidol in schizophrenic patients. Biol Psychiatry 1989; 26(3): 239-249.
  32. Terry Jr AV, Gearhart DA, Warner SE, et al. Oral haloperidol or risperidone treatment in rats: temporal effects on nerve growth factor receptors, cholinergic neurons, and memory performance. Neuroscience 2007; 146(3): 1316-1332.
  33. Romanovsky AA, Kulchitsky VA, Akulich NV, et al. First and second phases of biphasic fever: two sequential stages of the sickness syndrome? Am J Physiol 1996; 271(1 pt 2): R244-R253.
  34. Steiner AA, Chakravarty S, Rudaya AY, et al. Bacterial lipopolysaccharide fever is initiated via Toll-like receptor 4 on hematopoietic cells. Blood 2006; 107 (10): 4000-4002.
  35. Gibson-Corley KN, Olivier AK, Meyerholz DK. Principles for valid histopathologic scoring in research. Vet Pathol 2013; 50(6): 1007-1015.
  36. Valko M, Rhodes CJ, Moncol J, et al. Free radicals, metals and antioxidants in oxidative stress-induced cancer. Chem Biol Interact 2006; 160(1): 1-40. doi: 10.1016/ j.cbi.2005.12.009.
  37. King T. Cell injury, cellular responses to injury, and cell death. In: King T. (Ed). Elsevier's integrated pathology. 1st ed. Philadelphia, USA: Mosby, 2007; 1-20
  38. Xia Z-B, Meng F-R, Fang Y-X, et al. Inhibition of NF-κB signaling pathway induces apoptosis and suppresses proliferation and angiogenesis of human fibroblast-like synovial cells in rheumatoid arthritis. Medicine (Baltimore) 2018; 97(23): e10920. doi: 10.1097/MD. 0000000000010920
  39. Cui X, Shen D, Kong C, et al. NF-κB suppresses apoptosis and promotes bladder cancer cell proliferation by upregulating survivin expression in vitro and in vivo. Sci Rep 2017; 7: 40723. doi: 10.1038/srep40723
  40. Alexander HR, Doherty GM, Buresh CM, et al. A Recombinant human receptor antagonist to interleukin 1 improves survival after lethal endotoxemia in mice. J Exp Med 1991; 173(4): 1029-1032.
  41. Hesse DG, Tracey KJ, Fong Y, et al. Cytokine appearance in human endotoxemia and primate bacteremia. Surg Gynecol Obstet. 1988; 166(2): 147-153.
  42. Mathison JC, Wolfson E, Ulevitch RJ. Participation of tumor necrosis factor in the mediation of gram negative bacterial lipopolysaccharide-induced injury in rabbits. J Clin Invest 1988; 81(6): 1925-1937.
  43. Michie HR, Manogue KR, Spriggs DR, et al. Detection of circulating tumor necrosis factor after endotoxin administration. N Engl J Med 1988; 318(23): 1481-1486.
  44. Tracey KJ, Fong Y, Hesse DG, et al. Anti-cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteraemia. Nature 1987; 330(6149): 662-664.
  45. Copeland S, Warren HS, Lowry SF, et al. Acute inflammatory response to endotoxin in mice and humans. Clin Diagn Lab Immunol 2005; 12(1): 60-67.
  46. Miyazaki S, Ishikawa F, Fujikawa T, et al. Intra-peritoneal injection of lipopolysaccharide induces dynamic migration of Gr-1high polymorphonuclear neutrophils in the murine abdominal cavity. Clin Diagn Lab Immunol 2004; 11(3): 452-457.
  47. Matalka KZ, Tutunji MF, Abu-Baker M, et al. Measurement of protein cytokines in tissue extracts by enzyme-linked immunosorbent assays: application to lipopolysaccharide-induced differential milieu of cytokines. Neuro Endocrinol Lett 2005; 26(3): 231-236.
  48. Lukacs NW, Strieter RM, Kunkel SL. Cytokines in acute Inflammation. Curr Opin Hematol 1993; 1993: 21-30.
  49. Wei FC, Jann MW, Lin HN, et al. A practical loading dose method for converting schizophrenic patients from oral to depot haloperidol therapy. J Clin Psychiatry 1996; 57(7): 298-302.
  50. Sun T, Zhang Y, Zhong S, et al. N-n-butyl haloperidol iodide, a derivative of the anti-psychotic haloperidol, antagonizes hypoxia/reoxygenation injury by inhibiting an Egr-1/ROS positive feedback loop in H9c2 cells. Front Pharmacol 2018; 9: 19. doi: 10.3389/ fphar.2018.00019.
Veterinary Research Forum
Volume 12, Issue 2
Spring 2021
Pages 175-183

  • Receive Date 05 April 2019
  • Revise Date 17 June 2019
  • Accept Date 09 July 2019

Home

Guide for Authors

Submit Manuscript

Reviewers

Contact Us