Abstract
Exposure to 3, 4-methylenedioxymethamphetamine (MDMA) leads to spatial memory impairment and hippocampal cell death. In the present study we have examined the protective effects of N-acetyl-L-cysteine (NAC) on MDMA-induced neurotoxicity. A total of 56 male Sprague Dawley rats (200–250 g) received twice daily intraperitoneal (IP) injections of 5, 10 or 20 mg/kg MDMA plus NAC (100 mg/kg). Rectal temperatures were recorded before and after daily treatment. We used a Morris water maze (MWM) to assess spatial learning and memory. At the end of the study rats’ brains were removed, cells were counted and the level of Bcl-2, Bax and caspase-3 expression in the hippocampi were measured. NAC pretreatment significantly reduced MDMA-induced hyperthermia. In the MWM, NAC significantly attenuated the MDMA-induced increase in distance traveled; however the observed increase in escape latency was not significant. The decrease in time spent in the target quadrant in MDMA animals was significantly attenuated (p < 0.001, all groups). NAC protected against MDMA-induced cell death and the up -regulation of Bax and Caspase-3, in addition to the down-regulation of Bcl-2. This data suggested a possible benefit of NAC in the treatment of neurotoxicity among those who use MDMA.
Similar content being viewed by others
References
Alves E, Summavielle T, Alves CJ, Custódio J, Fernandes E, De Lourdes Bastos M (2009) Ecstasy-induced oxidative stress to adolescent rat brain mitochondria in vivo: influence of monoamine oxidase type. An Addict Biol 14:185–193
Bowyer JF, Thomas M, Schmued LC, Ali SF (2008) Brain region-specific neurodegenerative profiles showing the relative importance of amphetamine dose, hyperthermia, seizures, and the blood–brain barrier. Ann N Y Acad Sci 1139:127–139
Capela JP, Macedo C, Branco PS, Ferreira LM, Lobo AM et al (2007) Neurotoxicity mechanisms of thioether ecstasy metabolites. Neuroscience 8:1743–1757
Choy KH, Dean O, Berk M, Bush AI, Van Den Buuse M (2010) Effects of N-acetyl-cysteine treatment on glutathione depletion and a short-term spatial memory deficit in 2-cyclohexene-1-one-treated rats. Eur J Pharmacol 15:224–228
Cuzzocrea S, Mazzon E, Costantino G, Serraino I, Dugo L, Calabrò G et al (2000) Beneficial effects of n-acetylcysteine on ischaemic brain injury. Br J Pharmacol 130:1219–1226
De Flora S, Izzotti A, D'Agostini F, Balansky RM (2001) Mechanisms of N-acetylcysteine in the prevention of DNA damage and cancer, with special reference to smoking-related end-points. Carcinogenesis 22:999–1013
Fcology Arre M, Mathuna BO, Roset PN et al (2004) Repeated doses administration of MDMA in humans: pharmacological effects and pharmacokinetics. Psychopharmacology (Berlin) 173(3–4):364–375
Franco R, Cidlowski JA (2012) Glutathione efflux and cell death. Antioxid Redox Signal 15:1694–1713
Fu AL, Dong ZH, Sun MJ (2006) Protective effect of N-acetyl-L-cysteine on amyloid beta-peptide-induced learning and memory deficits in mice. Brain Res 13:201–206
Fukami G, Hashimoto K, Koike K, Okamura N, Shimizu E, Iyo M (2004) Effect of antioxidant N-acetyl-L-cysteine on behavioral changes and neurotoxicity in rats after administration of methamphetamine. Brain Res 30:90–95
Gabryel B, Toborek T, Małecki A (2005) Immunosuppressive immunophilin ligands attenuate damage in cultured rat astrocytes depleted of glutathione and exposed to simulated ischemia in vitro. Comparison with N-acetylcysteine. Neurotoxicology 26(3):373–384
Gonçalves J, Martins T, Ferreira R, Milhazes N, Borges F, Ribeiro CF et al (2008) Methamphetamine-induced early increase of IL-6 and TNF-alpha mRNA expression in the mouse brain. Ann N Y Acad Sci 1139:103–111
Hashimoto S, Gon Y, Matsumoto K, Takeshita I, Horie T (2001) N-acetylcysteine attenuates TNF-alpha-induced p38 MAP kinase activation and p38 MAP kinase-mediated IL-8 production by human pulmonary vascular endothelial cells. Br J Pharmacol 132:270–276
Jayanthi S, Deng X, Bordelon M, McCoy MT, Cadet JL (2001) Methamphetamine causes differential regulation of pro-death and anti-death Bcl-2 genes in the mouse neocortex. FASEB J 15:1745–1752
Jiménez A, Jordà Elvira G, Verdaguer E, Pubill D, Sureda F, Canudas AM et al (2004) Neurotoxicity of amphetamine derivatives is mediated by caspase pathway activation in rat cerebellar granule cells. Follow Toxicol Appl Pharmacol 196:223–234
Kamboj SS, Chopra K, Sandhir R (2008) Neuroprotective effect of N-acetylcysteine in the development of diabetic encephalopathy in streptozotocin-induced diabetes. Metab Brain Dis 23(4):427–443
Kermanian F, Mehdizadeh M, Soleimani M, Ebrahimzadeh Bideskan AR et al (2012) The role of adenosine receptor agonist and antagonist on Hippocampal MDMA detrimental effects; a structural and behavioral study. Metab Brain Dis 27:459–469
Kroemer G, Galluzzi L, Vandenabeele P, Abrams J, Alnemri ES, Baehrecke EH et al (2009) Classification of cell death: recommendations of the Nomenclature Committee on Cell Death Cell Death Differ. Cell Death Differ 16(1):3–11
Kuypers KP, Wingen M, Heinecke A, Formisano E, Ramaekers JG (2011) MDMA intoxication and verbal memory performance: a placebo-controlled pharmaco-MRI study. J Psychopharmacol 25(8):1053–1061
Lan A, Liao X, Mo L, Yang C, Yang Z, Wang X, Hu F et al (2011) Hydrogen sulfide protects against chemical hypoxia-induced injury by inhibiting ROS-activated ERK1/2 and p38MAPK signaling pathways in PC12 cells. PLoS One 6:e25921
Lee DH, Gold R, Linker RA (2012) Mechanisms of oxidative damage in multiple sclerosis and neurodegenerative diseases: therapeutic modulation via fumaric acid esters. Int J Mol Sci 13(9):11783–11803
Mehdizadeh M, Dabaghian F, Nejhadi A, Fallah-huseini H, Choopani S, Shekarriz N et al (2012) Zingiber officinale alters 3, 4-methylenedioxymetham-induced neurotoxicity in rat brain. Cell J 14(3):177–184
Mills EM, Rusyniak DE, Sprague JE (2004) The role of the sympathetic nervous system and uncoupling proteins in the thermogenesis induced by 3,4-methylenedioxymethamphetamine. J Mol Med (Berl) 82:787–799
Miura M (2012) Apoptotic and nonapoptotic caspase functions in animal development. Cold Spring Harb Perspect Biol 4(10):1
Montgomery T, Sitte H, McBean G (2010) 4-Methylthioamphetamine (4-MTA) induces mitochondrial-dependent apoptosis in SH-SY5Y cells independently of dopamine and noradrenaline transporters. BMC Pharmacology 10(supp 1):A22
Navarrete M, Núñez H, Ruiz S, Soto-Moyano R, Valladares L, White A et al (2007) Prenatal undernutrition decreases the sensitivity of the hypothalamo-pituitary-adrenal axis in rat, as revealed by subcutaneous and intra-paraventricular dexamethasone challenges. Neurosci Lett 29:99–103
O'Leary G, Nargiso J, Weiss RD (2001) 3, 4-methylenedioxymethamphetamine (MDMA): a review. Curr Psychiatr Rep 3(6):477–483
Oltvai ZN, Milliman CL, Korsmeyer SJ (1993) Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell 74(4):609–619, 27
Pedersen NP, Blessing WW (2001) Cutaneous vasoconstriction contributes to hyperthermia induced by 3, 4-methylenedioxymethamphetamine (ecstasy) in conscious rabbits. J Neurosci 1:8648–8654
Pinnen F, Sozio P, Cacciatore I, Cornacchia C, Mollica A, Iannitelli A et al (2011) Ibuprofen and glutathione conjugate as a potential therapeutic agent for treating Alzheimer’s disease. Arch Pharm (Weinheim) 344:139–148
Sarkar S, Schmued L (2010) Neurotoxicity of ecstasy (MDMA): an overview. Curr Pharm Biotechnol 11(5):460–469
Schmued LC (2003) Demonstration and localization of neuronal degeneration in the rat forebrain following a single exposure to MDMA. Brain Res 974(1–2):127–133
Shankaran M, Yamamoto BK, Gudelsky GA (1999) Involvement of the serotonin transporter in the formation of hydroxyl radicals induced by 3, 4-methylenedioxymethamphetamine. Eur J Pharmacol 385:103–110
Simantov R, Tauber M (1997) The abused drug MDMA (Ecstasy) induces programmed death of human serotonergic cells. FASEB J 11(2):141–146
Slivka A, Mytilineou C, Cohen G (1987) Histochemical evaluation of glutathione in brain. Brain Res 21:275–284
Soleimani Asl S, Naghdi N, Choopani S, Farhadi MH, Samzadeh-Kermani A, Mehdizadeh M (2011) Non-acute effects of different doses of 3–4, methylenedioxymethamphetamine (MDMA) on spatial memory in the Morris water maze in Sprague Dawley male rats. NRR 6:1715–1719
Soleimani Asl S, Farhadi MH, Moosavizadeh K, Samadi Kuchak Saraei A, Soleimani M et al (2012) Evaluation of Bcl-2 family gene expression in hippocampus of 3–4 methylenedioxymethamphetamine treated rats. Cell J 13:275–280
Sprague JE, Nichols DE (1995) The monoamine oxidase-B inhibitor L-deprenyl protects against 3,4-methylenedioxymethamphetamine-induced lipid peroxidation and long-term serotonergic deficits. J Pharmacol Exp Ther 273(2):667–673
Sprague JE, Preston AS, Leifheit M, Woodside B (2003) Hippocampal serotonergic damage induced by MDMA (ecstasy): effects on spatial learning. Physiol Behav 79:281–287
Viegas CM, Tonin AM, Zanatta A, Seminotti B, Busanello EN, Fernandes CG et al (2012) Impairment of brain redox homeostasis caused by the major metabolites accumulating in hyperornithinemia-hyperammonemia-homocitrullinuria syndrome in vivo. Metab Brain Dis 27(4):521–530
Vorhees CV, Reed TM, Skelton MR, Williams MT (2004) Exposure to 3, 4-methylenedioxymethamphetamine (MDMA) on postnatal days 11–20 induces reference but not working memory deficits in the Morris water maze in rats: implications of prior learning. Int J Dev Neurosci 22:247–259
Xue C, Liu W, Wu J, Yang X, Xu H (2011) Chemoprotective effect of N-acetylcysteine (NAC) on cellular oxidative damages and apoptosis induced by nano titanium dioxide under UVA irradiation. Toxicol in Vitro 25:110–116
Yamamoto BK, Raudensky J (2008) The role of oxidative stress, metabolic compromise, and inflammation in neuronal injury produced by amphetamine-related drugs of abuse. J Neuroimmune Pharmacol 3:203–217
Zhang H, Spapen H, Nguyen DN, Benlabed M, Buurman WA, Vincent JL (1994) Protective effects of N-acetyl-L-cysteine in endotoxemia. Am J Physiol 266:1746–1754
Acknowledgments
This research was supported by a grant from Tehran University of Medical Sciences, No. P/664.
Conflict of interest statement
None of the authors of this paper have a financial interest to report.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Soleimani Asl, S., Mousavizedeh, K., Pourheydar, B. et al. Protective effects of N-acetylcysteine on 3, 4-methylenedioxymethamphetamine-induced neurotoxicity in male Sprague–Dawley rats. Metab Brain Dis 28, 677–686 (2013). https://doi.org/10.1007/s11011-013-9423-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11011-013-9423-1