Neurochemical Research

, Volume 43, Issue 1, pp 66–78 | Cite as

Role of Mitochondria in Methamphetamine-Induced Dopaminergic Neurotoxicity: Involvement in Oxidative Stress, Neuroinflammation, and Pro-apoptosis—A Review

  • Eun-Joo Shin
  • Hai-Quyen Tran
  • Phuong-Tram Nguyen
  • Ji Hoon Jeong
  • Seung-Yeol Nah
  • Choon-Gon Jang
  • Toshitaka Nabeshima
  • Hyoung-Chun KimEmail author
Original Paper


Methamphetamine (MA), an amphetamine-type psychostimulant, is associated with dopaminergic toxicity and has a high abuse potential. Numerous in vivo and in vitro studies have suggested that impaired mitochondria are critical in dopaminergic toxicity induced by MA. Mitochondria are important energy-producing organelles with dynamic nature. Evidence indicated that exposure to MA can disturb mitochondrial energetic metabolism by inhibiting the Krebs cycle and electron transport chain. Alterations in mitochondrial dynamic processes, including mitochondrial biogenesis, mitophagy, and fusion/fission, have recently been shown to contribute to dopaminergic toxicity induced by MA. Furthermore, it was demonstrated that MA-induced mitochondrial impairment enhances susceptibility to oxidative stress, pro-apoptosis, and neuroinflammation in a positive feedback loop. Protein kinase Cδ has emerged as a potential mediator between mitochondrial impairment and oxidative stress, pro-apoptosis, or neuroinflammation in MA neurotoxicity. Understanding the role and underlying mechanism of mitochondrial impairment could provide a molecular target to prevent or alleviate dopaminergic toxicity induced by MA.


Methamphetamine Dopaminergic toxicity Mitochondria Apoptosis Protein kinase Cδ 



This study was supported by a Grant (#14182MFDS979) from the Korea Food and Drug Administration and, in part, by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning (#NRF-2017R1A2B1003346 and #NRF-2016R1A1A1A05005201), Republic of Korea. Hai-Quyen Tran and Phuong-Tram Nguyen were supported by the BK21 PLUS program, NRF, Republic of Korea. The English in this document has been checked by at least two professional editors, both native English speakers (e-World Editing, Inc. Eugene, OR 97401, USA).

Compliance with Ethical Standards

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    United Nations Office on Drugs and Crime (2015) World Drug Report 2015. United Nations. Accessed 28 June 2015
  2. 2.
    Nordahl TE, Salo R, Leamon M (2003) Neuropsychological effects of chronic methamphetamine use on neurotransmitters and cognition: a review. J Neuropsychiatry Clin Neurosci 15:317–325. doi: Google Scholar
  3. 3.
    Baumann MH, Ayestas MA, Sharpe LG, Lewis DB, Rice KC, Rothman RB (2002) Persistent antagonism of methamphetamine-induced dopamine release in rats pretreated with GBR12909 decanoate. J Pharmacol Exp Ther 301:1190–1197Google Scholar
  4. 4.
    Wagner GC, Lucot JB, Schuster CR, Seiden LS (1983) Alpha-methyltyrosine attenuates and reserpine increases METH-induced neuronal changes. Brain Res 270:285–288Google Scholar
  5. 5.
    Fumagalli F, Gainetdinov RR, Wang YM, Valenzano KJ, Miller GW, Caron MG (1999) Increased methamphetamine neurotoxicity in heterozygous vesicular monoamine transporter 2 knock-out mice. J Neurosci 19:2424–2431Google Scholar
  6. 6.
    Guillot TS, Shepherd KR, Richardson JR, Wang MZ, Li Y, Emson PC, Miller GW (2008) Reduced vesicular storage of dopamine exacerbates methamphetamine-induced neurodegeneration and astrogliosis. J Neurochem 106:2205–2217. doi: Google Scholar
  7. 7.
    Sulzer D, Sonders MS, Poulsen NW, Galli A (2005) Mechanisms of neurotransmitter release by amphetamines: a review. Prog Neurobiol 75:406–433. doi: Google Scholar
  8. 8.
    Panenka WJ, Procyshyn RM, Lecomte T, MacEwan GW, Flynn SW, Honer WG, Barr AM (2013) Methamphetamine use: a comprehensive review of molecular, preclinical and clinical findings. Drug Alcohol Depend 129:167–179. doi: Google Scholar
  9. 9.
    Morgan ME, Gibb JW (1980) Short-term and long-term effects of methamphetamine on biogenic amine metabolism in extra-striatal dopaminergic nuclei. Neuropharmacology 19:989–995Google Scholar
  10. 10.
    Eisch AJ, Gaffney M, Weihmuller FB, O’Dell SJ, Marshall JF (1992) Striatal subregions are differentially vulnerable to the neurotoxic effects of methamphetamine. Brain Res 598:321–326Google Scholar
  11. 11.
    Cass WA (1997) Decreases in evoked overflow of dopamine in rat striatum after neurotoxic doses of methamphetamine. J Pharmacol Exp Ther 280:105–113Google Scholar
  12. 12.
    Seiden LS, Commins DL, Vosmer G, Axt K, Marek G (1988) Neurotoxicity in dopamine and 5-hydroxytryptamine terminal fields: a regional analysis in nigrostriatal and mesolimbic projections. Ann N Y Acad Sci 537:161–172Google Scholar
  13. 13.
    Son JH, Kuhn J, Keefe KA (2013) Perseverative behavior in rats with methamphetamine-induced neurotoxicity. Neuropharmacology 67:95–103. doi: Google Scholar
  14. 14.
    Gross NB, Duncker PC, Marshall JF (2011) Striatal dopamine D1 and D2 receptors: widespread influences on methamphetamine-induced dopamine and serotonin neurotoxicity. Synapse 65:1144–1155. doi: Google Scholar
  15. 15.
    Burrows KB, Meshul CK (1999) High-dose methamphetamine treatment alters presynaptic GABA and glutamate immunoreactivity. Neuroscience 90:833–850Google Scholar
  16. 16.
    Brown JM, Quinton MS, Yamamoto BK (2005) Methamphetamine-induced inhibition of mitochondrial complex II: roles of glutamate and peroxynitrite. J Neurochem 95:429–436Google Scholar
  17. 17.
    Thrash B, Karuppagounder SS, Uthayathas S, Suppiramaniam V, Dhanasekaran M (2010) Neurotoxic effects of methamphetamine. Neurochem Res 35:171–179. doi: Google Scholar
  18. 18.
    Feier G, Valvassori SS, Lopes-Borges J, Varela RB, Bavaresco DV, Scaini G, Morais MO, Andersen ML, Streck EL, Quevedo J (2012) Behavioral changes and brain energy metabolism dysfunction in rats treated with methamphetamine or dextroamphetamine. Neurosci Lett 530:75–79. doi: Google Scholar
  19. 19.
    Thrash-Williams B, Ahuja M, Karuppagounder SS, Uthayathas S, Suppiramaniam V, Dhanasekaran M (2013) Assessment of therapeutic potential of amantadine in methamphetamine induced neurotoxicity. Neurochem Res 38:2084–2094. doi: Google Scholar
  20. 20.
    Nakahara T, Kuroki T, Ohta E, Kajihata T, Yamada H, Yamanaka M, Hashimoto K, Tsutsumi T, Hirano M, Uchimura H (2003) Effect of the neurotoxic dose of methamphetamine on gene expression of parkin and Pael-receptors in rat striatum. Parkinsonism Relat Disord 9:213–219Google Scholar
  21. 21.
    Tian C, Murrin LC, Zheng JC (2009) Mitochondrial fragmentation is involved in methamphetamine-induced cell death in rat hippocampal neural progenitor cells. PLoS ONE 4:e5546. doi: Google Scholar
  22. 22.
    Moszczynska A, Yamamoto BK (2011) Methamphetamine oxidatively damages parkin and decreases the activity of 26 S proteasome in vivo. J Neurochem 116:1005–1017. doi: Google Scholar
  23. 23.
    Lenzi P, Marongiu R, Falleni A, Gelmetti V, Busceti CL, Michiorri S, Valente EM, Fornai F (2012) A subcellular analysis of genetic modulation of PINK1 on mitochondrial alterations, autophagy and cell death. Arch Ital Biol 150:194–217. doi: Google Scholar
  24. 24.
    Lin M, Chandramani-Shivalingappa P, Jin H, Ghosh A, Anantharam V, Ali S, Kanthasamy AG, Kanthasamy A (2012) Methamphetamine-induced neurotoxicity linked to ubiquitin-proteasome system dysfunction and autophagy-related changes that can be modulated by protein kinase C delta in dopaminergic neuronal cells. Neuroscience 210:308–332. doi: Google Scholar
  25. 25.
    Parameyong A, Charngkaew K, Govitrapong P, Chetsawang B (2013) Melatonin attenuates methamphetamine-induced disturbances in mitochondrial dynamics and degeneration in neuroblastoma SH-SY5Y cells. J Pineal Res 55:313–323. doi: Google Scholar
  26. 26.
    Parameyong A, Govitrapong P, Chetsawang B (2015) Melatonin attenuates the mitochondrial translocation of mitochondrial fission proteins and Bax, cytosolic calcium overload and cell death in methamphetamine-induced toxicity in neuroblastoma SH-SY5Y cells. Mitochondrion 24:1–8. doi: Google Scholar
  27. 27.
    Wilson JM, Kalasinsky KS, Levey AI, Bergeron C, Reiber G, Anthony RM, Schmunk GA, Shannak K, Haycock JW, Kish SJ (1996) Striatal dopamine nerve terminal markers in human, chronic methamphetamine users. Nat Med 2:699–703Google Scholar
  28. 28.
    McCann UD, Wong DF, Yokoi F, Villemagne V, Dannals RF, Ricaurte GA (1998) Reduced striatal dopamine transporter density in abstinent methamphetamine and methcathinone users: evidence from positron emission tomography studies with [11C]WIN-35,428. J Neurosci 18:8417–8422Google Scholar
  29. 29.
    Volkow ND, Chang L, Wang GJ, Fowler JS, Franceschi D, Sedler M, Gatley SJ, Miller E, Hitzemann R, Ding YS, Logan J (2001) Loss of dopamine transporters in methamphetamine abusers recovers with protracted abstinence. J Neurosci 21:9414–9418Google Scholar
  30. 30.
    Volkow ND, Chang L, Wang GJ, Fowler JS, Leonido-Yee M, Franceschi D, Sedler MJ, Gatley SJ, Hitzemann R, Ding YS, Logan J, Wong C, Miller EN (2001) Association of dopamine transporter reduction with psychomotor impairment in methamphetamine abusers. Am J Psychiatry 158:377–382Google Scholar
  31. 31.
    Moszczynska A, Fitzmaurice P, Ang L, Kalasinsky KS, Schmunk GA, Peretti FJ, Aiken SS, Wickham DJ, Kish SJ (2004) Why is parkinsonism not a feature of human methamphetamine users? Brain 127:363–370Google Scholar
  32. 32.
    Sekine Y, Iyo M, Ouchi Y, Matsunaga T, Tsukada H, Okada H, Yoshikawa E, Futatsubashi M, Takei N, Mori N (2001) Methamphetamine-related psychiatric symptoms and reduced brain dopamine transporters studied with PET. Am J Psychiatry 158:1206–1214Google Scholar
  33. 33.
    O’Callaghan JP, Miller DB. Neurotoxicity profiles of substituted amphetamines in the C57BL/6 J mouse (1994). J Pharmacol Exp Ther 270:741–751Google Scholar
  34. 34.
    Kim HC, Jhoo WK, Choi DY, Im DH, Shin EJ, Suh JH, Floyd RA, Bing G (1999) Protection of methamphetamine nigrostriatal toxicity by dietary selenium. Brain Res 851:76–86Google Scholar
  35. 35.
    Kim HC, Jhoo WK, Shin EJ, Bing G (2000) Selenium deficiency potentiates methamphetamine-induced nigral neuronal loss; comparison with MPTP model. Brain Res 862:247–252Google Scholar
  36. 36.
    Hashimoto K, Tsukada H, Nishiyama S, Fukumoto D, Kakiuchi T, Shimizu E, Iyo M (2004) Protective effects of N-acetyl-L-cysteine on the reduction of dopamine transporters in the striatum of monkeys treated with methamphetamine. Neuropsychopharmacology 29:2018–2023Google Scholar
  37. 37.
    Shin EJ, Duong CX, Nguyen TX, Bing G, Bach JH, Park DH, Nakayama K, Ali SF, Kanthasamy AG, Cadet JL, Nabeshima T, Kim HC (2011) PKCδ inhibition enhances tyrosine hydroxylase phosphorylation in mice after methamphetamine treatment. Neurochem Int 59:39–50. doi: Google Scholar
  38. 38.
    Wang Q, Shin EJ, Nguyen XK, Li Q, Bach JH, Bing G, Kim WK, Kim HC, Hong JS (2012) Endogenous dynorphin protects against neurotoxin-elicited nigrostriatal dopaminergic neuron damage and motor deficits in mice. J Neuroinflammation 9:124. doi: Google Scholar
  39. 39.
    Shin EJ, Shin SW, Nguyen TT, Park DH, Wie MB, Jang CG, Nah SY, Yang BW, Ko SK, Nabeshima T, Kim HC (2014) Ginsenoside Re rescues methamphetamine-induced oxidative damage, mitochondrial dysfunction, microglial activation, and dopaminergic degeneration by inhibiting the protein kinase Cδ gene. Mol Neurobiol 49:1400–1421. doi: Google Scholar
  40. 40.
    McConnell SE, O’Banion MK, Cory-Slechta DA, Olschowka JA, Opanashuk LA (2015) Characterization of binge-dosed methamphetamine-induced neurotoxicity and neuroinflammation. Neurotoxicology 50:131–141. doi: Google Scholar
  41. 41.
    Nguyen XK, Lee J, Shin EJ, Dang DK, Jeong JH, Nguyen TT, Nam Y, Cho HJ, Lee JC, Park DH, Jang CG, Hong JS, Nabeshima T, Kim HC (2015) Liposomal melatonin rescues methamphetamine-elicited mitochondrial burdens, pro-apoptosis, and dopaminergic degeneration through the inhibition PKCδ gene. J Pineal Res 58:86–106. doi: Google Scholar
  42. 42.
    Dang DK, Shin EJ, Nam Y, Ryoo S, Jeong JH, Jang CG, Nabeshima T, Hong JS, Kim HC (2016) Apocynin prevents mitochondrial burdens, microglial activation, and pro-apoptosis induced by a toxic dose of methamphetamine in the striatum of mice via inhibition of p47phox activation by ERK. J Neuroinflammation 13:12. doi: Google Scholar
  43. 43.
    Melega WP, Jorgensen MJ, Laćan G, Way BM, Pham J, Morton G, Cho AK, Fairbanks LA (2008) Long-term methamphetamine administration in the vervet monkey models aspects of a human exposure: brain neurotoxicity and behavioral profiles. Neuropsychopharmacology 33:1441–1452Google Scholar
  44. 44.
    Schwendt M, Rocha A, See RE, Pacchioni AM, McGinty JF, Kalivas PW (2009) Extended methamphetamine self-administration in rats results in a selective reduction of dopamine transporter levels in the prefrontal cortex and dorsal striatum not accompanied by marked monoaminergic depletion. J Pharmacol Exp Ther 331:555–562. doi: Google Scholar
  45. 45.
    Krasnova IN, Chiflikyan M, Justinova Z, McCoy MT, Ladenheim B, Jayanthi S, Quintero C, Brannock C, Barnes C, Adair JE, Lehrmann E, Kobeissy FH, Gold MS, Becker KG, Goldberg SR, Cadet JL (2013) CREB phosphorylation regulates striatal transcriptional responses in the self-administration model of methamphetamine addiction in the rat. Neurobiol Dis 58:132–143. doi: Google Scholar
  46. 46.
    Kousik SM, Carvey PM, Napier TC (2014) Methamphetamine self-administration results in persistent dopaminergic pathology: implications for Parkinson’s disease risk and reward-seeking. Eur J Neurosci 40:2707–2714. doi: Google Scholar
  47. 47.
    Segal DS, Kuczenski R, O’Neil ML, Melega WP, Cho AK (2005) Prolonged exposure of rats to intravenous methamphetamine: behavioral and neurochemical characterization. Psychopharmacology 180:501–512Google Scholar
  48. 48.
    Segal DS, Kuczenski R, O’Neil ML, Melega WP, Cho AK (2003) Escalating dose methamphetamine pretreatment alters the behavioral and neurochemical profiles associated with exposure to a high-dose methamphetamine binge. Neuropsychopharmacology 28:1730–1740Google Scholar
  49. 49.
    Bowyer JF, Davies DL, Schmued L, Broening HW, Newport GD, Slikker W Jr, Holson RR (1994) Further studies of the role of hyperthermia in methamphetamine neurotoxicity. J Pharmacol Exp Ther 268:1571–1580Google Scholar
  50. 50.
    Truong JG, Wilkins DG, Baudys J, Crouch DJ, Johnson-Davis KL, Gibb JW, Hanson GR, Fleckenstein AE (2005) Age-dependent methamphetamine-induced alterations in vesicular monoamine transporter-2 function: implications for neurotoxicity. J Pharmacol Exp Ther 314:1087–1092Google Scholar
  51. 51.
    Sonsalla PK, Jochnowitz ND, Zeevalk GD, Oostveen JA, Hall ED (1996) Treatment of mice with methamphetamine produces cell loss in the substantia nigra. Brain Res 738:172–175Google Scholar
  52. 52.
    Granado N, Ares-Santos S, Oliva I, O’Shea E, Martin ED, Colado MI, Moratalla R (2011) Dopamine D2-receptor knockout mice are protected against dopaminergic neurotoxicity induced by methamphetamine or MDMA. Neurobiol Dis 42:391–403. doi: Google Scholar
  53. 53.
    Ares-Santos S, Granado N, Espadas I, Martinez-Murillo R, Moratalla R (2014) Methamphetamine causes degeneration of dopamine cell bodies and terminals of the nigrostriatal pathway evidenced by silver staining. Neuropsychopharmacology 39:1066–1080. doi: Google Scholar
  54. 54.
    Deng X, Cadet JL (2000) Methamphetamine-induced apoptosis is attenuated in the striata of copper-zinc superoxide dismutase transgenic mice. Brain Res Mol Brain Res 83:121–124Google Scholar
  55. 55.
    Deng X, Wang Y, Chou J, Cadet JL (2001) Methamphetamine causes widespread apoptosis in the mouse brain: evidence from using an improved TUNEL histochemical method. Brain Res Mol Brain Res 93:64–69Google Scholar
  56. 56.
    Zhu JP, Xu W, Angulo JA (2006) Methamphetamine-induced cell death: selective vulnerability in neuronal subpopulations of the striatum in mice. Neuroscience 140:607–622Google Scholar
  57. 57.
    Fornai F, Lenzi P, Ferrucci M, Lazzeri G, di Poggio AB, Natale G, Busceti CL, Biagioni F, Giusiani M, Ruggieri S, Paparelli A (2005) Occurrence of neuronal inclusions combined with increased nigral expression of alpha-synuclein within dopaminergic neurons following treatment with amphetamine derivatives in mice. Brain Res Bull 65:405–413Google Scholar
  58. 58.
    Castino R, Lazzeri G, Lenzi P, Bellio N, Follo C, Ferrucci M, Fornai F, Isidoro C (2008) Suppression of autophagy precipitates neuronal cell death following low doses of methamphetamine. J Neurochem 106:1426–1439. doi: Google Scholar
  59. 59.
    Wu XF, Wang AF, Chen L, Huang EP, Xie WB, Liu C, Huang WY, Chen CX, Qiu PM, Wang HJ (2014) S-Nitrosylating protein disulphide isomerase mediates α-synuclein aggregation caused by methamphetamine exposure in PC12 cells. Toxicol Lett 230:19–27. doi: Google Scholar
  60. 60.
    Callaghan RC, Cunningham JK, Sajeev G, Kish SJ (2010) Incidence of Parkinson’s disease among hospital patients with methamphetamine-use disorders. Mov Disord 25:2333–2339. doi: Google Scholar
  61. 61.
    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: Google Scholar
  62. 62.
    Curtin K, Fleckenstein AE, Robison RJ, Crookston MJ, Smith KR, Hanson GR (2015) Methamphetamine/amphetamine abuse and risk of Parkinson’s disease in Utah: a population-based assessment. Drug Alcohol Depend 146:30–38. doi: Google Scholar
  63. 63.
    Atamna H, Frey WH 2nd (2007) Mechanisms of mitochondrial dysfunction and energy deficiency in Alzheimer’s disease. Mitochondrion 7:297–310Google Scholar
  64. 64.
    Barbosa DJ, Capela JP, Feio-Azevedo R, Teixeira-Gomes A, Bastos Mde L, Carvalho F (2015) Mitochondria: key players in the neurotoxic effects of amphetamines. Arch Toxicol 89:1695–1725. doi: Google Scholar
  65. 65.
    Zong WX, Rabinowitz JD, White E (2016) Mitochondria and Cancer. Mol Cell 61:667–676. doi: Google Scholar
  66. 66.
    Burrows KB, Nixdorf WL, Yamamoto BK (2000) Central administration of methamphetamine synergizes with metabolic inhibition to deplete striatal monoamines. J Pharmacol Exp Ther 292:853–860Google Scholar
  67. 67.
    Huang NK, Wan FJ, Tseng CJ, Tung CS (1997) Nicotinamide attenuates methamphetamine-induced striatal dopamine depletion in rats. Neuroreport 8:1883–1885Google Scholar
  68. 68.
    Stephans SE, Whittingham TS, Douglas AJ, Lust WD, Yamamoto BK (1998) Substrates of energy metabolism attenuate methamphetamine-induced neurotoxicity in striatum. J Neurochem 71:613–621Google Scholar
  69. 69.
    Prince JA, Yassin MS, Oreland L (1997) Normalization of cytochrome-c oxidase activity in the rat brain by neuroleptics after chronic treatment with PCP or methamphetamine. Neuropharmacology 36:1665–1678Google Scholar
  70. 70.
    Burrows KB, Gudelsky G, Yamamoto BK (2000) Rapid and transient inhibition of mitochondrial function following methamphetamine or 3,4-methylenedioxymethamphetamine administration. Eur J Pharmacol 398:11–18Google Scholar
  71. 71.
    Klongpanichapak S, Govitrapong P, Sharma SK, Ebadi M (2006) Attenuation of cocaine and methamphetamine neurotoxicity by coenzyme Q10. Neurochem Res 31:303–311Google Scholar
  72. 72.
    Wu CW, Ping YH, Yen JC, Chang CY, Wang SF, Yeh CL, Chi CW, Lee HC (2007) Enhanced oxidative stress and aberrant mitochondrial biogenesis in human neuroblastoma SH-SY5Y cells during methamphetamine induced apoptosis. Toxicol Appl Pharmacol 220:243–251Google Scholar
  73. 73.
    Chin MH, Qian WJ, Wang H, Petyuk VA, Bloom JS, Sforza DM, Laćan G, Liu D, Khan AH, Cantor RM, Bigelow DJ, Melega WP, Camp DG 2nd, Smith RD, Smith DJ (2008) Mitochondrial dysfunction, oxidative stress, and apoptosis revealed by proteomic and transcriptomic analyses of the striata in two mouse models of Parkinson’s disease. J Proteome Res 7:666–677. doi: Google Scholar
  74. 74.
    Bachmann RF, Wang Y, Yuan P, Zhou R, Li X, Alesci S, Du J, Manji HK (2009) Common effects of lithium and valproate on mitochondrial functions: protection against methamphetamine-induced mitochondrial damage. Int J Neuropsychopharmacol 12:805–822. doi: Google Scholar
  75. 75.
    Lau JW, Senok S, Stadlin A (2000) Methamphetamine-induced oxidative stress in cultured mouse astrocytes. Ann N Y Acad Sci 914:146–156Google Scholar
  76. 76.
    Deng X, Cai NS, McCoy MT, Chen W, Trush MA, Cadet JL (2002) Methamphetamine induces apoptosis in an immortalized rat striatal cell line by activating the mitochondrial cell death pathway. Neuropharmacology 42:837–845Google Scholar
  77. 77.
    Nam Y, Wie MB, Shin EJ, Nguyen TT, Nah SY, Ko SK, Jeong JH, Jang CG, Kim HC (2015) Ginsenoside Re protects methamphetamine-induced mitochondrial burdens and proapoptosis via genetic inhibition of protein kinase C δ in human neuroblastoma dopaminergic SH-SY5Y cell lines. J Appl Toxicol 35:927–944. doi: Google Scholar
  78. 78.
    Chan P, Di Monte DA, Luo JJ, DeLanney LE, Irwin I, Langston JW (1994) Rapid ATP loss caused by methamphetamine in the mouse striatum: relationship between energy impairment and dopaminergic neurotoxicity. J Neurochem 62:2484–2487Google Scholar
  79. 79.
    Ajjimaporn A, Swinscoe J, Shavali S, Govitrapong P, Ebadi M (2005) Metallothionein provides zinc-mediated protective effects against methamphetamine toxicity in SK-N-SH cells. Brain Res Bull 67:466–475Google Scholar
  80. 80.
    da Silva DD, Silva E, Carmo H (2014) Combination effects of amphetamines under hyperthermia—the role played by oxidative stress. J Appl Toxicol 34:637–650. doi: Google Scholar
  81. 81.
    Anne Stetler R, Leak RK, Gao Y, Chen J (2013) The dynamics of the mitochondrial organelle as a potential therapeutic target. J Cereb Blood Flow Metab 33:22–32. doi: Google Scholar
  82. 82.
    Barrett T, Xie T, Piao Y, Dillon-Carter O, Kargul GJ, Lim MK, Chrest FJ, Wersto R, Rowley DL, Juhaszova M, Zhou L, Vawter MP, Becker KG, Cheadle C, Wood WH 3rd, McCann UD, Freed WJ, Ko MS, Ricaurte GA, Donovan DM (2001) A murine dopamine neuron-specific cDNA library and microarray: increased COX1 expression during methamphetamine neurotoxicity. Neurobiol Dis 8:822–833Google Scholar
  83. 83.
    Xie T, Tong L, Barrett T, Yuan J, Hatzidimitriou G, McCann UD, Becker KG, Donovan DM, Ricaurte GA (2002) Changes in gene expression linked to methamphetamine-induced dopaminergic neurotoxicity. J Neurosci 22:274–283Google Scholar
  84. 84.
    Valian N, Ahmadiani A, Dargahi L (2016) Escalating methamphetamine regimen induces compensatory mechanisms, mitochondrial biogenesis, and GDNF expression, in substantia nigra. J Cell Biochem. doi:
  85. 85.
    Palikaras K, Tavernarakis N (2012) Mitophagy in neurodegeneration and aging. Front Genet 3:297. doi: Google Scholar
  86. 86.
    Fornai F, Lenzi P, Gesi M, Soldani P, Ferrucci M, Lazzeri G, Capobianco L, Battaglia G, De Blasi A, Nicoletti F, Paparelli A (2004) Methamphetamine produces neuronal inclusions in the nigrostriatal system and in PC12 cells. J Neurochem 88:114–123Google Scholar
  87. 87.
    Liu B, Traini R, Killinger B, Schneider B, Moszczynska A (2013) Overexpression of parkin in the rat nigrostriatal dopamine system protects against methamphetamine neurotoxicity. Exp Neurol 247:359–372. doi: Google Scholar
  88. 88.
    Twig G, Hyde B, Shirihai OS (2008) Mitochondrial fusion, fission and autophagy as a quality control axis: the bioenergetic view. Biochim Biophys Acta 1777:1092–1097. doi: Google Scholar
  89. 89.
    Mouli PK, Twig G, Shirihai OS (2009) Frequency and selectivity of mitochondrial fusion are key to its quality maintenance function. Biophys J 96:3509–3518. doi: Google Scholar
  90. 90.
    Koshiba T, Detmer SA, Kaiser JT, Chen H, McCaffery JM, Chan DC (2004) Structural basis of mitochondrial tethering by mitofusin complexes. Science 305:858–862Google Scholar
  91. 91.
    Olichon A, Baricault L, Gas N, Guillou E, Valette A, Belenguer P, Lenaers G (2003) Loss of OPA1 perturbates the mitochondrial inner membrane structure and integrity, leading to cytochrome c release and apoptosis. J Biol Chem 278:7743–7746Google Scholar
  92. 92.
    Labrousse AM, Zappaterra MD, Rube DA, van der Bliek AM (1999) C. elegans dynamin-related protein DRP-1 controls severing of the mitochondrial outer membrane. Mol Cell 4:815–826Google Scholar
  93. 93.
    Chen H, Chan DC (2009) Mitochondrial dynamics-fusion, fission, movement, and mitophagy-in neurodegenerative diseases. Hum Mol Genet 18:R169–R176. doi: Google Scholar
  94. 94.
    Santos D, Esteves AR, Silva DF, Januário C, Cardoso SM (2015) The impact of mitochondrial fusion and fission modulation in Sporadic Parkinson’s Disease. Mol Neurobiol 52:573–586. doi: Google Scholar
  95. 95.
    Winyard PG, Moody CJ, Jacob C (2005) Oxidative activation of antioxidant defence. Trends Biochem Sci 30:453–461Google Scholar
  96. 96.
    Fitzmaurice PS, Tong J, Yazdanpanah M, Liu PP, Kalasinsky KS, Kish SJ (2006) Levels of 4-hydroxynonenal and malondialdehyde are increased in brain of human chronic users of methamphetamine. J Pharmacol Exp Ther 319:703–709Google Scholar
  97. 97.
    Huang MC, Lin SK, Chen CH, Pan CH, Lee CH, Liu HC (2013) Oxidative stress status in recently abstinent methamphetamine abusers. Psychiatry Clin Neurosci 67:92–100. doi: Google Scholar
  98. 98.
    Solhi H, Malekirad A, Kazemifar AM, Sharifi F (2014) Oxidative stress and lipid peroxidation in prolonged users of methamphetamine. Drug Metab Lett 7:79–82Google Scholar
  99. 99.
    LaVoie MJ, Hastings TG (1999) Dopamine quinone formation and protein modification associated with the striatal neurotoxicity of methamphetamine: evidence against a role for extracellular dopamine. J Neurosci 19:1484–1491Google Scholar
  100. 100.
    Hermida-Ameijeiras A, Méndez-Alvarez E, Sánchez-Iglesias S, Sanmartín-Suárez C, Soto-Otero R (2004) Autoxidation and MAO-mediated metabolism of dopamine as a potential cause of oxidative stress: role of ferrous and ferric ions. Neurochem Int 45:103–116Google Scholar
  101. 101.
    Thrash-Williams B, Karuppagounder SS, Bhattacharya D, Ahuja M, Suppiramaniam V, Dhanasekaran M (2016) Methamphetamine-induced dopaminergic toxicity prevented owing to the neuroprotective effects of salicylic acid. Life Sci 154:24–29. doi: Google Scholar
  102. 102.
    Sipos I, Tretter L, Adam-Vizi V (2003) Quantitative relationship between inhibition of respiratory complexes and formation of reactive oxygen species in isolated nerve terminals. J Neurochem 84:112–118Google Scholar
  103. 103.
    Adam-Vizi V (2005) Production of reactive oxygen species in brain mitochondria: contribution by electron transport chain and non-electron transport chain sources. Antioxid Redox Signal 7:1140–1149Google Scholar
  104. 104.
    Zhang Y, Marcillat O, Giulivi C, Ernster L, Davies KJ (1990) The oxidative inactivation of mitochondrial electron transport chain components and ATPase. J Biol Chem 265:16330–16336Google Scholar
  105. 105.
    Açikgöz O, Gönenç S, Kayatekin BM, Uysal N, Pekçetin C, Semin I, Güre A (1998) Methamphetamine causes lipid peroxidation and an increase in superoxide dismutase activity in the rat striatum. Brain Res 813:200–202Google Scholar
  106. 106.
    Zhang X, Tobwala S, Ercal N (2012) N-acetylcysteine amide protects against methamphetamine-induced tissue damage in CD-1 mice. Hum Exp Toxicol 31:931–944Google Scholar
  107. 107.
    Cadet JL, Sheng P, Ali S, Rothman R, Carlson E, Epstein C (1994) Attenuation of methamphetamine-induced neurotoxicity in copper/zinc superoxide dismutase transgenic mice. J Neurochem 62:380–383Google Scholar
  108. 108.
    Hirata H, Ladenheim B, Carlson E, Epstein C, Cadet JL (1996) Autoradiographic evidence for methamphetamine-induced striatal dopaminergic loss in mouse brain: attenuation in CuZn-superoxide dismutase transgenic mice. Brain Res 714:95–103Google Scholar
  109. 109.
    Maragos WF, Jakel R, Chesnut D, Pocernich CB, Butterfield DA, St Clair D, Cass WA (2000) Methamphetamine toxicity is attenuated in mice that overexpress human manganese superoxide dismutase. Brain Res 878:218–222Google Scholar
  110. 110.
    Imam SZ, Newport GD, Itzhak Y, Cadet JL, Islam F, Slikker W Jr, Ali SF (2001) Peroxynitrite plays a role in methamphetamine-induced dopaminergic neurotoxicity: evidence from mice lacking neuronal nitric oxide synthase gene or overexpressing copper-zinc superoxide dismutase. J Neurochem 76:745–749Google Scholar
  111. 111.
    Koriem KM, Abdelhamid AZ, Younes HF (2013) Caffeic acid protects tissue antioxidants and DNA content in methamphetamine induced tissue toxicity in Sprague Dawley rats. Toxicol Mech Methods 23:134–143. doi: Google Scholar
  112. 112.
    Imam SZ, Newport GD, Islam F, Slikker W Jr, Ali SF (1999) Selenium, an antioxidant, protects against methamphetamine-induced dopaminergic neurotoxicity. Brain Res 818:575–578Google Scholar
  113. 113.
    Mirecki A, Fitzmaurice P, Ang L, Kalasinsky KS, Peretti FJ, Aiken SS, Wickham DJ, Sherwin A, Nobrega JN, Forman HJ, Kish SJ (2004) Brain antioxidant systems in human methamphetamine users. J Neurochem 89:1396–1408Google Scholar
  114. 114.
    Park MJ, Lee SK, Lim MA, Chung HS, Cho SI, Jang CG, Lee SM (2006) Effect of alpha-tocopherol and deferoxamine on methamphetamine-induced neurotoxicity. Brain Res 1109:176–182Google Scholar
  115. 115.
    Shokrzadeh M, Zamani E, Mehrzad M, Norian Y, Shaki F (2015) Protective effects of propofol against methamphetamine-induced neurotoxicity. Toxicol Int 22:92–99. doi: Google Scholar
  116. 116.
    Annepu J, Ravindranath V (2000) 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced complex I inhibition is reversed by disulfide reductant, dithiothreitol in mouse brain. Neurosci Lett 289:209–212Google Scholar
  117. 117.
    Beer SM, Taylor ER, Brown SE, Dahm CC, Costa NJ, Runswick MJ, Murphy MP (2004) Glutaredoxin 2 catalyzes the reversible oxidation and glutathionylation of mitochondrial membrane thiol proteins: implications for mitochondrial redox regulation and antioxidant DEFENSE. J Biol Chem 279:47939–47951Google Scholar
  118. 118.
    Shin EJ, Nam Y, Tu TH, Lim YK, Wie MB, Kim DJ, Jeong JH, Kim HC (2016) Protein kinase Cδ mediates trimethyltin-induced neurotoxicity in mice in vivo via inhibition of glutathione defense mechanism. Arch Toxicol 90:937–953. doi: Google Scholar
  119. 119.
    LaVoie MJ, Ostaszewski BL, Weihofen A, Schlossmacher MG, Selkoe DJ (2005) Dopamine covalently modifies and functionally inactivates parkin. Nat Med 11:1214–1221Google Scholar
  120. 120.
    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 15:1745–1752Google Scholar
  121. 121.
    Beauvais G, Atwell K, Jayanthi S, Ladenheim B, Cadet JL (2011) Involvement of dopamine receptors in binge methamphetamine-induced activation of endoplasmic reticulum and mitochondrial stress pathways. PLoS ONE 6:e28946. doi: Google Scholar
  122. 122.
    RaINeri M, Gonzalez B, Goitia B, Garcia-Rill E, Krasnova IN, Cadet JL, Urbano FJ, Bisagno V (2012) Modafinil abrogates methamphetamine-induced neuroinflammation and apoptotic effects in the mouse striatum. PLoS ONE 7:e46599. doi: Google Scholar
  123. 123.
    Kroemer G, Galluzzi L, Brenner C (2007) Mitochondrial membrane permeabilization in cell death. Physiol Rev 87:99–163Google Scholar
  124. 124.
    Bleicken S, Hofhaus G, Ugarte-Uribe B, Schröder R, García-Sáez AJ (2016) cBid, Bax and Bcl-xL exhibit opposite membrane remodeling activities. Cell Death Dis 7:e2121. doi: Google Scholar
  125. 125.
    Galluzzi L, Blomgren K, Kroemer G (2009) Mitochondrial membrane permeabilization in neuronal injury. Nat Rev Neurosci 10:481–494. doi: Google Scholar
  126. 126.
    Qiao D, Xu J, Le C, Huang E, Liu C, Qiu P, Lin Z, Xie WB, Wang H (2014) Insulin-like growth factor binding protein 5 (IGFBP5) mediates methamphetamine-induced dopaminergic neuron apoptosis. Toxicol Lett 230:444–453. doi: Google Scholar
  127. 127.
    Jayanthi S, Deng X, Noailles PA, Ladenheim B, Cadet JL (2004) Methamphetamine induces neuronal apoptosis via cross-talks between endoplasmic reticulum and mitochondria-dependent death cascades. FASEB J 18:238–251Google Scholar
  128. 128.
    Imam SZ, Jankovic J, Ali SF, Skinner JT, Xie W, Conneely OM, Le WD (2005) Nitric oxide mediates increased susceptibility to dopaminergic damage in Nurr1 heterozygous mice. FASEB J 19:1441–1450Google Scholar
  129. 129.
    Kanthasamy AG, Kitazawa M, Kanthasamy A, Anantharam V (2003) Role of proteolytic activation of protein kinase Cdelta in oxidative stress-induced apoptosis. Antioxid Redox Signal 5:609–620Google Scholar
  130. 130.
    Latchoumycandane C, Anantharam V, Jin H, Kanthasamy A, Kanthasamy A (2011) Dopaminergic neurotoxicant 6-OHDA induces oxidative damage through proteolytic activation of PKCδ in cell culture and animal models of Parkinson’s disease. Toxicol Appl Pharmacol 256:314–323. doi: Google Scholar
  131. 131.
    Brodie C, Blumberg PM (2003) Regulation of cell apoptosis by protein kinase c delta. Apoptosis 8:19–27Google Scholar
  132. 132.
    Shin EJ, Duong CX, Nguyen XK, Li Z, Bing G, Bach JH, Park DH, Nakayama K, Ali SF, Kanthasamy AG, Cadet JL, Nabeshima T, Kim HC (2012) Role of oxidative stress in methamphetamine-induced dopaminergic toxicity mediated by protein kinase Cδ. Behav Brain Res 232:98–113. doi: Google Scholar
  133. 133.
    Kanthasamy AG, Kitazawa M, Yang Y, Anantharam V, Kanthasamy A (2008) Environmental neurotoxin dieldrin induces apoptosis via caspase-3-dependent proteolytic activation of protein kinase C delta (PKCdelta): implications for neurodegeneration in Parkinson’s disease. Mol Brain 1:12. doi: Google Scholar
  134. 134.
    Di Filippo M, Chiasserini D, Tozzi A, Picconi B, Calabresi P (2010) Mitochondria and the link between neuroinflammation and neurodegeneration. J Alzheimers Dis 20:S369–S379. doi: Google Scholar
  135. 135.
    Hébert G, Arsaut J, Dantzer R, Demotes-Mainard J (2003) Time-course of the expression of inflammatory cytokines and matrix metalloproteinases in the striatum and mesencephalon of mice injected with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, a dopaminergic neurotoxin. Neurosci Lett 349:191–195Google Scholar
  136. 136.
    Yasuda Y, Shinagawa R, Yamada M, Mori T, Tateishi N, Fujita S (2007) Long-lasting reactive changes observed in microglia in the striatal and substantia nigral of mice after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Brain Res 1138:196–202Google Scholar
  137. 137.
    Bian MJ, Li LM, Yu M, Fei J, Huang F (2009) Elevated interleukin-1beta induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine aggravating dopaminergic neurodegeneration in old male mice. Brain Res 1302:256–264. doi: Google Scholar
  138. 138.
    Ferris CF, Marella M, Smerkers B, Barchet TM, Gershman B, Matsuno-Yagi A, Yagi T (2013) A phenotypic model recapitulating the neuropathology of Parkinson’s disease. Brain Behav 3:351–366. doi: Google Scholar
  139. 139.
    Javed H, Azimullah S, Abul Khair SB, Ojha S, Haque ME (2016) Neuroprotective effect of nerolidol against neuroinflammation and oxidative stress induced by rotenone. BMC Neurosci 17:58. doi: Google Scholar
  140. 140.
    Hunter RL, Dragicevic N, Seifert K, Choi DY, Liu M, Kim HC, Cass WA, Sullivan PG, Bing G (2007) Inflammation induces mitochondrial dysfunction and dopaminergic neurodegeneration in the nigrostriatal system. J Neurochem 100:1375–1386Google Scholar
  141. 141.
    Choi DY, Liu M, Hunter RL, Cass WA, Pandya JD, Sullivan PG, Shin EJ, Kim HC, Gash DM, Bing G (2009) Striatal neuroinflammation promotes Parkinsonism in rats. PLoS ONE 4:e5482. doi: Google Scholar
  142. 142.
    Tran TA, Nguyen AD, Chang J, Goldberg MS, Lee JK, Tansey MG (2011) Lipopolysaccharide and tumor necrosis factor regulate Parkin expression via nuclear factor-kappa B. PLoS ONE 6:e23660. doi: Google Scholar
  143. 143.
    Ye J, Jiang Z, Chen X, Liu M, Li J, Liu N (2016) Electron transport chain inhibitors induce microglia activation through enhancing mitochondrial reactive oxygen species production. Exp Cell Res 340:315–326. doi: Google Scholar
  144. 144.
    Thomas DM, Walker PD, Benjamins JA, Geddes TJ, Kuhn DM (2004) Methamphetamine neurotoxicity in dopamine nerve endings of the striatum is associated with microglial activation. J Pharmacol Exp Ther 311:1–7Google Scholar
  145. 145.
    Fantegrossi WE, Ciullo JR, Wakabayashi KT, De La Garza R 2nd, Traynor JR, Woods JH (2008) A comparison of the physiological, behavioral, neurochemical and microglial effects of methamphetamine and 3,4-methylenedioxymethamphetamine in the mouse. Neuroscience 151:533–543.Google Scholar
  146. 146.
    Sekine Y, Ouchi Y, Sugihara G, Takei N, Yoshikawa E, Nakamura K, Iwata Y, Tsuchiya KJ, Suda S, Suzuki K, Kawai M, Takebayashi K, Yamamoto S, Matsuzaki H, Ueki T, Mori N, Gold MS, Cadet JL (2008) Methamphetamine causes microglial activation in the brains of human abusers. J Neurosci 28:5756–5761. doi: Google Scholar
  147. 147.
    Robson MJ, Turner RC, Naser ZJ, McCurdy CR, Huber JD, Matsumoto RR (2013) SN79, a sigma receptor ligand, blocks methamphetamine-induced microglial activation and cytokine upregulation. Exp Neurol 247:134–142. doi: Google Scholar
  148. 148.
    Flora G, Lee YW, Nath A, Maragos W, Hennig B, Toborek M (2002) Methamphetamine-induced TNF-alpha gene expression and activation of AP-1 in discrete regions of mouse brain: potential role of reactive oxygen intermediates and lipid peroxidation. Neuromolecular Med 2:71–85Google Scholar
  149. 149.
    Gonçalves J, Martins T, Ferreira R, Milhazes N, Borges F, Ribeiro CF, Malva JO, Macedo TR, Silva AP (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. doi: Google Scholar
  150. 150.
    Zhang L, Kitaichi K, Fujimoto Y, Nakayama H, Shimizu E, Iyo M, Hashimoto K (2006) Protective effects of minocycline on behavioral changes and neurotoxicity in mice after administration of methamphetamine. Prog Neuropsychopharmacol Biol Psychiatry 30:1381–1393Google Scholar
  151. 151.
    Hashimoto K, Tsukada H, Nishiyama S, Fukumoto D, Kakiuchi T, Iyo M (2007) Protective effects of minocycline on the reduction of dopamine transporters in the striatum after administration of methamphetamine: a positron emission tomography study in conscious monkeys. Biol Psychiatry 61:577–581Google Scholar
  152. 152.
    Asanuma M, Tsuji T, Miyazaki I, Miyoshi K, Ogawa N (2003) Methamphetamine-induced neurotoxicity in mouse brain is attenuated by ketoprofen, a non-steroidal anti-inflammatory drug. Neurosci Lett 352:13–16Google Scholar
  153. 153.
    Tsuji T, Asanuma M, Miyazaki I, Miyoshi K, Ogawa N (2009) Reduction of nuclear peroxisome proliferator-activated receptor gamma expression in methamphetamine-induced neurotoxicity and neuroprotective effects of ibuprofen. Neurochem Res 34:764–774. doi: Google Scholar
  154. 154.
    Saha K, Sambo D, Richardson BD, Lin LM, Butler B, Villarroel L, Khoshbouei H (2014) Intracellular methamphetamine prevents the dopamine-induced enhancement of neuronal firing. J Biol Chem 289:22246–22257. doi: Google Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  1. 1.Neuropsychopharmacology and Toxicology Program, College of PharmacyKangwon National UniversityChunchonRepublic of Korea
  2. 2.Department of Pharmacology, College of MedicineChung-Ang UniversitySeoulRepublic of Korea
  3. 3.Ginsentology Research Laboratory and Department of Physiology, College of Veterinary MedicineKonkuk UniversitySeoulRepublic of Korea
  4. 4.Department of Pharmacology, School of PharmacySungkyunkwan UniversitySuwonRepublic of Korea
  5. 5.Advanced Diagnostic System Research LaboratoryFujita Health University Graduate School of Health ScienceToyoakeJapan

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