Abstract
Exposure to 3, 4-methylenedioxymethamphetamine (MDMA) can lead to spatial memory impairments and hippocampal cell death. Numerous evidence indicates that the antioxidant N-acetylcysteine (NAC) exerts protective effects in the brain. The present study evaluates the effects of NAC on MDMA–induced neurotoxicity. Methods: We intraperitoneally injected 28 adult male Sprague–Dawley rats (200–250 g) with either 0, 10 mg/kg of MDMA, or 10 mg/kg of MDMA plus 100 mg/kg of NAC. Spatial memory was assessed with a Morris Water Maze (MWM). At the end of the study, rats' brains were removed to study the structure and ultrastructure of CA1, and measure Bcl-2 and Bax expressions in the hippocampus. In the MWM, NAC treatment significantly attenuated the MDMA-induced increase in distance traveled (p < 0.05) and escape latency (p < 0.001). The decreased time spent in the target quadrant in MDMA-treated animals was attenuated by NAC (p < 0.01). NAC significantly protected against MDMA-induced apoptosis and the up- and down-regulation of Bax and Bcl-2, respectively. These data have suggested that NAC could protect against behavioral changes and apoptosis in the hippocampus following administration of MDMA. NAC might be useful for the treatment of neurotoxicity in MDMA users.
Similar content being viewed by others
References
Abdullah JM, Ahmad F, Ahmad KA, Ghazali MM, Jaafar H, Ideris A et al (2007) Molecular genetic analysis of BAX and cyclin D1 genes in patients with malignant glioma. Neurol Res 29:239��242
Adori C, And RD, Kovacs GG, Gr B (2006) Damage of serotonergic axons and immunolocalization of Hsp27, Hsp72, and Hsp90 molecular chaperones after a single dose of MDMA administration in Dark Agouti rat: temporal, spatial, and cellular patterns. J Comp Neurol 497:251–269
Alboni S, Gibellini L, Montanari C, Benatti C, Benatti S, Tascedda F et al (2013) N-acetyl-cysteine prevents toxic oxidative effects induced by IFN-α in human neurons. Int J Neuropsychopharmacol 16:1–17
Arakawa M (2007) N-acetylcysteine and neurodegenerative diseases: basic and clinical pharmacology. Cerebellum 6:308–314
Atkuri KR, Mantovani JJ, Herzenberg LA, Herzenberg LA (2007) N-Acetylcysteine a safe antidote for cysteine/glutathione deficiency. Curr Opin Pharmacol 7:355–359
Bankson MG, Cunningham KA (2001) 3, 4-Methylenedioxymethamphetamine (MDMA) as a unique model of serotonin receptor function and serotonin-dopamine interactions. J Pharmacol Exp Ther 297:846–852
Bar-Or A1, Nuttall RK, Duddy M, Alter A, Kim HJ, Ifergan I et al (2003) Analyses of all matrix metalloproteinase members in leukocytes emphasize monocytes as major inflammatory mediators in multiple sclerosis. Brain 126:2738–2749
Bhattachary S, Powell HJ (2001) Recreational use of 3, 4-methylenedioxymethamphetamine (MDMA) or ecstasy: evidence for cognitive impairment. Psychol Med 31:647–658
Biezonski DK, Meyer JS (2011) The nature of 3, 4-methylenedioxymethamphetamine (MDMA)-induced serotonergic dysfunction: evidence for and against the neurodegeneration hypothesis. Curr Neuropharmacol 9:84–90
Byrne T, Baker LE, Poling A (2000) MDMA and learning: effects of acute and neurotoxic exposure in the rat. Pharmacol Biochem Behav 66:501–508
Capela JP, Carmo H, Remio F, Bastos ML, Meisel A, Fl C (2009) Molecular and cellular mechanisms of ecstasy-induced neurotoxicity: an overview. Mol Neurobiol 39:210–271
Fiala M, Liu QN, Sayre J, Pop V, Brahmandam V, Graves MC et al (2002) Cyclooxygenase positive macrophages infiltrate the Alzheimer's disease brain and damage the blood brain barrier. Eur J Clin Investig 32:360–371
Fonsart J, Menet MC, Declèves X, Galons H, Crété D, Debray M et al (2008) Sprague–Dawley rats display metabolism-mediated sex differences in the acute toxicity of 3, 4-methylenedioxymethamphetamine (MDMA, ecstasy). Toxicol Appl Pharmacol 230:117–125
Franzese S, Capasso A (2008) The Effects of the 3, 4-Methylenedioxymethamphetamine (Ecstasy) in Some Cerebral Areas: Role of the Oxidative Stress. Drug Metab Lett 2:95–99
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 1016:90–95
Green AR, Cross AJ, Goodwin GM (1995) Review of the pharmacology and clinical pharmacology of 3, 4-methylenedioxymethamphetamine (MDMA or Ecstasy). Psychopharmacol (Berl) 119:247–260
Hicdonmez T, Kanter M, Tiryaki M, Parsak T, Cobanoglu S (2006) Neuroprotective effects of N-acetylcysteine on experimental closed head trauma in rats. Neurochem Res 31:473–481
Hogg N (1999) The effect of cyst(e) ine on the auto-oxidation of homocysteine. Free Radic Biol Med 27:28–33
Jayanthi S, Deng X, Noailles P-AH, Ladenheim B, Cadet JL (2004) Methamphetamine induces neuronal apoptosis via cross-talks between endoplasmic reticulum and mitochondria-dependent death cascades. FASEB J 18:238–251
Jiménez A, Jordà EG, Verdaguer E, Pubill D, Sureda FX, Canudas AM et al (2004) Neurotoxicity of amphetamine derivatives is mediated by caspase pathway activation in rat cerebellar granule cells. Toxicol Appl Pharmacol 196:223–234
Jones DC, Duvauchelle C, Ikegami A, Olsen CM, Lau SS, de la Torre R et al (2005) Serotonergic neurotoxic metabolites of ecstasy identified in rat brain. J Pharmacol Exp Ther 313:422–431
Lim HK, Foltz RL (1988) In vivo and in vitro metabolism of 3, 4-(methylenedioxy) methamphetamine in the rat: identification of metabolites using an ion trap detector. Chem Res Toxicol 1:370–378
Lyles J, Cadet JL (2003) Methylenedioxymethamphetamine (MDMA, Ecstasy) neurotoxicity: cellular and molecular mechanisms. Brain Res Rev 42:155–168
McClure EA, Gipson CD, Malcolm RJ, Kalivas PW, Gray KM (2014) Potential Role of N-Acetylcysteine in the Management of Substance Use Disorders. CNS Drugs 28(2):95–106
Mehdizadeh M, Dabaghian F, Nejhadi A, Fallah-Huseini H, Choopani S, Shekarriz N et al (2012) Zingiber officinale alters 3, 4-methylenedioxymethamphetamine-induced neurotoxicity in rat brain. Cell J (Yakhteh) 14:177–178
Meyer JS, Grande M, Johnson K, Ali SF (2004) Neurotoxic effects of MDMA (ecstasy) administration to neonatal rats. Int J Dev Neurosci 22:261–271
Mogensen J, Pedersen TK, Sr H, Bang LE (1995) Prefrontal cortical mediation of rats’ place learning in a modified water maze. Brain Res Bull 38:425–434
Olivieri G, Baysang G, Meier F, Mller Spahn F, Sthelin HB, Brockhaus M et al (2001) N Acetyl cysteine protects SHSY5Y neuroblastoma cells from oxidative stress and cell cytotoxicity: effects on amyloid secretion and tau phosphorylation. J Neurochem 76:224–233
Parrott AC, Lees A, Garnham NJ, Jones M, Wesnes K (1998) Cognitive performance in recreational users of MDMA or‘ecstasy’: Evidence for memory deficits. J Psychopharmacol 12:79–83
Pawlas N, Nierwiska K, Stolecka A, Gabryel B, Pudelko A, Malecki A (2009) Effects of N-acetylcysteine and ebselen on arachidonic acid release from astrocytes and neurons cultured in normoxic or simulated ischemic conditions. Pharmacol Rep 61:941
Peroutka SJ, Newman H, Harris H (1988) Subjective effects of 3, 4-methylenedioxymethamphetamine in recreational users. Neuropsychopharmacology 1:273–277
Pourahmad J, Eskandari MR, Nosrati M, Kobarfard F, Khajeamiri AR (2010) Involvement of mitochondrial/lysosomal toxic cross-talk in ecstasy induced liver toxicity under hyperthermic condition. Eur J Pharmacol 643:162–169
Prakash A, Kumar A (2009) Effect of N Acetyl Cysteine against Aluminium-induced Cognitive Dysfunction and Oxidative Damage in Rats. Basic Clin Pharmacol Toxicol 105:98–104
Reneman L, Booij J, Schmand B, van den Brink W, Gunning B (2000) Memory disturbances in Ecstasy users are correlated with an altered brain serotonin neurotransmission. Psychopharmacol (Berl) 148:322–324
Reneman L, Majoie CBLM, Schmand B, van den Brink W, den Heeten GJ (2001) Prefrontal N-acetylaspartate is strongly associated with memory performance in (abstinent) ecstasy users: preliminary report. Biol Psychiatry 50:550–554
Riezzo I, Cerretani D, Fiore C, Bello S, Centini F, D’Errico S et al (2010) Enzymatic- nonenzymatic cellular antioxidant defense systems response and immunohistochemical detection of MDMA, VMAT2, HSP70, and apoptosis as biomarkers for MDMA (ecstasy) neurotoxicity. J Neurosci Res 88:905–916
Rodgers J, Buchanan T, Scholey AB, Heffernan TM, Ling J, Parrott A (2001) Differential effects of Ecstasy and cannabis on self reports of memory ability: a web-based study. Hum Psychopharmacol Clin Exp 16:619–625
Sagara J, Bannai S, Shikano N, Makino N (2010) Conflicting effects of N-acetylcysteine on purified neurons derived from rat cortical culture. Neuroreport 21(6):416–421
Samuni Y, Goldstein S, Dean OM, Berk M (2013) The chemistry and biological activities of N-acetylcysteine. Biochim Biophys Acta, Gen Subj 1830:4117–4129
Schmued LC (2003) Demonstration and localization of neuronal degeneration in the rat forebrain following a single exposure to MDMA. Brain Res 974:127–133
Sekhon B, Sekhon C, Khan M, Patel SJ, Singh I, Singh AK (2003) N-Acetyl cysteine protects against injury in a rat model of focal cerebral ischemia. Brain Res 971:1–8
Simantov R, Tauber M (1997) The abused drug MDMA (Ecstasy) induces programmed death of human serotonergic cells. FASEB J 11:141–146
Soleimani Asl S1, Farhadi MH, Moosavizadeh K, Samadi Kuchak Saraei A, Soleimani M, Jamei SB et al (2012a) Evaluation of Bcl-2 family gene expression in hippocampus of 3, 4-methylenedioxymethamphetamine treated rats. Cell Journal (Yakhteh) 13:275–280
Soleimani Asl S, Farhadi HM, Naghdi N, Choopani S, Samzadeh-Kermani A, Mehdizadeh M (2012b) Non-acute effects of different doses of 3, 4-methylenedioxymethamphetamine on spatial memory in the Morris water maze in Sprague–Dawley male rats. Neural Regen Res 6:1715–1719
Soleimani Asl S, Mousavizedeh K, Pourheydar B, Soleimani M, Rahbar E, Mehdizadeh M (2013) Protective effects of N-acetylcysteine on 3, 4-methylenedioxymethamphetamine-induced neurotoxicity in male Sprague- Dawley rats. Metab Brain Dis 28:677–686
Soleimani Asl S, Mehdizadeh M, Hamedi Shahraki S, Artimani T, Joghataei MT (2014) Sex Differences in MDMA- induced Toxicity in Sprague–Dawley Rats. Functional Neurology In press
Spagnuolo G, Ant DV, Cosentino C, Schmalz G, Schweikl H, Rengo S (2006) Effect of N-acetyl-l-cysteine on ROS production and cell death caused by HEMA in human primary gingival fibroblasts. Biomaterials 27:1803–1809
Sprague JE, Everman SL, Nichols DE (1998) An integrated hypothesis for the serotonergic axonal loss induced by 3, 4-methylenedioxymethamphetamine. Neurotoxicology 19:427–442
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
Srinivasan S, Avadhani NG (2012) Cytochrome c oxidase dysfunction in oxidative stress. Free Radic Biol Med 53:1252–1263
Stanislaus R, Gilg AG, Singh AK, Singh I (2005) N-acetyl-L-cysteine ameliorates the inflammatory disease process in experimental autoimmune encephalomyelitis in Lewis rats. J Autoimmun Dis 3; 2(1):4
Stephenson AP, Schneider JA, Nelson BC, Atha DH, Jain A, Soliman KF et al (2013) Manganese-induced oxidative DNA damage in neuronal SH-SY5Y cells: attenuation of thymine base lesions by glutathione and N-acetylcysteine. Toxicol Lett 218:299–307
United Nations Office on Drugs and Crime (2011) World Drug Report. United Nations. Publication, Sales No. E. 11. XI. 10, NY,
Valvassori SS, Petronilho FC, Réus GZ, Steckert AV, Oliveira VB, Boeck CR, Kapczinski F, Dal-Pizzol F, Quevedo J (2008) Effect of N-acetylcysteine and/or deferoxamine on oxidative stress and hyperactivity in an animal model of mania. Prog Neuro-Psychopharmacol Biol Psychiatry 32:1064–1068
Wang X, Zhu SP, Kuang WH, Li J, Sun X, Huang MS et al (2009) Neuron apoptosis induced by 3, 4-methylenedioxy methamphetamine and expression of apoptosis-related factors in rat brain. Sichuan Da Xue Xue Bao Yi Xue Ban 40:1000–1002
Winter K, Pagoria D, Geurtsen W (2005) The effect of antioxidants on oxidative DNA damage induced by visible-light-irradiated camphorquinone N N-dimethyl- p-toluidine. Biomaterials 26:5321–5329
Xu T, Pandey SC (2000) Cellular localization of serotonin- 2A (5HT- 2A) receptors in the rat brain. Brain Res Bull 51:499–505
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
Zhou C, Yu J, Zhang J, Jiang T, Xu S, Yu Q, Zhu Q (2013) N-acetylcysteine attenuates subcutaneous administration of bleomycin-induced skin fibrosis and oxidative stress in a mouse model of scleroderma. Clin Exp Dermatol 38:403–409
Acknowledgments
This research was supported by a grant from Iran University of Medical Sciences No. P/664.
Conflict of interest statement
None of the authors of this paper have any financial interest to report.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Soleimani Asl, S., Saifi, B., Sakhaie, A. et al. Attenuation of ecstasy-induced neurotoxicity by N-acetylcysteine. Metab Brain Dis 30, 171–181 (2015). https://doi.org/10.1007/s11011-014-9598-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11011-014-9598-0