Abstract
Methamphetamine (METH) is a highly addictive CNS stimulant that its long-term use is associated with the loss of neurons in substantia nigra and development of Parkinson’s disease later in life. Common form of METH is Ya-Ba tablet, in which, large portion of caffeine is added to the mass to enhance the stimulatory effect. Previous study demonstrated that caffeine potentiates the toxic effect of METH in association with the production of reactive oxygen species and the induction of apoptosis. Since METH causes induction of autophagy, the question was raised whether this pathway participates in the potentiating effect of caffeine on METH neurotoxicity. We used SH-SY5Y, a neuroblastoma cell line, as an in vitro model to study the effect of METH and caffeine. Co-treatment of non-toxic concentrations of METH, at 0.5 mM, and caffeine, at 1 mM, caused reduction of the cell viability. Reduction of the cell viability was associated with attenuation of autophagy, demonstrated by reduction of LC3-II levels and the number of autophagosome puncta, together with increase of caspase-3 activation. Similar effect was produced by treatment with autophagy inhibitors, 3-MA and wortmanin. Our results suggested that caffeine potentiates METH toxicity through inhibition of autophagy and that autophagy serves as a protective mechanism. In conclusion, we proposed the augmented hazard associated with caffeine and METH combination in Ya-Ba abusers.
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References
Aguiar LM et al (2006) Neuroprotective effects of caffeine in the model of 6-hydroxydopamine lesion in rats. Pharmacol Biochem Behav 84:415–419. doi:10.1016/j.pbb.2006.05.027
Borycz J et al (2007) Differential glutamate-dependent and glutamate-independent adenosine A1 receptor-mediated modulation of dopamine release in different striatal compartments. J Neurochem 101:355–363. doi:10.1111/j.1471-4159.2006.04386.x
Callaghan RC, Cunningham JK, Sykes J, Kish SJ (2012) Increased risk of Parkinson’s disease in individuals hospitalized with conditions related to the use of methamphetamine or other amphetamine-type drugs. Drug Alcohol Depend 120:35–40. doi:10.1016/j.drugalcdep.2011.06.013
Castino R et al (2008) Suppression of autophagy precipitates neuronal cell death following low doses of methamphetamine. J Neurochem 106:1426–1439. doi:10.1111/j.1471-4159.2008.05488.x
Castino R, Bellio N, Follo C, Murphy D, Isidoro C (2010) Inhibition of PI3k class III-dependent autophagy prevents apoptosis and necrosis by oxidative stress in dopaminergic neuroblastoma cells. Toxicol Sci 117:152–162. doi:10.1093/toxsci/kfq170
Chen JF et al (2001) Neuroprotection by caffeine and A(2A) adenosine receptor inactivation in a model of Parkinson’s disease. J Neurosci 21:RC143
Cherra SJ 3rd, Kulich SM, Uechi G, Balasubramani M, Mountzouris J, Day BW, Chu CT (2010) Regulation of the autophagy protein LC3 by phosphorylation. J Cell Biol 190:533–539. doi:10.1083/jcb.201002108
Delle Donne KT, Sonsalla PK (1994) Protection against methamphetamine-induced neurotoxicity to neostriatal dopaminergic neurons by adenosine receptor activation. J Pharmacol Exp Ther 271:1320–1326
Eisenberg-Lerner A, Bialik S, Simon HU, Kimchi A (2009) Life and death partners: apoptosis, autophagy and the cross-talk between them. Cell Death Differ 16:966–975. doi:10.1038/cdd.2009.33
Eshleman AJ, Henningsen RA, Neve KA, Janowsky A (1994) Release of dopamine via the human transporter. Mol Pharmacol 45:312–316
Foukas LC, Daniele N, Ktori C, Anderson KE, Jensen J, Shepherd PR (2002) Direct effects of caffeine and theophylline on p110 delta and other phosphoinositide 3-kinases. Differential effects on lipid kinase and protein kinase activities. J Biol Chem 277:37124–37130. doi:10.1074/jbc.M202101200
Francis SH, Sekhar KR, Ke H, Corbin JD (2011) Inhibition of cyclic nucleotide phosphodiesterases by methylxanthines and related compounds. Handb Exp Pharmacol. doi:10.1007/978-3-642-13443-2_4
Gordy C, He YW (2012) The crosstalk between autophagy and apoptosis: where does this lead? Protein Cell 3:17–27. doi:10.1007/s13238-011-1127-x
Guerreiro S, Toulorge D, Hirsch E, Marien M, Sokoloff P, Michel PP (2008) Paraxanthine, the primary metabolite of caffeine, provides protection against dopaminergic cell death via stimulation of ryanodine receptor channels. Mol Pharmacol 74:980–989. doi:10.1124/mol.108.048207
Guerreiro S, Marien M, Michel PP (2011) Methylxanthines and ryanodine receptor channels. Handb Exp Pharmacol. doi:10.1007/978-3-642-13443-2_5
Howell LL (1993) Comparative effects of caffeine and selective phosphodiesterase inhibitors on respiration and behavior in rhesus monkeys. J Pharmacol Exp Ther 266:894–903
Inoue H, Hase K, Segawa A, Takita T (2013) H89 (N-[2-p-bromocinnamylamino-ethyl]-5-isoquinolinesulphonamide) induces autophagy independently of protein kinase A inhibition. Eur J Pharmacol 714:170–177. doi:10.1016/j.ejphar.2013.06.018
Jacobson KA, Gao ZG (2006) Adenosine receptors as therapeutic targets. Nat Rev Drug Discov 5:247–264. doi:10.1038/nrd1983
Jang MH et al (2002) Caffeine induces apoptosis in human neuroblastoma cell line SK-N-MC. J Korean Med Sci 17:674–678
Kachroo A, Irizarry MC, Schwarzschild MA (2010) Caffeine protects against combined paraquat and maneb-induced dopaminergic neuron degeneration. Exp Neurol 223:657–661. doi:10.1016/j.expneurol.2010.02.007
Kalda A, Yu L, Oztas E, Chen JF (2006) Novel neuroprotection by caffeine and adenosine A(2A) receptor antagonists in animal models of Parkinson’s disease. J Neurol Sci 248:9–15. doi:10.1016/j.jns.2006.05.003
Kongsuphol P, Mukda S, Nopparat C, Villarroel A, Govitrapong P (2009) Melatonin attenuates methamphetamine-induced deactivation of the mammalian target of rapamycin signaling to induce autophagy in SK-N-SH cells. J Pineal Res 46:199–206. doi:10.1111/j.1600-079X.2008.00648.x
Krasnova IN, Cadet JL (2009) Methamphetamine toxicity and messengers of death. Brain Res Rev 60:379–407. doi:10.1016/j.brainresrev.2009.03.002
Ku BM et al (2011) Caffeine inhibits cell proliferation and regulates PKA/GSK3beta pathways in U87MG human glioma cells. Mol Cells 31:275–279. doi:10.1007/s10059-011-0027-5
Kudchodkar SB, Yu Y, Maguire TG, Alwine JC (2006) Human cytomegalovirus infection alters the substrate specificities and rapamycin sensitivities of raptor- and rictor-containing complexes. Proc Natl Acad Sci USA 103:14182–14187. doi:10.1073/pnas.0605825103
Larsen KE, Fon EA, Hastings TG, Edwards RH, Sulzer D (2002) Methamphetamine-induced degeneration of dopaminergic neurons involves autophagy and upregulation of dopamine synthesis. J Neurosci 22:8951–8960
Li Y et al (2012) Taurine attenuates methamphetamine-induced autophagy and apoptosis in PC12 cells through mTOR signaling pathway. Toxicol Lett 215:1–7. doi:10.1016/j.toxlet.2012.09.019
Ma J, Wan J, Meng J, Banerjee S, Ramakrishnan S, Roy S (2014) Methamphetamine induces autophagy as a pro-survival response against apoptotic endothelial cell death through the Kappa opioid receptor. Cell Death Dis 5:e1099. doi:10.1038/cddis.2014.64
Machado-Filho JA et al (2014) Caffeine neuroprotective effects on 6-OHDA-lesioned rats are mediated by several factors, including pro-inflammatory cytokines and histone deacetylase inhibitions. Behav Brain Res 264:116–125. doi:10.1016/j.bbr.2014.01.051
Marino G, Niso-Santano M, Baehrecke EH, Kroemer G (2014) Self-consumption: the interplay of autophagy and apoptosis. Nat Rev Mol Cell Biol 15:81–94. doi:10.1038/nrm3735
Mathew R et al (2009) Autophagy suppresses tumorigenesis through elimination of p62. Cell 137:1062–1075. doi:10.1016/j.cell.2009.03.048
Miyazaki I, Asanuma M (2008) Dopaminergic neuron-specific oxidative stress caused by dopamine itself. Acta Med Okayama 62:141–150
Mizushima N (2004) Methods for monitoring autophagy. Int J Bio Cell Biol 36:2491–2502. doi:10.1016/j.biocel.2004.02.005
Mizushima N, Levine B, Cuervo AM, Klionsky DJ (2008) Autophagy fights disease through cellular self-digestion. Nature 451:1069–1075. doi:10.1038/nature06639
Parsons WJ, Stiles GL (1985) Methylxanthines as adenosine receptor antagonists. Ann Intern Med 103:643
Pasquali L, Lazzeri G, Isidoro C, Ruggieri S, Paparelli A, Fornai F (2008) Role of autophagy during methamphetamine neurotoxicity. Ann N Y Acad Sci 1139:191–196. doi:10.1196/annals.1432.016
Pessah IN, Stambuk RA, Casida JE (1987) Ca2+ -activated ryanodine binding: mechanisms of sensitivity and intensity modulation by Mg2+, caffeine, and adenine nucleotides. Mol Pharmacol 31:232–238
Puthaviriyakorn V, Siriviriyasomboon N, Phorachata J, Pan-ox W, Sasaki T, Tanaka K (2002) Identification of impurities and statistical classification of methamphetamine tablets (Ya-Ba) seized in Thailand. Forensic Sci Int 126:105–113
Ricaurte GA, Schuster CR, Seiden LS (1980) Long-term effects of repeated methylamphetamine administration on dopamine and serotonin neurons in the rat brain: a regional study. Brain Res 193:153–163
Saiki S et al (2011) Caffeine induces apoptosis by enhancement of autophagy via PI3K/Akt/mTOR/p70S6K inhibition. Autophagy 7:176–187
Sinchai T et al (2011) Caffeine potentiates methamphetamine-induced toxicity both in vitro and in vivo. Neurosci Lett 502:65–69. doi:10.1016/j.neulet.2011.07.026
Taylor MP, Kirkegaard K (2008) Potential subversion of autophagosomal pathway by picornaviruses. Autophagy 4:286–289
UNODC (2014) World Drug Report 2014 United Nations publication, Sales No E14XI7
Wu CW et al (2007) Enhanced oxidative stress and aberrant mitochondrial biogenesis in human neuroblastoma SH-SY5Y cells during methamphetamine induced apoptosis. Toxicol Appl Pharmacol 220:243–251. doi:10.1016/j.taap.2007.01.011
Xie Z, Klionsky DJ (2007) Autophagosome formation: core machinery and adaptations. Nat Cell Biol 9:1102–1109. doi:10.1038/ncb1007-1102
Xu K, Xu YH, Chen JF, Schwarzschild MA (2010) Neuroprotection by caffeine: time course and role of its metabolites in the MPTP model of Parkinson’s disease. Neuroscience 167:475–481. doi:10.1016/j.neuroscience.2010.02.020
Acknowledgments
This work was supported by the following Grants; young investigator award from Mahidol University for Grant to PS*, the graduate student training award from National Research Council of Thailand (NRCT) for RP, and the office of the higher education commission and Mahidol University under the National Research Universities Initiative (NRU).
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Pitaksalee, R., Sanvarinda, Y., Sinchai, T. et al. Autophagy Inhibition by Caffeine Increases Toxicity of Methamphetamine in SH-SY5Y Neuroblastoma Cell Line. Neurotox Res 27, 421–429 (2015). https://doi.org/10.1007/s12640-014-9513-9
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DOI: https://doi.org/10.1007/s12640-014-9513-9