Agmatine reduces chlorpromazine prooxidant effects in rat hippocampus and striatum


  • Bratislav Dejanović Military Medical Academy, Institute of Medical Biochemistry, 11000 Belgrade, Serbia
  • Vesna Begović-Kuprešanin Clinic for Infectious and Tropic Diseases, Military Medical Academy, Belgrade, Serbia
  • Ivana Stevanović Medical Faculty of Military Medical Academy, University of Defense, Institute of Medical Research, Military Medical Academy, 11000 Belgrade, Serbia
  • Irena Lavrnja Institute for Biological Research “Sinisa Stanković” – National Institute of Republic of Serbia, University of Belgrade, 11000 Belgrade, Serbia
  • Branka Šošić-Jurjević Institute for Biological Research “Sinisa Stanković” – National Institute of Republic of Serbia, University of Belgrade, 11000 Belgrade, Serbia
  • Milica Ninković Medical Faculty of Military Medical Academy, University of Defense, Institute of Medical Research, Military Medical Academy, 11000 Belgrade, Serbia
  • Svetlana Trifunović Institute for Biological Research “Sinisa Stanković” – National Institute of Republic of Serbia, University of Belgrade, 11000 Belgrade, Serbia



chlorpromazine, agmatine, oxidative stress, hippocampus, striatum


Paper description:

  • Administration of the antidepressant drug chlorpromazine is linked to increased oxidative stress in the hippocampus and striatum. Agmatine is an adjunct to chlorpromazine therapy used to neutralize its side effects.
  • The ability of agmatine to diminish chlorpromazine prooxidant effects was examined in male rats. Antioxidant enzyme activities were measured in the hippocampus and striatum.
  • Combined chlorpromazine/agmatine treatment decreased the pro-oxidative effects of chlorpromazine.
  • These results validate the coadministration of chlorpromazine and agmatine as a treatment strategy.

Abstract: The use of the antidepressant drug chlorpromazine (CPZ) is linked to the occurrence of oxidative stress in some brain structures. Thus, overcoming the side effects of CPZ is of great importance. Because agmatine (AGM) can act as a free radical scavenger, it is an interesting compound as an adjunct to CPZ therapy. The aim of our study was to investigate the enzymatic parameters of oxidative stress in the hippocampus and striatum of rats after CPZ treatment, and the potential protective effects of AGM. Rats were injected as follows with (i) 1 mL/kg b.w. saline; (ii) a single intraperitoneal (i.p.) dose of CPZ (38.7 mg/kg); (iii) CPZ (38.7 mg/kg) and AGM (75 mg/kg); (iv) AGM (75 mg/kg). CPZ induced an increase in superoxide anion radical (O2•-) concentration, while the activities of the antioxidant enzymes, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione reductase (GR), were lowered in both the hippocampus and striatum. Cotreatment with CPZ and AGM protected the examined brain structures by reversing the antioxidant enzyme activities to the control values. Following CPZ treatment, the effects were more pronounced for SOD and GPx in the hippocampus, and for SOD, CAT and GPx in the striatum. The full effect of restored superoxide production was achieved in the striatum, which points to the role of CAT. The obtained results suggest that CPZ in combination with AGM may be considered as a new treatment strategy.


Download data is not yet available.


Van Os J, Kenis G, Rutten BPF. The environment and schizophrenia. Nature. 2010;468:203-12.

Brunton L, Chabner B, Knollman B. Goodman and Gilman’s the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill Professional; 2010. 1984 p.

Breitbart W, Marotta R, Platt MM, Weisman H, Derevenco M, Grau C, Corbera K, Raymond S, Lund S, Jacobson P. A double-blind trial of haloperidol, chlorpromazine, and lorazepam in the treatment of delirium in hospitalized AIDS patients. Am J Psychiatry. 1996;153(2):231-7.

Seeman P, Lee T. Antipsychotic drugs: Direct correlation between clinical potency and presynaptic action on dopamine neurons. Science. 1975;188:1217-9.

Patterson A, Schenk O. Effects of acute and chronic systemic administration of some typical antipsychotic drugs on turnover of dopamine and potassium ion induced release of dopamine in the striatum of the rat in vivo. Neuropharmacol. 1991;30:943-52.

Henderson DC. Schizophrenia and comorbid metabolic disorders. J Clin Psychiatry. 2005;66(6):11-20.

McIntyre S, McCann M, Kennedy H. Antipsychotic metabolic effects: weight gain, diabetes mellitus, and lipid abnormalities. Can J Psychiatry. 2001;46(3):273-81.

Newcomer JW. Abnormalities of glucose metabolism associated with atypical antipsychotic drugs. J Clin Psychiatry. 2004;65(18):36-46.

Lohr B, Underhill S, Moir S, Jeste D. Increased indices of free radical activity in the cerebrospinal fluid of patients with tardive dyskinesia. Biol Psychiatry. 1990;28:535-9.

Peet M, Laugharne J, Rangarajan N, Reynolds P. Tardive dyskinesia, lipid peroxidation, and sustained amelioration with vitamin E treatment. Int Clin Psychopharmacol. 1993;8:(3)151-3.

Parikh V, Khan M, Mahadik S. Differential effects of antipsychotics on expression of antioxidant enzymes and membrane lipid peroxidation in rat brain. J Psychiatr Res. 2003;37:43-51.

Atama C, Nnaji E, Ezeoyili I, Udeani F, Onovo C, Ossai N, Aguzie I, Nwani C. Neuromodulatory and oxidative stress evaluations in African catfish Clarias gariepinus exposed to antipsychotic drug chlorpromazine. Drug Chem Toxicol. 2020;22:1-7.

Mahadik SP, Sitasawad S, Mulchandani M. Membrane peroxidation and the neuropathology of schizophrenia. In: Peet M, Glen I, Horribin DF, editors. Phospholipid spectrum disorders in psychiatry. Lancashire: Marius Press; 1999. p. 99-111.

Tabor C, Tabor H. Polyamines. Annu Rev Biochem. 1984;53:749-90.

Galgano F, Caruso M, Favati F, Romano P. HPLC determination of agmatine and other amines in wine. Int J Sci Wine. 2003;37:237-42.

Reis DJ, Regunathan S. Is agmatine a novel neurotransmitter in brain? Trends Pharmacol Sci. 2020;21(5):187-93.

Akasaka N, Fujiwara S. The therapeutic and nutraceutical potential of agmatine, and its enhanced production using Aspergillus oryzae. Amino Acids. 2020;52:181-97.

El-Agamy D, Makled M, Gamil N. Protective effects of agmatine against D-galactosamine and lipopolysaccharide-induced fulminant hepatic failure in mice. Inflammopharmacology. 2014;22(3):187-94.

Freitas A, Bettio L, Neis V, Santos D, Ribeiro C, Rosa P, Farina M, Rodrigues A. Agmatine abolishes restraint stress-induced depressive-like behavior and hippocampal antioxidant imbalance in mice. Prog Neuropsychopharmacol Bio Psychiatry. 2014;3(50):143-50.

Gilad G, Gilad V. Long-Term (5 Years), high daily dosage of dietary agmatine-evidence of safety. J Med Food. 2014;17(11):1256-9.

Lowry OH, Rosenbrongh NJ, Farr AL, Randal RJ. Protein measurement with the folin phenol reagent. J Biol Chem. 1951;193:265-75.

Auclair C, Voisin E. Nitroblue tetrazolium reduction. In: Greenwald RA, editor. Handbook of Methods for Oxygen Radical Research. Florida: CRC Press; 1985. p. 123-32.

Misra P, Fridovich I.The role of superoxide anion in the autoxidation of epinephrine and a simple assay for superoxide dismutase. J Biol Chem. 1972;247(10):3170-5.

Goth L. A simple method for determination of serum catalase activity and revision of reference range. Clin Chim Acta. 1991;196(2-3):143-51.

Maral J, Puget K, Michelson AM. Comparative study of superoxide dismutase, catalase and glutathione peroxidase levels in erythrocytes of different animals. Biochem Biophys Res Commun. 1977;77(4):1525-35.

Freifelder D. Physical biochemistry–application to biochemistry and molecular biology. San Francisco: Freeman WH and Co.;1976. 624 p.

Dejanovic B, Stevanovic I. A clinical and experimental study of the chlorpromazine toxicity. Saarbrücken: Lap Lambert Academic Publishing; 2019; 108 p.

Mahadik S, Evans D, Lal H. Oxidative stress and role of antioxidant and omega-3 essential fatty acid supplementation in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 2001;25(3):463-93.

Antherieu S, Bachour-El Azzi P, Dumont J, Abdel-Razzak Z, Guguen-Guillouzo C, Fromenty B. Oxidative stress plays a major role in chlorpromazine-induced cholestasis in human Hepa RG cells. Hepatology. 2013;57:1518-29.

Dejanović B, Ninković M, Stojanović I, Lavrnja I, Radičević T Vuković-Dejanović V, Stevanović I. Agmatine prevents acute chlorpromazine-induced neurotoxicity in rats. Arh Farm. 2015;65:329-49.

Naidu S, Singh A, Kulkarni K. Carvedilol attenuates neuroleptic-induced orofacial dyskinesia: possible antioxidant mechanisms. Br J Pharmacol. 2002;136:193-200.

Pillai A, Parikh V, Terry V, Mahadik P. Long-term antipsychotic treatments and crossover studies in rats: differential effects of typical and atypical agents on the expression of antioxidant enzymes and membrane lipid peroxidation in rat brain. J Psychiatr Res. 2007;41:372-86.

Dejanović B, Vuković-Dejanović V, Stevanović I, Stojanović I, Mandić Gajić G, Dilber S. Oxidative stress induced by chlorpromazine in patients treated and acutely poisoned with the drug. Vojnosanit Pregl. 2016;73(4):312-7.

Hu J, Kulkarni A. Metabolic fate of chemical mixtures. I. "Shuttle Oxidant" effect of lipoxygenase-generated radical of chlorpromazine and related phenothiazines on the oxidation of benzidine and other xenobiotics. Teratog Carcinog Mutagen 2000;20(4):195-208.<195::aid-tcm2>;2-2

Lopert P, Patel M. Brain mitochondria from DJ-1 knockout mice show increased respiration-dependent hydrogen peroxide consumption. Redox Biol. 2014;2:667-72.

Hodgson EK, Fridovich I. The interaction of bovine erythrocyte superoxide dismutase with hydrogen peroxide: chemiluminescence and peroxidation. Biochemistry. 1975;14(24):5299-303.

Halliwell B. Superoxide dismutase, catalase, and glutathione peroxidase: Solutions to the problem of living with oxygen. New Phytol. 1974;73:1075-86.

Saint-Denis M, Labrot F, Narbonne JF, Ribera D. Glutathione, glutathione-related enzymes, and catalase activities in the earthworm Eisenia fetida Andrei. Arch Environ Contam Toxicol. 1998;35:602-14.

Barua S, Kim J, Kim J, Kim J, Lee J. Therapeutic Effect of Agmatine on Neurological Disease: Focus on Ion Channels and Receptors. Neurochem Res. 2019;44:735-50.

El-Awady M, Nader M, Sharawy M. The inhibition of inducible nitric oxide synthase and oxidative stress by agmatine attenuates vascular dysfunction in rat acute endotoxemic model. Environ Toxicol Pharmacol. 2017;55:74-80.

Sharawy M, Abdelrahman R, El-Kashef D. Agmatine attenuates rhabdomyolysis-induced acute kidney injury in rats in a dose dependent manner. Life Sci. 2018;208:79-86.




How to Cite

Dejanović B, Begović-Kuprešanin V, Stevanović I, Lavrnja I, Šošić-Jurjević B, Ninković M, Trifunović S. Agmatine reduces chlorpromazine prooxidant effects in rat hippocampus and striatum. Arch Biol Sci [Internet]. 2021Oct.12 [cited 2022Aug.9];73(3):353-9. Available from:




Most read articles by the same author(s)