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.

Department of Pathological Physiology Faculty of Medicine; Brno University of Technology Brno Czech Republic

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Janssen PA, Soudijn W, van Wijngaarden I, 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. 1968;18:282–287. PubMed

Ikemura M, Nakagawa Y, Shinone K, Inoue H, Nata M. The blood concentration and organ distribution of haloperidol at therapeutic and toxic doses in severe fatty liver disease. Leg Med (Tokyo) 2012;14:147–153. PubMed

Maxa JL, Taleghani AM, Ogu CC, Tanzi M. Possible toxic encephalopathy following high-dose intravenous haloperidol. Ann Pharmacother. 1997;31:736–737. PubMed

Tsujimoto A, Tsujimoto G, Ishizaki T, Nakazawa S, Ichihashi Y. Toxic haloperidol reactions with observation of serum haloperidol concentration in two children. Dev Pharmacol Ther. 1982;4:12–17. PubMed

Engel N, Mahlknecht U. Aging and anti-aging: Unexpected side effects of everyday medication through sirtuin1 modulation. Int J Mol Med. 2008;21:223–232. PubMed

Huang QY, Li XF, Liu SP. E-cadherin and caveolin-1 alterations in the heart of rats having undergone chlorpromazine-induced toxicity. Mol Med Rep. 2012;5:705–709. PubMed

Breier A, Schreiber JL, Dyer J, Pickar D. National Institute of Mental Health longitudinal study of chronic schizophrenia. Prognosis and predictors of outcome. Arch Gen Psychiatry. 1991;48:239–246. PubMed

Baldessarini RJ, Cohen BM, Teicher MH. Significance of neuroleptic dose and plasma level in the pharmacological treatment of psychoses. Arch Gen Psychiatry. 1988;45:79–91. PubMed

Levenson JL. Neuroleptic malignant syndrome. Am J Psychiatry. 1985;142:1137–1145. PubMed

Gorrod JW, Fang J. On the metabolism of haloperidol. Xenobiotica. 1993;23:495–508. PubMed

Wright AM, Bempong J, Kirby ML, Barlow RL, Bloomquist JR. Effects of haloperidol metabolites on neurotransmitter uptake and release: possible role in neurotoxicity and tardive dyskinesia. Brain Res. 1998;788:215–222. PubMed

Forsman A, Larsson M. Metabolism of haloperidol. Curr Ther Res Clin Exp. 1978;24:567–568.

Fang J, Baker GB, Silverstone PH, Coutts RT. Involvement of CYP3A4 and CYP2D6 in the metabolism of haloperidol. Cell Mol Neurobiol. 1997;17:227–233. PubMed

Eyles DW, McGrath JJ, Pond SM. Formation of pyridinium species of haloperidol in human liver and brain. Psychopharmacology (Berl) 1996;125:214–219. PubMed

Korpi ER, Costakos DT, Wyatt RJ. Rapid formation of reduced haloperidol in guinea pigs following haloperidol administration. Acta Pharmacol Toxicol (Copenh) 1985;56:94–98. PubMed

Burkhardt C, Kelly JP, Lim YH, Filley CM, Parker WD. Neuroleptic medications inhibit complex I of the electron transport chain. Ann Neurol. 1993;33:512–517. PubMed

Shivakumar BR, Ravindranath V. Oxidative stress and thiol modification induced by chronic administration of haloperidol. J Pharmacol Exp Ther. 1993;265:1137–1141. PubMed

Behl C, Lezoualc’h F, Widmann M, Rupprecht R, Holsboer F. Oxidative stress-resistant cells are protected against haloperidol toxicity. Brain Res. 1996;717:193–195. PubMed

Peet M, Laugharne J, Rangarajan N, Reynolds GP. Tardive dyskinesia, lipid peroxidation, and sustained amelioration with vitamin E treatment. Int Clin Psychopharmacol. 1993;8:151–153. PubMed

Pai BN, Janakiramaiah N, Gangadhar BN, Ravindranath V. Depletion of glutathione and enhanced lipid peroxidation in the CSF of acute psychotics following haloperidol administration. Biol Psychiatry. 1994;36:489–491. PubMed

Sochor J, Ryvolova M, Krystofova O, et al. Fully automated spectrometric protocols for determination of antioxidant activity: advantages and disadvantages. Molecules. 2010;15:8618–8640. PubMed PMC

Lawler JM, Powers SK. Oxidative stress, antioxidant status, and the contracting diaphragm. Can J Appl Physiol. 1998;23:23–55. PubMed

Vaziri ND, Dicus M, Ho ND, Boroujerdi-Rad L, Sindhu RK. Oxidative stress and dysregulation of superoxide dismutase and NADPH oxidase in renal insufficiency. Kidney Int. 2003;63:179–185. PubMed

Salinas AE, Wong MG. Glutathione S-transferases - a review. Curr Med Chem. 1999;6:279–309. PubMed

Tan KL, Board PG. Purification and characterization of a recombinant human Theta-class glutathione transferase (GSTT2-2) Biochem J. 1996;315:727–732. PubMed PMC

Hubatsch I, Ridderström M, 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. 1998;330:175–179. PubMed PMC

Adler V, Yin ZM, Fuchs SY, et al. Regulation of JNK signaling by GSTp. EMBO J. 1999;18:1321–1334. PubMed PMC

Seeman PM, Bialy HS. The surface activity of tranquilizers. Biochem Pharmacol. 1963;12:1181–1191. PubMed