Animal cells and systems

The Korean Society for Integrative Biology (한국통합생물학회)
권호 표지
DOI QR코드

DOI QR Code

Perphenazine and trifluoperazine induce mitochondria-mediated cell death in SH-SY5Y cells

  • Received : 2011.07.01
  • Accepted : 2011.06.24
  • Published : 2012.02.28
Download PDF
⟨ Previous Next ⟩

Abstract

Drug-induced parkinsonism has been associated with an increased risk for Parkinson's disease. Antipsychotic drugs have long been known to cause parkinsonian symptoms. However, it remains unclear whether antipsychotics can directly damage the nigrostriatal pathway. In the present study, we investigated the toxicity mechanism of two typical antipsychotics, perphenazine and trifluoperazine, in a human dopaminergic cell line, SH-SY5Y. Perphenazine and trifluoperazine induced mitochondrial damage as evidenced by fragmentation of mitochondria, activation of Bax, cytochrome c release and a decrease in cellular ATP level. In addition, activation of caspase-3 and apoptotic nuclei were observed following the drug treatment. However, pan-caspase inhibitor did not suppress the cell death induced by the antipsychotics, suggesting that the initiated apoptosis was possibly shifted to necrosis upon caspase inhibition. Damaged mitochondria may have induced oxidative stress since the drug-induced cell death was partially suppressed by an antioxidant. Taken together, our results suggest that perphenazine and trifluoperazine can induce apoptotic cell death in a dopaminergic cell line via mitochondrial damage accompanied by oxidative stress.

Keywords

References

  1. Broekemeier KM, Pfeiffer DR. 1989. Cyclosporin A-sensitive and insensitive mechanisms produce the permeability transition in mitochondria. Biochem Biophys Res Commun. 163:561-566. https://doi.org/10.1016/0006-291X(89)92174-8
  2. Broekemeier KM, Schmid PC, Schmid HH, Pfeiffer DR. 1985. Effects of phospholipase A2 inhibitors on ruthenium red-induced Ca2+ release from mitochondria. J Biol Chem. 260:105-113.
  3. Bueler H. 2009. Impaired mitochondrial dynamics and function in the pathogenesis of Parkinson's disease. Exp Neurol. 218:235-246. https://doi.org/10.1016/j.expneurol.2009.03.006
  4. Cho DH, Nakamura T, Lipton SA. 2010. Mitochondrial dynamics in cell death and neurodegeneration. Cell Mol Life Sci. 67:3435-3447. https://doi.org/10.1007/s00018-010-0435-2
  5. Cicchetti F, Drouin-Ouellet J, Gross RE. 2009. Environmental toxins and Parkinson's disease: what have we learned from pesticide-induced animal models? Trends Pharmacol Sci. 30:475-483. https://doi.org/10.1016/j.tips.2009.06.005
  6. Cruz TS, Faria PA, Santana DP, Ferreira JC, Oliveira V, Nascimento OR, Cerchiaro G, Curti C, Nantes IL, Rodrigues T. 2010. On the mechanisms of phenothiazineinduced mitochondrial permeability transition: Thiol oxidation, strict Ca2+ dependence, and cyt c release. Biochem Pharmacol. 80:1284-1295. https://doi.org/10.1016/j.bcp.2010.06.052
  7. Dagda RK, Cherra 3rd SJ, Kulich SM, Tandon A, Park D, Chu CT. 2009. Loss of PINK1 function promotes mitophagy through effects on oxidative stress and mitochondrial fission. J Biol Chem. 284:13843-13855. https://doi.org/10.1074/jbc.M808515200
  8. Dick FD, De Palma G, Ahmadi A, Scott NW, Prescott GJ, Bennett J, Semple S, Dick S, Counsell C, Mozzoni P, Haites N, Wettinger SB, Mutti A, Otelea M, Seaton A, Soderkvist P, Felice A; Geoparkinson study group. 2007. Environmental risk factors for Parkinson's disease and parkinsonism: the Geoparkinson study Occup Environ Med. 64:666-672. https://doi.org/10.1136/oem.2006.027003
  9. Flanagan RJ, Dunk L. 2008. Haematological toxicity of drugs used in psychiatry. Hum Psychopharmacol. 23(Suppl. 1):27-41. https://doi.org/10.1002/hup.917
  10. Gil-Ad I, Shtaif B, Shiloh R, Weizman A. 2001. Evaluation of the neurotoxic activity of typical and atypical neuroleptics: relevance to iatrogenic extrapyramidal symptoms. Cell Mol Neurobiol. 21:705-716. https://doi.org/10.1023/A:1015152021192
  11. Gil-Ad I, Shtaif B, Levkovitz Y, Nordenberg J, Taler M, Korov I, Weizman A. 2006. Phenothiazines induce apoptosis in a B16 mouse melanoma cell line and attenuate in vivo melanoma tumor growth. Oncol Rep. 15:107-112.
  12. Gomez-Lazaro M, Bonekamp NA, Galindo MF, Jordan J, Schrader M. 2008. 6-Hydroxydopamine (6-OHDA) induces Drp1-dependent mitochondrial fragmentation in SH-SY5Y cells. Free Radic Biol Med. 44:1960-1969. https://doi.org/10.1016/j.freeradbiomed.2008.03.009
  13. Ho BC, Andreasen NC, Ziebell S, Pierson R, Magnotta V. 2011. Long-term antipsychotic treatment and brain volumes: a longitudinal study of first-episode schizophrenia. Arch Gen Psychiatry. 68:128-137. https://doi.org/10.1001/archgenpsychiatry.2010.199
  14. Lader M. 1999. Some adverse effects of antipsychotics: prevention and treatment. J Clin Psychiatry. 60(Suppl. 12):18-21.
  15. Lee SJ, Youn YC, Han ES, Lee CS. 2005. Depressant effect of mitochondrial respiratory complex inhibitors on proteasome inhibitor-induced mitochondrial dysfunction and cell death in PC12 cells. Neurochem Res. 30:1191-1200. https://doi.org/10.1007/s11064-005-8158-8
  16. Lemasters JJ, Nieminen AL, Qian T, Trost LC, Elmore SP, Nishimura Y, Crowe RA, Cascio WE, Bradham CA, Brenner DA, Herman B. 1998. The mitochondrial permeability transition in cell death: a common mechanism in necrosis, apoptosis and autophagy. Biochim Biophys Acta. 1366:177-196. https://doi.org/10.1016/S0005-2728(98)00112-1
  17. Lim JS, Kim H, Choi YS, Kwon H, Shin KS, Joung I, Shin M, Kwon YK. 2008. Neuroprotective effects of berberine in neurodegeneration model rats induced by ibotenic acid. Anim Cells Syst. 12:203-209. https://doi.org/10.1080/19768354.2008.9647174
  18. Lirk P, Haller I, Hausott B, Ingorokva S, Deibl M, Gerner P, Klimaschewski L. 2006. The neurotoxic effects of amitriptyline are mediated by apoptosis and are effectively blocked by inhibition of caspase activity. Anesth Analg. 102:1728-1733. https://doi.org/10.1213/01.ane.0000216018.62549.bb
  19. Liu S, Han Y, Zhang T, Yang Z. 2011. Protective effect of trifluoperazine on hydrogen peroxide-induced apoptosis in PC12 cells. Brain Res Bull. 84:183-188. https://doi.org/10.1016/j.brainresbull.2010.12.008
  20. Mena MA, de Ye'benes JG. 2006. Drug-induced parkinsonism. Expert Opin Drug Saf. 5:759-771. https://doi.org/10.1517/14740338.5.6.759
  21. Nikam SS, Awasthi AK. 2008. Evolution of schizophrenia drugs: a focus on dopaminergic systems. Curr Opin Investig Drugs. 9:37-46.
  22. Tang TS, Slow E, Lupu V, Stavrovskaya IG, Sugimori M, linas RL, Kristal BS, Hayden MR, Bezprozvanny I. 2005. Disturbed Ca2+ signaling and apoptosis of medium spiny neurons in Huntington's disease. Proc Natl Acad Sci USA. 102:2602-2607. https://doi.org/10.1073/pnas.0409402102
  23. Zhang L, Yu J, Pan H, Hu P, Hao Y, Cai W, Zhu H, Yu AD, Xie X, Ma D, Yuan J. 2007. Small molecule regulators of autophagy identified by an image-based high-throughput screen. Proc Natl Acad Sci USA. 104:19023-19028. https://doi.org/10.1073/pnas.0709695104
  24. Zhelev Z, Ohba H, Bakalova R, Hadjimitova V, Ishikawa M, Shinohara Y, Baba Y. 2004. Phenothiazines suppress proliferation and induce apoptosis in cultured leukemic cells without any influence on the viability of normal lymphocytes. Phenothiazines and leukemia. Cancer Chemother Pharmacol. 53:267-275. https://doi.org/10.1007/s00280-003-0738-1

Cited by

  1. Effect of Selected Anionic and Cationic Drugs Affecting the Central Nervous System on Electrical Properties of Phosphatidylcholine Liposomes: Experiment and Theory vol.22, pp.5, 2021, https://doi.org/10.3390/ijms22052270