Abstract
Antioxidants have possible therapeutic value in neurodegenerative disorders, although they may have pro-oxidant effects under certain conditions. Glutathione (GSH) is a key free radical scavenger. N-acetylcysteine (NAC) bolsters GSH and intracellular cysteine and also has effective free radical scavenger properties. The effects of chronic NAC administration (50 mg/kg/day, 500 mg/kg/day, 1500 mg/kg/day × 21 days) on cellular markers of oxidative status was studied in striatum of healthy male Sprague-Dawley rats as well as in animals with apparent striatal oxidative stress following chronic haloperidol treatment (1.5 mg/kg/day × 3 weeks). In non-haloperidol treated animals, NAC 50 and 500 mg/kg did not affect oxidative status, although NAC 1,500 mg/kg significantly increased striatal superoxide levels, decreased lipid peroxidation and increased consumption of reduced glutathione (GSH). Haloperidol alone evoked a significant increase in superoxide and lipid peroxidation. All NAC doses blocked haloperidol induced increases in superoxide levels, while NAC 500 mg/kg and 1,500 mg/kg prevented haloperidol-associated lipid peroxidation levels and also increased the GSSG/GSH ratio. NAC may protect against conditions of striatal oxidative stress, although possible pro-oxidative actions at high doses in otherwise healthy individuals, e.g. to offset worsening of neurodegenerative illness, should be viewed with caution.
Similar content being viewed by others
References
Dorado-Martinez C, Paredes-Carbajal C, Mascher D et al (2001) Effects of different ozone doses on memory, motor activity and lipid peroxidation levels, in rats. Int J Neurosci 108:149–161
Dringen R, Gutterer JM, Hirrlinger J (2000) Glutathione metabolism in brain - Metabolic interaction between astrocytes and neurons in the defense against reactive oxygen species. Eur J Biochem 267:4912–4916
Mariani E, Polidori MC, Cherubini A et al (2005). Oxidative stress in brain aging, neurodegenerative and vascular diseases: an overview. J Chromatogr B 827:65–75
Gilgun-Sherki Y, Melamed E, Offen D (2001) Oxidative stress induced-neurodegenerative diseases: the need for antioxidants that penetrate the blood brain barrier. Neuropharmacology 40:959–975
Bilici M, Efe H, Köroğlu MA et al (2001) Antioxidative enzyme activities and lipid peroxidation in major depression: alterations by antidepressant treatments. J Affect Disord 64:43–51
Kuloglu M, Ustundag B, Atmaca M et al (2002) Lipid peroxidation and antioxidant enzyme levels in patients with schizophrenia and bipolar disorder. Cell Biochem Funct 20:171–175
Chuahan A, Chauhan V, Brown WT et al (2004) Oxidative stress in autism: increased lipid peroxidation and reduced serum levels of ceruloplasmin and transferrin–the antioxidant proteins. Life Sci 75:2539–2549
Schulz JB, Lindenau J, Seyfried J et al (2000) Glutathione, oxidative stress and neurodegeneration. Eur J Biochem 267:4904–4911
Kontush A (2001) Amyloid-beta: an antioxidant that becomes a pro-oxidant and critically contributes to Alzheimer’s disease. Free Radic Biol Med 31:1120–1131
Andreassen OA, Jorgensen HA (2000) Neurotoxicity associated with neuroleptic-induced oral dyskinesias in rats. Implications for tardive dyskinesia? Prog Neurobiol 61:525–541
Zhang XY, Zhou DF, Cao LY et al (2003) Blood superoxide dismutase level in schizophrenic patients with tardive dyskinesia: association with dyskinetic movements. Schizophrenia Res 62:245–250
Ratnam DV, Ankola DD, Bhardwaj V et al (2006) Role of antioxidants in prophylaxis and therapy: a pharmaceutical perspective. J Contr Rel 113:189–207
Liu Q, Xie F, Rolston R et al (2007) Prevention and treatment of Alzheimer disease and aging: antioxidants. Mini Rev Med Chem 7:171–180
Singh N, Pillay V, Choonara YE (2007) Advances in the treatment of Parkinson’s disease. Prog Neurobiol 81:29–44
LaRowe SD, Mardikian P, Malcolm R et al (2006) Safety and tolerability of N-acetylcysteine in cocaine-dependent individuals. Am J Addict 15:105–110
Grant JE, Kim SW, Odlaug BL (2007) N-acetyl cysteine, a glutamate-modulating agent, in the treatment of pathological gambling: a pilot study. Biol Psychiatry Apr 17 [Epub ahead of print]
Choi EJ (2006) The prooxidant, rather than antioxidant, acts of daidzein in vivo and in vitro: daidzein suppresses glutathione metabolism. Eur J Pharmacol 542:162–169
Rietjens IMCM, Boersma MG, de Haan L et al (2002) The pro-oxidant chemistry of the natural antioxidants vitamin C, vitamin E, carotenoids and flavonoids. Environ Toxicol Pharmacol 11:321–333
Wang AL, Wang JP, Wang H et al (2006) A dual effect of N-acetylcysteine on acute ethanol-induced liver damage in mice. Hepatol Res 34:199–206
Adair JC, Knoefel JE, Morgan N (2001). Controlled trial of N-acetylcysteine for patients with probable Alzheimer’s disease. Neurology 57:1515–1517
Tchantchou F, Graves M, Rogers E et al (2005) N-acteyl cysteine alleviates oxidative damage to central nervous system of ApoE-deficient mice following folate and vitamin E-deficiency. J Alzheimers Dis 7:135–138
Kawanishi S, Oikawa S, Murata M (2005) Evaluation for safety of antioxidant chemopreventive agents. Antioxid Redox Signal 7:1728–1739
Behl C, Lezoulac’h F, Widmann M et al (1996) Oxidative stress-resistant cells are protected against haloperidol toxicity. Brain Res 717:193–195
Parikh V, Khan MM, Mahadik SP (2003) Differential effects of antipsychotics on expression of antioxidant enzymes and membrane lipid peroxidation in rat brain. J Psychiatric Res 37:43–51
Post A, Rucker M, Ohl F et al (2002) Mechanisms underlying the protective potential of alpha-tocopherol (vitamin E) against haloperidol-associated neurotoxicity. Neuropsychopharmacology 26:397–407
Sadan O, Bahat-Stromza M, Gilshun-Sherki Y et al (2005) A novel brain-targeted antioxidant (AD4) attenuates haloperidol-induced abnormal movement in rats: implications for tardive dyskinesia. Clin Neuropharmacol 28:285–288
Koros C, Papalexi E, Anastasopoulos D et al (2007) Effects of AraC treatment on motor coordination and cerebellar cytoarchitecture in the adult rat: a possible protective role of NAC. Neuro Toxicol 28:83–92
Song D, Hutchings S, Pang CCY (2005) Chronic N-acetylcysteine prevents fructose-induced insulin resistance and hypertension in rats. Eur J Pharmacol 508:205–210
Harvey BH, Nel A (2003) Role of aging and striatal nitric oxide synthase activity in an animal model of tardive dyskinesia. Brain Res Bull 61:407–416
Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254
Ottino P, Duncan JR (1997) Effect of alpha-tocopherol succinate on free radical and lipid peroxidation levels in BL6 melanoma cells. Free Radic Biol Med 22:1145–1151
Bouligand J, Deroussent A, Paci A et al (2006) Liquid chromatography-tandem mass spectrometry assay of reduced and oxidized glutathione and main precursors in mice liver. J Chromatogr B 832:67–74
Demedts M, Behr J, Buhl R et al (2005) High-dose acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med 353:2229–2242
Van Schooten FJ, Besaratinia A, De Flora S et al (2002) Effects of oral administration of N-acetyl-L-cysteine: a multi-biomarker study in smokers. Cancer Epidemiol Biomarkers Prev 11:167–175
Behr J, Degenkolb B, Krombach F et al (2002) Intracellular glutathione and bronchoalveolar cells in fibrosing alveolitis: effects of N-acetylcysteine. Eur Respir J 19:906–911
Lohr JB, Kuczenski R, Bracha HS et al (1990) Increased indices of free radical activity in the cerebrospinal fluid of patients with tardive dyskinesia. Biol Psychiatry 28:535–539
Harvey BH, Stein DJ, Emsley RA (1999) The new generation antipsychotics: integrating the neuropathology and pharmacology of schizophrenia. S Afr Med J 89:661–672
Cooper JR, Bloom F, Roth RH (2003) Dopamine. In: The biochemical basis of neuropharmacology, 8th ed. Oxford University Press, New York, pp 225–270
Loeffler DA, Lewitt PA, Juneau PL et al (1998) Time-dependent effects of levodopa on regional brain dopamine metabolism and lipid peroxidation. Brain Res Bull 47:663–667
Ben-Shachar D, Zuk R, Gazawi H et al (2004) Dopamine toxicity involves mitochondrial complex I inhibition: implications to dopamine-related neuropsychiatric disorders. Biochem Pharmacol 67:1965–1974
Van der Schyf CJ, Usuki E, Pond SM et al (1998) Haloperidol-derived pyridinium metabolites. In: Kostrzewa RM (ed) Highly selective neurotoxins: basic and clinical applications. Humana Press Inc., Totowa, NJ, USA, pp 195–210
Harvey BH, Bester A (2000) Withdrawal-associated changes in peripheral nitrogen oxides and striatal cyclic GMP after chronic haloperidol treatment. Behav Brain Res 111:203–211
Wink DA, Vodovotz Y, Grisham MB et al (1999) Antioxidant effects of nitric oxide. Meth Enzymol 301:413–424
Abilio VC, Araujo CC, Bergamo M et al (2003) Vitamin E attenuates reserpine-induced oral dyskinesia and striatal oxidized glutathione/reduced glutathione ratio (GSSG/GSH) enhancement in rats. Prog Neuropsychopharmacol Biol Psychiatry 27:109–114
Polydoro M, Schroder N, Lima MN et al (2004). Haloperidol- and clozapine-induced oxidative stress in the rat brain. Pharmacol Biochem Behav 78:751–756
Valko M, Leibfritz D, Moncol J et al (2007) Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol 39:44–84
Vairetti M, Battaglia A, Carfagna N et al (2002) Antioxidant properties of MDL and MMDL, two nicergoline metabolites, during chronic administration of haloperidol. Eur J Pharmacol 453:69–73
Vairetti M, Feletti F, Battaglia A et al (1999) Haloperidol-induced changes in glutathione and energy metabolism: effect of nicergoline. Eur J Pharmacol 367:67–72
Adler LA, Edson R, Lavori P et al (1998) Long-term treatment effects of vitamin E for tardive dyskinesia. Biol Psychiatry 43:868–872
Dorevitch A, Kalian M, Shlafman M et al (1997) Treatment of long-term tardive dyskinesia with vitamin E. Biol Psychiatry 41:114–116
Zana M, Janka Z, Kalman J (2006) Oxidative stress: a bridge between Down’s syndrome and Alzheimer’s disease. Neurobiol Aging 28:648–676
De La Fuente M, Miquel J, Catalan MP et al (2002) The amount of thiolic antioxidant ingestion needed to improve several immune functions is higher in aged than in adult mice. Free Radic Res 36:119–126
Sagrista ML, Garcia AE, Africa De Madariaga M et al (2002) Antioxidant and pro-oxidant effect of the thiolic compounds N-acetyl-L-cysteine and glutathione against free radical-induced lipid peroxidation. Free Radic Res 36:329–340
Dean O, van den Buuse M, Copolov DL, Berk M, Bush AI (2004) N-acetylcysteine treatment inhibits depletion of brain glutathione levels in rats. Implications for schizophrenia. Int J Neuropsychopharmacol 7:S262
Benrahmoune M, Therond P, Abedinzadeh Z (2000) The reaction of superoxide radical with N-acetylcysteine. Free Radic Biol Med 29:775–782
Ghizoni DM, Pavanati KCA, Arent AM et al (2006). Alterations in glutathione levels of brain structures caused by acute restraint stress and by nitric oxide synthase inhibition but not by intraspecific agonistic interaction. Behav Brain Res 166:71–77
Arnaiz SL, Coronel MF, Boveris A (1999) Nitric oxide, superoxide, and hydrogen peroxide production in brain mitochondria after haloperidol treatment. Nitric Oxide 3:235–243
Failli P, Palmieri L, D’Alfonso C et al (2002) Effect of N-acetyl-L-cysteine on peroxynitrite and superoxide anion production of lung alveolar macrophages in systemic sclerosis. Nitric Oxide 7:277–282
Schneider MP, Delles C, Schmidt BM et al (2005) Superoxide scavenging effects of N-acetylcysteine and vitamin C in subjects with essential hypertension. Am J Hypertens 18:1111–1117
Hininger I, Waters R, Osman M et al (2005) Acute prooxidant effects of vitamin C in EDTA chelation therapy and long-term antioxidant benefits of therapy. Free Radic Biol Med 38:1565–1570
Oikawa S, Yamada K, Yamashita N et al (1999) N-acetylcysteine, a cancer chemopreventive agent, causes oxidative damage to cellular and isolated DNA. Carcinogenesis 20:1485–1490
Ahmad S (1995) Oxidative stress and antioxidant defences in biology. Chapman & Hall, New York
Zunquin G, Rouleau V, Bouhallab S et al (2006) Iron and exercise induced alterations in antioxidant status. Protection by dietary milk proteins. Free Radic Res 40:535–542
Nelson SK, Bose SK, McCord JM (1994) The toxicity of high-dose superoxide dismutase suggests that superoxide can both initiate and terminate lipid peroxidation in the reperfused heart. Free Radic Biol Med 16:195–200
Hultberg B, Andersson A, Isaksson A (2001) Interaction of metals and thiols in cell damage and glutathione distribution: potentiation of mercury toxicity by dithiothreitol. Toxicology 156:93–100
Acknowledgements
The authors would like to acknowledge the University of Melbourne (Barwon Health) for funding, Cor Bester and Antoinette Fick at the North-West University Animal Research Centre for the welfare of the animals, and Nico Liebenberg for his valuable assistance in the preparation of the manuscript.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Harvey, B.H., Joubert, C., du Preez, J.L. et al. Effect of Chronic N-Acetyl Cysteine Administration on Oxidative Status in the Presence and Absence of Induced Oxidative Stress in Rat Striatum. Neurochem Res 33, 508–517 (2008). https://doi.org/10.1007/s11064-007-9466-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11064-007-9466-y