Determination of oxidative stress and activities of antioxidant enzymes in guinea pigs treated with haloperidol

Gumulec,Jaromir; Raudenska,Martina; Hlavna,Marian; Stracina,Tibor; Sztalmachova,Marketa; Tanhauserova,Veronika; Pacal,Lukas; Ruttkay‑Nedecky,Branislav; Sochor,Jiri; Zitka,Ondrej; Babula,Petr; Adam,Vojtech; Kizek,Rene; Novakova,Marie; Masarik,Michal

doi:10.3892/etm.2012.822

Determination of oxidative stress and activities of antioxidant enzymes in guinea pigs treated with haloperidol

Authors:
- Jaromir Gumulec
- Martina Raudenska
- Marian Hlavna
- Tibor Stracina
- Marketa Sztalmachova
- Veronika Tanhauserova
- Lukas Pacal
- Branislav Ruttkay‑Nedecky
- Jiri Sochor
- Ondrej Zitka
- Petr Babula
- Vojtech Adam
- Rene Kizek
- Marie Novakova
- Michal Masarik
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Affiliations: Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic, Department of Physiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic, Department of Chemistry and Biochemistry, Faculty of Agronomy, Mendel University in Brno, Brno, Czech Republic, Department of Natural Drugs, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences, Brno, Czech Republic
Published online on: November 20, 2012 https://doi.org/10.3892/etm.2012.822
Pages: 479-484

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Abstract

Guinea pigs (Cavia porcellus) were treated with haloperidol (HP), and free radical (FR) and ferric reducing antioxidant power (FRAP) assays were used to determine oxidative stress levels. Furthermore, the superoxide dismutase (SOD), glutathione reductase (GR) and glutathione‑S‑transferase (GST) activity levels were detected and glucose levels and the reduced and oxidized glutathione (GSH/GSSG) ratio were measured in HP‑treated and untreated guinea pigs. The present study demonstrated that the administration of HP causes significant oxidative stress in guinea pigs (P=0.022). In animals treated with HP, the activity of GST was significantly increased compared with a placebo (P=0.007). The elevation of SOD and GR activity levels and increase in the levels of glutathione (GSH) in HP‑treated animals were not statistically significant. In the HP‑untreated animals, a significant positive correlation was observed between oxidative stress detected by the FR method and GST (r=0.88, P=0.008) and SOD (r=0.86, P=0.01) activity levels, respectively. A significant negative correlation between the levels of plasma glucose and oxidative stress detected by the FRAP method was observed (r=‑0.78, P=0.04). Notably, no significant correlations were observed in the treated animals. In the HP‑treated group, two subgroups of animals were identified according to their responses to oxidative stress. The group with higher levels of plasma HP had higher enzyme activity and reactive oxygen species production compared with the group with lower plasma levels of HP. The greatest difference in activity (U/µl) between the two groups of animals was for GR.

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1.	Janssen PA, Soudijn W, van Wijngaarden I and Dresse A: Pimozide, a chemically novel highly potent and orally long-acting neuroleptic drug. 3. Regional distribution of pimozide and of haloperidol in dog brain. Arzneimittelforschung. 18:282–287. 1968.PubMed/NCBI
2.	Ikemura M, Nakagawa Y, Shinone K, Inoue H and Nata M: The blood concentration and organ distribution of haloperidol at therapeutic and toxic doses in severe fatty liver disease. Leg Med (Tokyo). 14:147–153. 2012. View Article : Google Scholar : PubMed/NCBI
3.	Maxa JL, Taleghani AM, Ogu CC and Tanzi M: Possible toxic encephalopathy following high-dose intravenous haloperidol. Ann Pharmacother. 31:736–737. 1997.PubMed/NCBI
4.	Tsujimoto A, Tsujimoto G, Ishizaki T, Nakazawa S and Ichihashi Y: Toxic haloperidol reactions with observation of serum haloperidol concentration in two children. Dev Pharmacol Ther. 4:12–17. 1982.PubMed/NCBI
5.	Engel N and Mahlknecht U: Aging and anti-aging: Unexpected side effects of everyday medication through sirtuin1 modulation. Int J Mol Med. 21:223–232. 2008.PubMed/NCBI
6.	Huang QY, Li XF and Liu SP: E-cadherin and caveolin-1 alterations in the heart of rats having undergone chlorpromazine-induced toxicity. Mol Med Rep. 5:705–709. 2012.PubMed/NCBI
7.	Breier A, Schreiber JL, Dyer J and Pickar D: National Institute of Mental Health longitudinal study of chronic schizophrenia. Prognosis and predictors of outcome. Arch Gen Psychiatry. 48:239–246. 1991. View Article : Google Scholar : PubMed/NCBI
8.	Baldessarini RJ, Cohen BM and Teicher MH: Significance of neuroleptic dose and plasma level in the pharmacological treatment of psychoses. Arch Gen Psychiatry. 45:79–91. 1988. View Article : Google Scholar : PubMed/NCBI
9.	Levenson JL: Neuroleptic malignant syndrome. Am J Psychiatry. 142:1137–1145. 1985. View Article : Google Scholar : PubMed/NCBI
10.	Gorrod JW and Fang J: On the metabolism of haloperidol. Xenobiotica. 23:495–508. 1993. View Article : Google Scholar : PubMed/NCBI
11.	Wright AM, Bempong J, Kirby ML, Barlow RL and Bloomquist JR: Effects of haloperidol metabolites on neurotransmitter uptake and release: possible role in neurotoxicity and tardive dyskinesia. Brain Res. 788:215–222. 1998. View Article : Google Scholar : PubMed/NCBI
12.	Forsman A and Larsson M: Metabolism of haloperidol. Curr Ther Res Clin Exp. 24:567–568. 1978.
13.	Fang J, Baker GB, Silverstone PH and Coutts RT: Involvement of CYP3A4 and CYP2D6 in the metabolism of haloperidol. Cell Mol Neurobiol. 17:227–233. 1997. View Article : Google Scholar : PubMed/NCBI
14.	Eyles DW, McGrath JJ and Pond SM: Formation of pyridinium species of haloperidol in human liver and brain. Psychopharmacology (Berl). 125:214–219. 1996. View Article : Google Scholar : PubMed/NCBI
15.	Korpi ER, Costakos DT and Wyatt RJ: Rapid formation of reduced haloperidol in guinea pigs following haloperidol administration. Acta Pharmacol Toxicol (Copenh). 56:94–98. 1985. View Article : Google Scholar : PubMed/NCBI
16.	Burkhardt C, Kelly JP, Lim YH, Filley CM and Parker WD: Neuroleptic medications inhibit complex I of the electron transport chain. Ann Neurol. 33:512–517. 1993. View Article : Google Scholar : PubMed/NCBI
17.	Shivakumar BR and Ravindranath V: Oxidative stress and thiol modification induced by chronic administration of haloperidol. J Pharmacol Exp Ther. 265:1137–1141. 1993.PubMed/NCBI
18.	Behl C, Lezoualc’h F, Widmann M, Rupprecht R and Holsboer F: Oxidative stress-resistant cells are protected against haloperidol toxicity. Brain Res. 717:193–195. 1996. View Article : Google Scholar : PubMed/NCBI
19.	Peet M, Laugharne J, Rangarajan N and Reynolds GP: Tardive dyskinesia, lipid peroxidation, and sustained amelioration with vitamin E treatment. Int Clin Psychopharmacol. 8:151–153. 1993. View Article : Google Scholar : PubMed/NCBI
20.	Pai BN, Janakiramaiah N, Gangadhar BN and Ravindranath V: Depletion of glutathione and enhanced lipid peroxidation in the CSF of acute psychotics following haloperidol administration. Biol Psychiatry. 36:489–491. 1994. View Article : Google Scholar : PubMed/NCBI
21.	Sochor J, Ryvolova M, Krystofova O, et al: Fully automated spectrometric protocols for determination of antioxidant activity: advantages and disadvantages. Molecules. 15:8618–8640. 2010. View Article : Google Scholar : PubMed/NCBI
22.	Lawler JM and Powers SK: Oxidative stress, antioxidant status, and the contracting diaphragm. Can J Appl Physiol. 23:23–55. 1998. View Article : Google Scholar : PubMed/NCBI
23.	Vaziri ND, Dicus M, Ho ND, Boroujerdi-Rad L and Sindhu RK: Oxidative stress and dysregulation of superoxide dismutase and NADPH oxidase in renal insufficiency. Kidney Int. 63:179–185. 2003. View Article : Google Scholar : PubMed/NCBI
24.	Salinas AE and Wong MG: Glutathione S-transferases - a review. Curr Med Chem. 6:279–309. 1999.
25.	Tan KL and Board PG: Purification and characterization of a recombinant human Theta-class glutathione transferase (GSTT2-2). Biochem J. 315:727–732. 1996.PubMed/NCBI
26.	Hubatsch I, Ridderström M and Mannervik B: Human glutathione transferase A4-4: an alpha class enzyme with high catalytic efficiency in the conjugation of 4-hydroxynonenal and other genotoxic products of lipid peroxidation. Biochem J. 330:175–179. 1998.
27.	Adler V, Yin ZM, Fuchs SY, et al: Regulation of JNK signaling by GSTp. EMBO J. 18:1321–1334. 1999. View Article : Google Scholar : PubMed/NCBI
28.	Seeman PM and Bialy HS: The surface activity of tranquilizers. Biochem Pharmacol. 12:1181–1191. 1963. View Article : Google Scholar : PubMed/NCBI