Advertisement

Neurotoxicity Research

, Volume 35, Issue 1, pp 49–62 | Cite as

Cytotoxic Effects of 3,4-Catechol-PV (One Major MDPV Metabolite) on Human Dopaminergic SH-SY5Y Cells

  • Teresa Coccini
  • Sarah Vecchio
  • Marta Crevani
  • Uliana De Simone
ORIGINAL ARTICLE
  • 88 Downloads

Abstract

3,4-Methylenedioxypyrovalerone (MDPV), one of the most commonly abused synthetic cathinones, has caused several intoxications and deaths despite its short presence on the market. Apart from its effects on the monoamine systems in the brain, recent in vitro investigations have revealed cytotoxicity. In this study, the effects of increasing concentrations (10–1000 μM) of 3,4-Catechol-PV, one of major MDPV metabolites, on cell viability, morphology, and apoptosis have been evaluated after acute exposure (24–48 h) in human neuroblastoma SH-SY5Y cells—undifferentiated and differentiated to a more mature neuronal-like phenotype. Results indicated the following: (i) Cell viability: concentration-dependent decrease (15–55%) in differentiated SH-SY5Y after 24 h, with no exacerbation after 48 h (LC50 values 1028 and 951 μM, respectively); marked concentration-dependent decrease after 48 h (20–63%) in undifferentiated SH-SY5Y (LC50 553.9 μM) with mild effect (18–22% cell death) after 24 h at ≥ 500 μM only; the lowest toxic concentrations were 500 and 100 μM after 24 h, for undifferentiated and differentiated SH-SY5Y, respectively, and 10 μM after 48 h. (ii) Concentration- and time-dependent alterations of cell morphology in both SH-SY5Y types characterized by several intracellular cytoplasmic vesicles (undifferentiated more susceptible (effect at ≥ 50 μM) than differentiated cells (effect at ≥ 100 μM)), loss of the typical cell shape, neurite retraction, and cell density decrease. (iii) Activation of caspase-3 enzyme in differentiated and undifferentiated cells after 48 h. These findings suggest the potential involvement of 3,4-Catechol-PV in MDPV-induced neurotoxicity and support the use of this human cellular model as a species-specific in vitro tool to clarify the neurotoxicity mechanisms of synthetic cathinones and metabolites.

Keywords

Novel psychoactive substances Synthetic cathinones Undifferentiated SH-SY5Y Differentiated SH-SY5Y CNS 3,4-Methylenedioxypyrovalerone 

Notes

Funding Information

This work was supported by grant from the Italian Ministries of Health, Research and Education,

Compliance with Ethical Standards

Conflict of Interest

The authors declare that there is no conflict of interests regarding the publication of this paper.

Supplementary material

12640_2018_9924_MOESM1_ESM.docx (25.1 mb)
Fig. 1cS (DOCX 25697 kb)
12640_2018_9924_MOESM2_ESM.docx (2.5 mb)
Fig. 4S (DOCX 2533 kb)
12640_2018_9924_MOESM3_ESM.docx (2.4 mb)
Fig. 5S (DOCX 2432 kb)

References

  1. Adam A, Gerecsei LI, Lepesi N, Csillag A (2014) Apoptotic effects of the ‘designer drug’ methylenedioxypyrovalerone (MDPV) on the neonatal mouse brain. NeuroToxicology 44:231–236.  https://doi.org/10.1016/j.neuro.2014.07.004 CrossRefPubMedGoogle Scholar
  2. Angoa-Pérez M, Anneken JH, Kuhn DM (2017) Neurotoxicology of synthetic cathinone analogs. Curr Top Behav Neurosci 32:209–230.  https://doi.org/10.1007/7854_2016_21 CrossRefPubMedPubMedCentralGoogle Scholar
  3. Anizan S, Concheiro M, Lehner KR, Bukhari MO, Suzuki M, Rice KC, Baumann MH, Huestis MA (2016) Linear pharmacokinetics of 3,4-methylenedioxypyrovalerone (MDPV) and its metabolites in the rat: relationship to pharmacodynamic effects. Addict Biol 21(2):339–347.  https://doi.org/10.1111/adb.12201 CrossRefPubMedGoogle Scholar
  4. Barbosa DJ, Capela JP, Silva R, Vilas-Boas V, Ferreira LM, Branco PS, Fernandes E, Bastos ML, Carvalho F (2014) The mixture of “ecstasy” and its metabolites is toxic to human SH-SY5Y differentiated cells at in vivo relevant concentrations. Arch Toxicol 88(2):455–473.  https://doi.org/10.1007/s00204-013-1120-7 CrossRefPubMedGoogle Scholar
  5. Baumann MH, Partilla JS, Lehner KR, Thorndike EB, Hoffman AF, Holy M, Rothman RB, Goldberg SR, Lupica CR, Sitte HH, Brandt SD, Tella SR, Cozzi NV, Schindler CW (2013) Powerful cocaine-like actions of 3,4-methylenedioxypyrovalerone (MDPV), a principal constituent of psychoactive ‘bath salts’ products. Neuropsychopharmacology 38:552–562.  https://doi.org/10.1038/npp.2012.204 CrossRefPubMedGoogle Scholar
  6. Baumann MH, Bukhari MO, Lehner KR, Anizan S, Rice KC, Concheiro M, Huestis MA (2017) Neuropharmacology of 3,4-methylenedioxypyrovalerone (MDPV), its metabolites, and related analogs. Curr Top Behav Neurosci 32:93–117.  https://doi.org/10.1007/7854_2016_53 CrossRefPubMedPubMedCentralGoogle Scholar
  7. Biedler JL, Roffler-Tarlov S, Schachner M, Freedman LS (1978) Multiple neurotransmitter synthesis by human neuroblastoma cell lines and clones. Cancer Res 38:3751–3757PubMedGoogle Scholar
  8. Binder LI, Frankfurter A, Rebhun LI (1985) The distribution of tau in the mammalian central nervous system. J Cell Biol 101:1371–1378CrossRefGoogle Scholar
  9. Borek HA, Holstege CP (2012) Hyperthermia and multiorgan failure after abuse of “bath salts” containing 3,4-methylenedioxypyrovalerone. Ann Emerg Med 60(1):103–105.  https://doi.org/10.1016/j.annemergmed.2012.01.005 CrossRefPubMedGoogle Scholar
  10. den Hollander B, Sundström M, Pelander A, Ojanperä I, Mervaala E, Korpi ER, Kankuri E (2014) Keto amphetamine toxicity-focus on the redox reactivity of the cathinone designer drug mephedrone. Toxicol Sci 141(1):120–131.  https://doi.org/10.1093/toxsci/kfu108 CrossRefGoogle Scholar
  11. den Hollander B, Sundström M, Pelander A, Siltanen A, Ojanperä I, Mervaala E, Korpi ER, Kankuri E (2015) Mitochondrial respiratory dysfunction due to the conversion of substituted cathinones to methylbenzamides in SH-SY5Y cells. Sci Rep 5:14924.  https://doi.org/10.1038/srep14924 CrossRefGoogle Scholar
  12. Drug Enforcement Administration, Office of Diversion Control (2014) Special report: synthetic cannabinoids and cathinones reported in NFLIS, 2010–2013. Available from: http://www.deadiversion.usdoj.gov/nflis/spec_rpt_CathCan_2013.pdf. Accessed 5 April 2018
  13. Duggal N, Hammond RR (2002) Nestin expression in ganglioglioma. Exp Neurol 174:89–95CrossRefGoogle Scholar
  14. Dutheil F, Jacob A, Dauchy S, Beaune P, Scherrmann JM, Declèves X, Loriot MA (2010) ABC transporters and cytochromes P450 in the human central nervous system: influence on brain pharmacokinetics and contribution to neurodegenerative disorders. Expert Opin Drug Metab Toxicol 6:1161–1174.  https://doi.org/10.1517/17425255.2010.510832 CrossRefPubMedGoogle Scholar
  15. European Drug Report (EMCDDA) (2016) Trends and developments (2016). Available from: http://www.emcdda.europa.eu/edr2016. Accessed 5 April 2018
  16. European Drug Report (EMCDDA) (2017) Trends and developments (2017). Available from: http://www.emcdda.europa.eu/edr2017. Accessed 5 April 2018
  17. Ferguson CS, Tyndale RF (2011) Cytochromes P450 in the brain: emerging evidence for biological significance. Trends Pharmacol Sci 32(12):708–714.  https://doi.org/10.1016/j.tips.2011.08.005 CrossRefPubMedPubMedCentralGoogle Scholar
  18. Ferreira PS, Nogueira TB, Costa VM, Branco PS, Ferreira LM, Fernandes E, Bastos ML, Meisel A, Carvalho F, Capela JP (2013) Neurotoxicity of “ecstasy” and its metabolites in human dopaminergic differentiated SH-SY5Y cells. Toxicol Lett 216:159–170.  https://doi.org/10.1016/j.toxlet.2012.11.015 CrossRefPubMedGoogle Scholar
  19. Gilany K, Elzen RV, Mous K, Coen E, Dongen WV, Vandamme S, Gevaert K, Timmerman E, Vandekerckhove J, Dewilde S, Van Ostade X, Moens L (2008) The proteome of the human neuroblastoma cell line SH-SY5Y: an enlarged proteome. Biochim Biophys Acta 1784:983–985.  https://doi.org/10.1016/j.bbapap.2008.03.003 CrossRefPubMedGoogle Scholar
  20. Grapp M, Kaufmann C, Ebbecke M (2017) Toxicological investigation of forensic cases related to the designer drug 3,4-methylenedioxypyrovalerone (MDPV): detection, quantification and studies on human metabolism by GC-MS. Forensic Sci Int 273:1–9.  https://doi.org/10.1016/j.forsciint.2017.01.021 CrossRefPubMedGoogle Scholar
  21. Karila L, Megarbane B, Cottencin O, Lejoyeux M (2015) Synthetic cathinones: a new health problem. Curr Neuropharmacol 13:12–20.  https://doi.org/10.2174/1570159X13666141210224137 CrossRefPubMedPubMedCentralGoogle Scholar
  22. Kesha K, Boggs CL, Ripple MG, Allan CH, Levine B, Jufer-Phipps R, Doyon S, Chi P, Fowler DR (2013) Methylenedioxypyrovalerone (“bath salts”), related death: case report and review of the literature. J Forensic Sci 58(6):1654–1659.  https://doi.org/10.1111/1556-4029.12202 CrossRefPubMedGoogle Scholar
  23. Kohler RJ, Perrine SA, Baker LE (2018) Repeated exposure to 3,4-methylenedioxypyrovalerone and cocaine produces locomotor sensitization with minimal effects on brain monoamines. Neuropharmacology 134:22–27.  https://doi.org/10.1016/j.neuropharm.2017.10.019 CrossRefPubMedGoogle Scholar
  24. Kriikku P, Wilhelm L, Schwarz O, Rintatalo J (2011) New designer drug of abuse: 3,4-Methylenedioxypyrovalerone (MDPV). Findings from apprehended drivers in Finland. Forensic Sci Int 210(1–3):195–200.  https://doi.org/10.1016/j.forsciint.2011.03.015 CrossRefPubMedGoogle Scholar
  25. Lee MK, Tuttle JB, Rebhun LI, Cleveland DW, Frankfurter A (1990) The expression and posttranslational modification of a neuron-specific beta-tubulin isotype during chick embryogenesis. Cell Motil Cytoskeleton 17:118–132CrossRefGoogle Scholar
  26. Liveri K, Constantinou MA, Afxentiou M, Kanari P (2016) A fatal intoxication related to MDPV and pentedrone combined with antipsychotic and antidepressant substances in Cyprus. Forensic Sci Int 265:160–165CrossRefGoogle Scholar
  27. Luethi D, Liechti ME, Krähenbühl S (2017) Mechanisms of hepatocellular toxicity associated with new psychoactive synthetic cathinones. Toxicology 387:57–66.  https://doi.org/10.1016/j.tox.2017.06.004 CrossRefPubMedGoogle Scholar
  28. Macleod MR, Allsopp TE, McLuckie J, Kelly JS (2001) Serum withdrawal causes apoptosis in SHSY 5Y cells. Brain Res 889(1–2):308–315CrossRefGoogle Scholar
  29. Mann A, Tyndale RF (2010) Cytochrome P450 2D6 enzyme neuroprotects against 1-methyl-4-phenylpyridinium toxicity in SH-SY5Y neuronal cells. Eur J Neurosci 31:1185–1193.  https://doi.org/10.1111/j.1460-9568.2010.07142.x CrossRefPubMedPubMedCentralGoogle Scholar
  30. Marinetti LJ, Antonides HM (2013) Analysis of synthetic cathinones commonly found in bath salts in human performance and postmortem toxicology: method development, drug distribution and interpretation of results. J Anal Toxicol 37(3):135–146.  https://doi.org/10.1093/jat/bks136 CrossRefPubMedGoogle Scholar
  31. Meltzer PC, Butler D, Deschamps JR, Madras BK (2006) 1-(4-Methylphenyl)-2-pyrrolidin-1-yl-pentan-1-one (pyrovalerone) analogues: a promising class of monoamine uptake inhibitors. J Med Chem 49(4):1420–1432CrossRefGoogle Scholar
  32. Meyer MR, Du P, Schuster F, Maurer HH (2010) Studies on the metabolism of the α-pyrrolidinophenone designer drug methylenedioxy-pyrovalerone (MDPV) in rat and human urine and human liver microsomes using GC-MS and LC-high-resolution MS and its detectability in urine by GC-MS. J Mass Spectrom 45:1426–1442.  https://doi.org/10.1002/jms.1859 CrossRefPubMedGoogle Scholar
  33. Miksys S, Tyndale RF (2013) 2011 CCNP Heinz Lehmann Award paper: cytochrome P450-mediated drug metabolism in the brain. J Psychiatry Neurosci 38(3):152–163.  https://doi.org/10.1503/jpn.120133 CrossRefPubMedPubMedCentralGoogle Scholar
  34. Miksys S, Rao Y, Sellers EM, Kwan M, Mendis D, Tyndale RF (2000) Regional and cellular distribution of CYP2D subfamily members in rat brain. Xenobiotica 30(6):547–564CrossRefGoogle Scholar
  35. Murray BL, Murphy CM, Beuhler MC (2012) Death following recreational use of designer drug “bath salts” containing 3,4-Methylenedioxypyrovalerone (MDPV). J Med Toxicol 8(1):69–75.  https://doi.org/10.1007/s13181-011-0196-9 CrossRefPubMedPubMedCentralGoogle Scholar
  36. Negreira N, Erratico C, Kosjek T, van Nuijs ALN, Heath E, Neels H, Covaci A (2015) In vitro phase I and phase II metabolism of α-pyrrolidinovalerophenone (α-PVP), methylenedioxypyrovalerone (MDPV) and methedrone by human liver microsomes and human liver cytosol. Anal Bioanal Chem 407:5803–5816.  https://doi.org/10.1007/s00216-015-8763-6 CrossRefPubMedGoogle Scholar
  37. Novellas J, López-Arnau R, Carbó ML, Pubill D, Camarasa J, Escubedo E (2015) Concentrations of MDPV in rat striatum correlate with the psychostimulant effect. J Psychopharmacol 29(11):1209–1218.  https://doi.org/10.1177/0269881115598415 CrossRefPubMedGoogle Scholar
  38. Presgraves SP, Ahmed T, Borwege S, Joyce JN (2004) Terminally differentiated SH-SY5Y cells provide a model system for studying neuroprotective effects of dopamine agonists. Neurotox Res 5:579–598CrossRefGoogle Scholar
  39. Rickli A, Hoener MC, Liechti ME (2015) Monoamine transporter and receptor interaction profiles of novel psychoactive substances: para-halogenated amphetamines and pyrovalerone cathinones. Eur Neuropsychopharmacol 25(3):365–376.  https://doi.org/10.1016/j.euroneuro.2014.12.012 CrossRefPubMedGoogle Scholar
  40. Rosas-Hernandez H, Cuevas E, Lantz SM, Imam SZ, Rice KC, Gannon BM, Fantegrossi WE, Paule MG, Ali SF (2016a) 3,4-Methylenedioxypyrovalerone (MDPV) induces cytotoxic effects on human dopaminergic SH-SY5Y cells. J Drug Alcohol Res 5:1–6.  https://doi.org/10.4303/jdar/235991 CrossRefGoogle Scholar
  41. Rosas-Hernandez H, Cuevas E, Lantz SM, Rice KC, Gannon BM, Fantegrossi WE, Gonzalez C, Paule MG, Ali SF (2016b) Methamphetamine, 3,4-methylenedioxymethamphetamine (MDMA) and 3,4-methylenedioxypyrovalerone (MDPV) induce differential cytotoxic effects in bovine brain microvessel endothelial cells. Neurosci Lett 629:125–130.  https://doi.org/10.1016/j.neulet.2016.06.029 CrossRefPubMedPubMedCentralGoogle Scholar
  42. Schindler CW, Thorndike EB, Goldberg SR, Lehner KR, Cozzi NV, Brandt SD, Baumann MH (2016) Reinforcing and neurochemical effects of the “bath salts” constituents 3,4-methylenedioxypyrovalerone (MDPV) and 3,4-methylenedioxy-N-methylcathinone (methylone) in male rats. Psychopharmacology 233(10):1981–1990.  https://doi.org/10.1007/s00213-015-4057-0 CrossRefPubMedGoogle Scholar
  43. Sewalia K, Watterson LR, Hryciw A, Belloc A, Ortiz JB, Olive MF (2017) Neurocognitive dysfunction following repeated binge-like self-administration of the synthetic cathinone 3,4-methylenedioxypyrovalerone (MDPV). Neuropharmacology.  https://doi.org/10.1016/j.neuropharm.2017.11.034
  44. Shanks KG, Dahn T, Behonick G, Terrell A (2012) Analysis of first and second generation legal highs for synthetic cannabinoids and synthetic stimulants by ultra-performance liquid chromatography and time of flight mass spectrometry. J Anal Toxicol 36:360–371.  https://doi.org/10.1093/jat/bks047 CrossRefPubMedGoogle Scholar
  45. Simmler LD, Buser TA, Donzelli M, Schramm Y, Dieu LH, Huwyler J, Chaboz S, Hoener MC, Liechti ME (2013) Pharmacological characterization of designer cathinones in vitro. Br J Pharmacol 168:458–470.  https://doi.org/10.1111/j.1476-5381.2012.02145.x CrossRefPubMedGoogle Scholar
  46. Spiller HA, Ryan ML, Weston RG, Jansen J (2011) Clinical experience with and analytical confirmation of “bath salts” and “legal highs” (synthetic cathinones) in the United States. Clin Toxicol (Phila) 49:499–505.  https://doi.org/10.3109/15563650.2011.590812 CrossRefGoogle Scholar
  47. Strano-Rossi S, Cadwallader AB, de la Torre X, Botre F (2010) Toxicological determination and in vitro metabolism of the designer drug methylenedioxypyrovalerone (MPDV) by gas chromatography/mass spectrometry and liquid chromatography/quadrupole time-of-flight mass spectrometry. Rapid Commun Mass Spectrom 24:2706–2714.  https://doi.org/10.1002/rcm.4692 CrossRefPubMedGoogle Scholar
  48. Takeuchi H, Yanagida T, Inden M, Takata K, Kitamura Y, Yamakawa K, Sawada H, Izumi Y, Yamamoto N, Kihara T, Uemura K, Inoue H, Taniguchi T, Akaike A, Takahashi R, Shimohama S (2009) Nicotinic receptor stimulation protects nigral dopaminergic neurons in rotenone-induced Parkinson’s disease models. J Neurosci Res 87:576–585.  https://doi.org/10.1002/jnr.21869 CrossRefPubMedGoogle Scholar
  49. Valente MJ, Araujo AM, Bastos Mde L, Fernandes E, Carvalho F, Guedes de Pinho P, Carvalho M (2016a) Characterization of hepatotoxicity mechanisms triggered by designer cathinone drugs (beta-Keto amphetamines). Toxicol Sci 153(1):89–102.  https://doi.org/10.1093/toxsci/kfw105 CrossRefPubMedGoogle Scholar
  50. Valente MJ, Araujo AM, Silva R, Bastos Mde L, Carvalho F, Guedes de Pinho P, Carvalho M (2016b) 3,4-Methylenedioxypyrovalerone (MDPV): in vitro mechanisms of hepatotoxicity under normothermic and hyperthermic conditions. Arch Toxicol 90(8):1959–1973.  https://doi.org/10.1007/s00204-015-1653-z CrossRefPubMedGoogle Scholar
  51. Valente MJ, Bastos ML, Fernandes E, Carvalho F, Guedes de Pinho P, Carvalho M (2017a) Neurotoxicity of β-keto amphetamines: deathly mechanisms elicited by methylone and MDPV in human dopaminergic SH-SY5Y cells. ACS Chem Neurosci 8(4):850–859.  https://doi.org/10.1021/acschemneuro.6b00421 CrossRefPubMedGoogle Scholar
  52. Valente MJ, Amaral C, Correia-da-Silva G, Duarte JA, de Lourdes Bastos M, Carvalho F, Guedes de Pinho P, Carvalho M (2017b) Methylone and MDPV activate autophagy in human dopaminergic SH-SY5Y cells: a new insight into the context of β-keto amphetamines-related neurotoxicity. Arch Toxicol 91(11):3663–3676.  https://doi.org/10.1007/s00204-017-1984-z CrossRefPubMedGoogle Scholar
  53. Wojcieszak J, Andrzejczak D, Woldan-Tambor A, Zawilska JB (2016) Cytotoxic activity of pyrovalerone derivatives, an emerging group of psychostimulant designer cathinones. Neurotox Res 30:239–250.  https://doi.org/10.1007/s12640-016-9640-6 CrossRefPubMedGoogle Scholar
  54. Wright TH, Cline-Parhamovich K, Lajoie D, Parsons L, Dunn M, Ferslew KE (2013) Deaths involving methylenedioxypyrovalerone (MDPV) in Upper East Tennessee. J Forensic Sci 58(6):1558–1562.  https://doi.org/10.1111/1556-4029.12260 CrossRefPubMedGoogle Scholar
  55. Wyman JF, Lavins ES, Engelhart D, Armstrong EJ, Snell KD, Boggs PD, Taylor SM, Norris RN, Miller FP (2013) Postmortem tissue distribution of MDPV following lethal intoxication by “bath salts”. J Anal Toxicol 37(3):182–185.  https://doi.org/10.1093/jat/bkt001 CrossRefPubMedGoogle Scholar
  56. Zawilska JB, Wojcieszak J (2013) Designer cathinones—an emerging class of novel recreational drugs. Forensic Sci Int 231:42–53.  https://doi.org/10.1016/j.forsciint.2013.04.015 CrossRefPubMedGoogle Scholar
  57. Zhao F, Wu T, Lau A, Jiang T, Huang Z, Wang XJ, Chen W, Wong PK, Zhang DD (2009) Nrf2 promotes neuronal cell differentiation. Free Radic Biol Med 47:867–879.  https://doi.org/10.1016/j.freeradbiomed.2009.06.029 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Teresa Coccini
    • 1
  • Sarah Vecchio
    • 2
  • Marta Crevani
    • 2
  • Uliana De Simone
    • 1
  1. 1.Laboratory of Clinical and Experimental ToxicologyICS Maugeri SpA - Benefit Corporation, IRCCS PaviaPaviaItaly
  2. 2.Poison Control Centre and National Toxicology Information Centre, Toxicology UnitICS Maugeri SpA - Benefit Corporation, IRCCS PaviaPaviaItaly

Personalised recommendations