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Neuroprotection of paliperidone on SH-SY5Y cells against β-amyloid peptide25-35, N-methyl-4-phenylpyridinium ion, and hydrogen peroxide-induced cell death

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Abstract

Rationale

Antipsychotic drugs (APDs) were widely used in treating schizophrenia. Some APDs were reported to have neuroprotective effects against neurotoxicants in the cell level.

Objectives

Thus, one typical APD (haloperidol) and three atypical APDs (paliperidone, olanzapine, and risperidone) were tested whether they provide neuroprotection against stressor-induced cell death of SH-SY5Y.

Methods

Hydrogen peroxide, N-methyl-4-phenylpyridinium ion, and β-amyloid peptide were used to treat cells with or without preconditioning by APDs; cell survival and indicators of oxidative stress were measured, respectively.

Results

Paliperidone has the lowest baseline cytotoxicity compared with other APDs at 24 h; in addition, the paliperidone group showed a better survival than the other APD groups (P < 0.05). In stressor challenging, with a fixed concentration of stressors, olanzapine provided the best neuroprotection at 100 μM against Aβ25-35 and MPP+ (P < 0.05). In contrast, paliperidone works finely at low concentrations (10 and 50 μM) against Aβ25-35 and MPP+ and solely protected SH-SY5Y from hydrogen peroxide. At 100 μM, paliperidone completely diminished cell reduction induced by different stressors, regardless of their dosages. Paliperidone was demonstrated with a higher oxidative stress-scavenging properties than other APDs in several aspects, such as generated bulk glutathione, low HNE, and protein carbonyl productions. Contradictorily, olanzapine, at 24 h, also enhanced HNE and protein carbonyl productions, which may underlie its induced cytotoxicity.

Conclusions

Different APDs exhibit variations against different stressors. Paliperidone might be useful not only in alleviating oxidative stress induced by Aβ25-35 and MPP+ but also in providing neuroprotection against hydrogen peroxide.

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References

  • Al-Chalabi BM, Thanoon IA, Ahmed FA (2009) Potential effect of olanzapine on total antioxidant status and lipid peroxidation in schizophrenic patients. Neuropsychobiology 59:8–11

    Article  PubMed  CAS  Google Scholar 

  • Alenius M, Wadelius M, Dahl ML, Hartvig P, Lindstrom L, Hammarlund-Udenaes M (2008) Gene polymorphism influencing treatment response in psychotic patients in a naturalistic setting. J Psychiatr Res 42:884–893

    Article  PubMed  Google Scholar 

  • Altar CA, Wasley AM, Neale RF, Stone GA (1986) Typical and atypical antipsychotic occupancy of D2 and S2 receptors: an autoradiographic analysis in rat brain. Brain Res Bull 16:517–525

    Article  PubMed  CAS  Google Scholar 

  • Arnt J (1995) Differential effects of classical and newer antipsychotics on the hypermotility induced by two dose levels of d-amphetamine. Eur J Pharmacol 283:55–62

    Article  PubMed  CAS  Google Scholar 

  • Bai O, Wei Z, Lu W, Bowen R, Keegan D, Li X-M (2002) Protective effects of atypical antipsychotic drugs on PC12 cells after serum withdrawal. J Neurosci Res 69:278–283

    Article  PubMed  CAS  Google Scholar 

  • Bai O, Chlan-Fourney J, Bowen R, Keegan D, Li XM (2003) Expression of brain-derived neurotrophic factor mRNA in rat hippocampus after treatment with antipsychotic drugs. J Neurosci Res 71:127–131

    Article  PubMed  CAS  Google Scholar 

  • Bai O, Zhang H, Li XM (2004) Antipsychotic drugs clozapine and olanzapine upregulate bcl-2 mRNA and protein in rat frontal cortex and hippocampus. Brain Res 1010:81–86

    Article  PubMed  CAS  Google Scholar 

  • Behl C, Rupprecht R, Skutella T, Holsboer F (1995) Haloperidol-induced cell death—mechanism and protection with vitamin E in vitro. Neuroreport 7:360–364

    PubMed  CAS  Google Scholar 

  • Bulut M, Savas HA, Altindag A, Virit O, Dalkilic A (2009) Beneficial effects of N-acetylcysteine in treatment resistant schizophrenia. World J Biol Psychiatry 10:626–628

    Article  PubMed  Google Scholar 

  • Cadet JL, Kahler LA (1994) Free radical mechanisms in schizophrenia and tardive dyskinesia. Neurosci Biobehav Rev 18:457–467

    Article  PubMed  CAS  Google Scholar 

  • Carter CJ (2006) Schizophrenia susceptibility genes converge on interlinked pathways related to glutamatergic transmission and long-term potentiation, oxidative stress and oligodendrocyte viability. Schizophr Res 86:1–14

    Article  PubMed  CAS  Google Scholar 

  • Cassarino DS, Fall CP, Swerdlow RH, Smith TS, Halvorsen EM, Miller SW, Parks JP, Parker WD Jr, Bennett JP Jr (1997) Elevated reactive oxygen species and antioxidant enzyme activities in animal and cellular models of Parkinson's disease. Biochim Biophys Acta 1362:77–86

    PubMed  CAS  Google Scholar 

  • Corena-Mcleod Mdel P, Oliveros A, Charlesworth C, Madden B, Liang YQ, Boules M, Shaw A, Williams K, Richelson E (2008) Paliperidone as a mood stabilizer: a pre-frontal cortex synaptoneurosomal proteomics comparison with lithium and valproic acid after chronic treatment reveals similarities in protein expression. Brain Res 1233:8–19

    Article  PubMed  Google Scholar 

  • Dakhale G, Khanzode S, Khanzode S, Saoji A, Khobragade L, Turankar A (2004) Oxidative damage and schizophrenia: the potential benefit by atypical antipsychotics. Neuropsychobiology 49:205–209

    Article  PubMed  Google Scholar 

  • Dakhale GN, Khanzode SD, Khanzode SS, Saoji A (2005) Supplementation of vitamin C with atypical antipsychotics reduces oxidative stress and improves the outcome of schizophrenia. Psychopharmacol Berl 182:494–498

    Article  CAS  Google Scholar 

  • Fendri C, Mechri A, Khiari G, Othman A, Kerkeni A, Gaha L (2006) Oxidative stress involvement in schizophrenia pathophysiology: a review. Encephale 32:244–252

    Article  PubMed  CAS  Google Scholar 

  • Fowler JA, Bettinger TL, Argo TR (2008) Paliperidone extended-release tablets for the acute and maintenance treatment of schizophrenia. Clin Ther 30:231–248

    Article  PubMed  CAS  Google Scholar 

  • Frangou S, Murray RM (1996) Imaging as a tool in exploring the neurodevelopment and genetics of schizophrenia. Br Med Bull 52:587–596

    PubMed  CAS  Google Scholar 

  • Gomez C, Reiriz J, Pique M, Gil J, Ferrer I, Ambrosio S (2001) Low concentrations of 1-methyl-4-phenylpyridinium ion induce caspase-mediated apoptosis in human SH-SY5Y neuroblastoma cells. J Neurosci Res 63:421–428

    Article  PubMed  CAS  Google Scholar 

  • Goyer PF, Berridge MS, Morris ED, Semple WE, Compton-Toth BA, Schulz SC, Wong DF, Miraldi F, Meltzer HY (1996) PET measurement of neuroreceptor occupancy by typical and atypical neuroleptics. J Nucl Med 37:1122–1127

    PubMed  CAS  Google Scholar 

  • Kinon BJ, Lieberman JA (1996) Mechanisms of action of atypical antipsychotic drugs: a critical analysis. Psychopharmacol Berl 124:2–34

    Article  CAS  Google Scholar 

  • Kodama M, Fujioka T, Duman RS (2004) Chronic olanzapine or fluoxetine administration increases cell proliferation in hippocampus and prefrontal cortex of adult rat. Biol Psychiatry 56:570–580

    Article  PubMed  CAS  Google Scholar 

  • Krebs M, Leopold K, Hinzpeter A, Schaefer M (2006) Current schizophrenia drugs: efficacy and side effects. Expert Opin Pharmacother 7:1005–1016

    Article  PubMed  CAS  Google Scholar 

  • Lee HS, Park CW, Kim YS (2000) MPP(+) increases the vulnerability to oxidative stress rather than directly mediating oxidative damage in human neuroblastoma cells. Exp Neurol 165:164–171

    Article  PubMed  CAS  Google Scholar 

  • Lieberman JA, Perkins D, Belger A, Chakos M, Jarskog F, Boteva K, Gilmore J (2001) The early stages of schizophrenia: speculations on pathogenesis, pathophysiology, and therapeutic approaches. Biol Psychiatry 50:884–897

    Article  PubMed  CAS  Google Scholar 

  • Lindenmayer JP, Khan A, Iskander A, Abad MT, Parker B (2007) A randomized controlled trial of olanzapine versus haloperidol in the treatment of primary negative symptoms and neurocognitive deficits in schizophrenia. J Clin Psychiatry 68:368–379

    Article  PubMed  CAS  Google Scholar 

  • Magliaro BC, Saldanha CJ (2009) Clozapine protects PC-12 cells from death due to oxidative stress induced by hydrogen peroxide via a cell-type specific mechanism involving inhibition of extracellular signal-regulated kinase phosphorylation. Brain Res 1283:14–24

    Article  PubMed  CAS  Google Scholar 

  • Mahadik SP, Pillai A, Joshi S, Foster A (2006) Prevention of oxidative stress-mediated neuropathology and improved clinical outcome by adjunctive use of a combination of antioxidants and omega-3 fatty acids in schizophrenia. Int Rev Psychiatry 18:119–131

    Article  PubMed  Google Scholar 

  • Miwa H, Kubo T, Morita S, Nakanishi I, Kondo T (2004) Oxidative stress and microglial activation in substantia nigra following striatal MPP+. Neuroreport 15:1039–1044

    Article  PubMed  CAS  Google Scholar 

  • Molteni R, Calabrese F, Racagni G, Fumagalli F, Riva MA (2009) Antipsychotic drug actions on gene modulation and signaling mechanisms. Pharmacol Ther 124:74–85

    Article  PubMed  CAS  Google Scholar 

  • Mossaheb N, Spindelegger C, Asenbaum S, Fischer P, Barnas C (2010) Favourable results in treatment-resistant schizophrenic patients under combination of aripiprazole with clozapine. World J Biol Psychiatry 11:502–505

    Article  PubMed  Google Scholar 

  • Ng F, Berk M, Dean O, Bush AI (2008) Oxidative stress in psychiatric disorders: evidence base and therapeutic implications. Int J Neuropsychopharmacol 11:851–876

    Article  PubMed  CAS  Google Scholar 

  • Nicotra A, Parvez S (2002) Apoptotic molecules and MPTP-induced cell death. Neurotoxicol Teratol 24:599–605

    Article  PubMed  CAS  Google Scholar 

  • Noh JS, Kang HJ, Kim EY, Sohn S, Chung YK, Kim SU, Gwag BJ (2000) Haloperidol-induced neuronal apoptosis: role of p38 and c-Jun-NH(2)-terminal protein kinase. J Neurochem 75:2327–2334

    Article  PubMed  CAS  Google Scholar 

  • Parikh V, Khan MM, Mahadik SP (2003) Differential effects of antipsychotics on expression of antioxidant enzymes and membrane lipid peroxidation in rat brain. J Psychiatr Res 37:43–51

    Article  PubMed  Google Scholar 

  • Perry PJ, Lund BC, Sanger T, Beasley C (2001) Olanzapine plasma concentrations and clinical response: acute phase results of the North American Olanzapine Trial. J Clin Psychopharmacol 21:14–20

    Article  PubMed  CAS  Google Scholar 

  • Prabakaran S, Swatton JE, Ryan MM, Huffaker SJ, Huang JT, Griffin JL, Wayland M, Freeman T, Dudbridge F, Lilley KS, Karp NA, Hester S, Tkachev D, Mimmack ML, Yolken RH, Webster MJ, Torrey EF, Bahn S (2004) Mitochondrial dysfunction in schizophrenia: evidence for compromised brain metabolism and oxidative stress. Mol Psychiatry 9(684–97):643

    Article  Google Scholar 

  • Qing H, Xu H, Wei Z, Gibson K, Li X-M (2003) The ability of atypical antipsychotic drugs vs. haloperidol to protect PC12 cells against MPP+-induced apoptosis. Eur J Neurosci 17:1563–1570

    Article  PubMed  Google Scholar 

  • Raffa M, Mechri A, Othman LB, Fendri C, Gaha L, Kerkeni A (2009) Decreased glutathione levels and antioxidant enzyme activities in untreated and treated schizophrenic patients. Prog Neuropsychopharmacol Biol Psychiatry 33:1178–1183

    Article  PubMed  CAS  Google Scholar 

  • Reddy R, Keshavan M, Yao JK (2003) Reduced plasma antioxidants in first-episode patients with schizophrenia. Schizophr Res 62:205–212

    Article  PubMed  Google Scholar 

  • Reinke A, Martins MR, Lima MS, Moreira JC, Dal-Pizzol F, Quevedo J (2004) Haloperidol and clozapine, but not olanzapine, induces oxidative stress in rat brain. Neurosci Lett 372:157–160

    Article  PubMed  CAS  Google Scholar 

  • Schaffner KF, McGorry PD (2001) Preventing severe mental illnesses—new prospects and ethical challenges. Schizophr Res 51:3–15

    Article  PubMed  CAS  Google Scholar 

  • Scherer J, Tatsch K, Schwarz J, Oertel W, Kirsch MC, Albus M (1994) Striatal D2-dopamine receptor occupancy during treatment with typical and atypical neuroleptics. Biol Psychiatry 36:627–629

    Article  PubMed  CAS  Google Scholar 

  • Schmidt AJ, Hemmeter UM, Krieg JC, Vedder H, Heiser P (2009) Impact of haloperidol and quetiapine on the expression of genes encoding antioxidant enzymes in human neuroblastoma SH-SY5Y cells. J Psychiatr Res 43:818–823

    Article  PubMed  Google Scholar 

  • Schmidt AJ, Krieg JC, Clement HW, Hemmeter UM, Schulz E, Vedder H, Heiser P (2010) Effects of quetiapine, risperidone, 9-hydroxyrisperidone and ziprasidone on the survival of human neuronal and immune cells in vitro. J Psychopharmacol 24:349–354

    Article  PubMed  CAS  Google Scholar 

  • Shadach E, Gaisler I, Schiller D, Weiner I (2000) The latent inhibition model dissociates between clozapine, haloperidol, and ritanserin. Neuropsychopharmacology 23:151–161

    Article  PubMed  CAS  Google Scholar 

  • Sharma SK, Carlson EC, Ebadi M (2003) Neuroprotective actions of Selegiline in inhibiting 1-methyl, 4-phenyl, pyridinium ion (MPP+)-induced apoptosis in SK-N-SH neurons. J Neurocytol 32:329–343

    Article  PubMed  CAS  Google Scholar 

  • Sheehan JP, Palmer PE, Helm GA, Tuttle JB (1997) MPP+ induced apoptotic cell death in SH-SY5Y neuroblastoma cells: an electron microscope study. J Neurosci Res 48:226–237

    Article  PubMed  CAS  Google Scholar 

  • Singh V, Singh SP, Chan K (2010) Review and meta-analysis of usage of ginkgo as an adjunct therapy in chronic schizophrenia. Int J Neuropsychopharmacol 13:257–271

    Article  PubMed  CAS  Google Scholar 

  • Song X, Perkins S, Jortner BS, Ehrich M (1997) Cytotoxic effects of MPTP on SH-SY5Y human neuroblastoma cells. Neurotoxicology 18:341–353

    PubMed  CAS  Google Scholar 

  • Tandon R, Keshavan MS, Nasrallah HA (2008) Schizophrenia, "just the facts" what we know in 2008. 2. Epidemiology and etiology. Schizophr Res 102:1–18

    Article  PubMed  Google Scholar 

  • Wakade CG, Mahadik SP, Waller JL, Chiu FC (2002) Atypical neuroleptics stimulate neurogenesis in adult rat brain. J Neurosci Res 69:72–79

    Article  PubMed  CAS  Google Scholar 

  • Wang JS, Ruan Y, Taylor RM, Donovan JL, Markowitz JS, Devane CL (2004) The brain entry of risperidone and 9-hydroxyrisperidone is greatly limited by P-glycoprotein. Int J Neuropsychopharmacol 7:415–419

    Article  PubMed  CAS  Google Scholar 

  • Wang H, Xu H, Dyck LE, Li X-M (2005) Olanzapine and quetiapine protect PC12 cells from beta-amyloid peptide(25-35)-induced oxidative stress and the ensuing apoptosis. J Neurosci Res 81:572–580

    Article  PubMed  CAS  Google Scholar 

  • Wei Z, Bai O, Richardson JS, Mousseau DD, Li X-M (2003a) Olanzapine protects PC12 cells from oxidative stress induced by hydrogen peroxide. J Neurosci Res 73:364–368

    Article  PubMed  CAS  Google Scholar 

  • Wei Z, Mousseau DD, Richardson JS, Dyck LE, Li XM (2003b) Atypical antipsychotics attenuate neurotoxicity of beta-amyloid(25-35) by modulating Bax and Bcl-X(l/s) expression and localization. J Neurosci Res 74:942–947

    Article  PubMed  CAS  Google Scholar 

  • Wyatt RJ, Henter ID (1998) The effects of early and sustained intervention on the long-term morbidity of schizophrenia. J Psychiatr Res 32:169–177

    Article  PubMed  CAS  Google Scholar 

  • Xiao XQ, Zhang HY, Tang XC (2002) Huperzine A attenuates amyloid beta-peptide fragment 25-35-induced apoptosis in rat cortical neurons via inhibiting reactive oxygen species formation and caspase-3 activation. J Neurosci Res 67:30–36

    Article  PubMed  CAS  Google Scholar 

  • Zeng H, Chen Q, Zhao B (2004) Genistein ameliorates beta-amyloid peptide (25-35)-induced hippocampal neuronal apoptosis. Free Radic Biol Med 36:180–188

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The authors are grateful to Shui-Hwau Lin for her excellent technical assistance. This study was sponsored by research grant no. 100-23 from Foundation of Outpatient Service of Kaohsiung Armed Forces General Hospital.

Conflict of interest

All of the authors declare that we have no affiliation with or financial involvement in any organization or conflict of interest.

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Authors and Affiliations

  1. Center for Genetic Laboratory, Kaohsiung, Taiwan

    Ming-Chang Yang

  2. Institute of Biological Science, National Sun Yat-san University, Kaohsiung City, Taiwan

    Ming-Chang Yang

  3. Center for Genetic Laboratory and Faculty Development, Kaohsiung, Taiwan

    For-Wey Lung

  4. Department of Psychiatry, National Defense Medical Center, Taipei, Taiwan

    For-Wey Lung

  5. Department of Neurology, Kaohsiung Medical University, Kaohsiung, Taiwan

    For-Wey Lung

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  1. Ming-Chang Yang
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Yang, MC., Lung, FW. Neuroprotection of paliperidone on SH-SY5Y cells against β-amyloid peptide25-35, N-methyl-4-phenylpyridinium ion, and hydrogen peroxide-induced cell death. Psychopharmacology 217, 397–410 (2011). https://doi.org/10.1007/s00213-011-2291-7

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  • DOI: https://doi.org/10.1007/s00213-011-2291-7

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