SummaryThe metabolic pathways of chlorpromazine (CPZ) toxicity were tracked by assessing oxidative/nitrosative stress markers. The main objective of the study was to test the hypothesis that agmatine (AGM) prevents oxidative/nitrosative stress in the liver of Wistar rats 15 days after administration of CPZ. All tested substances were administered intraperitoneally (i.p.) for 15 consecutive days. The rats were divided into four groups: the control group (C, 0.9 % saline solution), the CPZ group (CPZ, 38.7 mg/kg b.w.), the CPZ+AGM group (AGM, 75 mg/kg b.w. immediately after CPZ, 38.7 mg/kg b.w. i.p.) and the AGM group (AGM, 75 mg/kg b.w.).Rats were decapitated 15 days after the appropriate treatment. In the CPZ group, CPZ concentration was significantly increased compared to C values (p<0.01), while AGM treatment induced the significant decrease in CPZ concentration in the CPZ+AGM group (p<0.05) and the AGM group (p<0.01). CPZ application to healthy rats did not lead to any changes of lipid peroxidation in the liver compared to the C group, but AGM treatment decreased that parameter compared to the CPZ group (p<0.05). In CPZ liver homogenates, nitrite and nitrate concentrations were increased compared to controls (p<0.001), and AGM treatment diminished that parameter in the CPZ group (p<0.05), as well as in the AGM group (p<0.001). In CPZ animals, glutathione level and catalase activity were decreased in comparison with C values (p<0.01 respectively), but AGM treatment increased the activity of catalase in comparison with CPZ animals (p<0.05 respectively). Western blot analysis supported biochemical findings in all groups. Our results showed that treatment with AGM significantly supressed the oxidative/nitrosative stress parameters and restored antioxidant defense in rat liver.
References
1.
Góth L. A simple method for determination of serum catalase activity and revision of reference range. Clinica Chimica Acta. 1991;196(2–3):143–51.
2.
Couée I, Tipton KF. The inhibition of glutamate dehydrogenase by some antipsychotic drugs. Biochemical Pharmacology. 1990;39(5):827–32.
3.
Lilic A, Dencic S, Pavlovic S, Blagojevic D, Spasic M, Stankovic N, et al. Activity of antioxidative defense enzymes in the blood of patients with liver echinococcosis. Vojnosanitetski pregled. 2007;64(4):235–40.
4.
Bannai S, Sato H, Ishii T, Taketani S. Enhancement of glutathione levels in mouse peritoneal macrophages by sodium arsenite, cadmium chloride and glucose/glucose oxidase. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1991;1092(2):175–9.
5.
Navarro-Gonzálvez JA, García-Benayas C, Arenas J. Semiautomated Measurement of Nitrate in Biological Fluids. Clinical Chemistry. 1998;44(3):679–81.
6.
Stanković MN, Mladenović D, Ninković M, Ðuričić I, Šobajić S, Jorgačević B, et al. The Effects ofα-Lipoic Acid on Liver Oxidative Stress and Free Fatty Acid Composition in Methionine–Choline Deficient Diet-Induced NAFLD. Journal of Medicinal Food. 2014;17(2):254–61.
7.
Parikh V, Khan MM, Mahadik SP. Differential effects of antipsychotics on expression of antioxidant enzymes and membrane lipid peroxidation in rat brain. Journal of Psychiatric Research. 2003;37(1):43–51.
8.
Li T, Zhou Q, Zhang N, Luo Y. Toxic effects of chlorpromazine onCarassius auratusand its oxidative stress. Journal of Environmental Science and Health, Part B. 2008;43(8):638–43.
9.
Naidu PS, Singh A, Kulkarni SK. Carvedilol attenuates neuroleptic‐induced orofacial dyskinesia: possible antioxidant mechanisms. British Journal of Pharmacology. 2002;136(2):193–200.
10.
Ostojić JN, Mladenović D, Ninković M, Vučević D, Bondžić K, Ješić-Vukićević R, et al. The effects of cold-induced stress on liver oxidative injury during binge drinking. Human & Experimental Toxicology. 2012;31(4):387–96.
11.
Lores-Arnaiz S, D’Amico G, Czerniczyniec A, Bustamante J, Boveris A. Brain mitochondrial nitric oxide synthase: in vitro and in vivo inhibition by chlorpromazine. Archives of Biochemistry and Biophysics. 2004;430(2):170–7.
12.
Qi X ming, Miao L ling, Cai Y, Gong L kun, Ren J. ROS generated by CYP450, especially CYP2E1, mediate mitochondrial dysfunction induced by tetrandrine in rat hepatocytes. Acta Pharmacologica Sinica. 2013;34(9):1229–36.
13.
YABUKI M, TANI N, YOSIOKA T, NISHIBE H, KANAMARU H, KANEKO H. Local Thrombus Formation in the Site of Intravenous Injection of Chlorpromazine. Possible Colloid-Osmotic Lysis of the Local Endothelial Cells. Biological and Pharmaceutical Bulletin. 2000;23(8):957–61.
14.
Akyol Ö, Herken H, Uz E, Fadıllıoǧlu E, Ünal S, Söǧüt S, et al. The indices of endogenous oxidative and antioxidative processes in plasma from schizophrenic patients. Progress in Neuro-Psychopharmacology and Biological Psychiatry. 2002;26(5):995–1005.
15.
Cardillo S, Iuliis AD, Battaglia V, Toninello A, Stevanato R, Vianello F. Novel copper amine oxidase activity from rat liver mitochondria matrix. Archives of Biochemistry and Biophysics. 2009;485(2):97–101.
16.
Maslak E, Zabielski P, Kochan K, Kus K, Jasztal A, Sitek B, et al. The liver-selective NO donor, V-PYRRO/NO, protects against liver steatosis and improves postprandial glucose tolerance in mice fed high fat diet. Biochemical Pharmacology. 2015;93(3):389–400.
17.
Tukov FF, Maddox JF, Amacher DE, Bobrowski WF, Roth RA, Ganey PE. Modeling inflammation–drug interactions in vitro: A rat Kupffer cell-hepatocyte coculture system. Toxicology in Vitro. 2006;20(8):1488–99.
18.
Agostinelli E, Marques MPM, Calheiros R, Gil FPSC, Tempera G, Viceconte N, et al. Polyamines: fundamental characters in chemistry and biology. Amino Acids. 2010;38(2):393–403.
19.
Koek GH, Liedorp PR, Bast A. The role of oxidative stress in non-alcoholic steatohepatitis. Clinica Chimica Acta. 2011;412(15–16):1297–305.
20.
Lopert P, Patel M. Brain mitochondria from DJ-1 knockout mice show increased respiration-dependent hydrogen peroxide consumption. Redox Biology. 2014;2:667–72.
21.
Hassan HA, Yousef MI. Ameliorating effect of chicory (Cichorium intybus L.)-supplemented diet against nitrosamine precursors-induced liver injury and oxidative stress in male rats. Food and Chemical Toxicology. 2010;48(8–9):2163–9.
22.
DiCiero Miranda M, de Bruin VMS, Vale MR, Viana GSB. Lipid Peroxidation and Nitrite plus Nitrate Levels in Brain Tissue from Patients with Alzheimer’s Disease. Gerontology. 2000;46(4):179–84.
23.
Dejanovic B, Stevanovic I, Ninkovic M, Stojanovic I, Vukovic-Dejanovic V. Protective effect of agmatine in acute chlorpromazine hepatotoxicity in rats. Acta Veterinaria Brno. 2014;83(4):305–12.
24.
El-Agamy DS, Makled MN, Gamil NM. Protective effects of agmatine against d-galactosamine and lipopolysaccharide-induced fulminant hepatic failure in mice. Inflammopharmacology. 2014;22(3):187–94.
25.
Gurd JW, Jones LR, Mahler HR, Moore WJ. ISOLATION AND PARTIAL CHARACTERIZATION OF RAT BRAIN SYNAPTIC PLASMA MEMBRANES1. Journal of Neurochemistry. 1974;22(2):281–90.
26.
Balijepalli S, Kenchappa RS, Boyd MR, Ravindranath V. Protein thiol oxidation by haloperidol results in inhibition of mitochondrial complex I in brain regions: comparison with atypical antipsychotics. Neurochemistry International. 2001;38(5):425–35.
27.
Can C. Contradictory effects of chlorpromazine on endothelial cells in a rat model of endotoxic shock in association with its actions on serum TNF-α levels and antioxidant enzyme activities. Pharmacological Research. 2003;48(3):223–30.
28.
GIROTTI MJ, KHAN N, MCLELLAN BA. Early Measurement of Systemic Lipid Peroxidation Products in the Plasma of Major Blunt Trauma Patients. The Journal of Trauma: Injury, Infection, and Critical Care. 1991;31(1):32–5.
29.
Harry GJ, Schmitt TJ, Gong Z, Brown H, Zawia N, Evans HL. Lead-Induced Alterations of Glial Fibrillary Acidic Protein (GFAP) in the Developing Rat Brain. Toxicology and Applied Pharmacology. 1996;139(1):84–93.
30.
Kelder PP, Fischer MJE, de Mol NJ, Janssen LHM. Oxidation of chlorpromazine by methemoglobin in the presence of hydrogen peroxide. Formation of chlorpromazine radical cation and its covalent binding to methemoglobin. Archives of Biochemistry and Biophysics. 1991;284(2):313–9.
The statements, opinions and data contained in the journal are solely those of the individual authors and contributors and not of the publisher and the editor(s). We stay neutral with regard to jurisdictional claims in published maps and institutional affiliations.
