Skip to main content
SpringerLink
Log in

Evaluation of the Neurotoxic Activity of Typical and Atypical Neuroleptics: Relevance to Iatrogenic Extrapyramidal Symptoms

  • Published:
Cellular and Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Typical neuroleptic therapy often results in extrapyramidal symptoms (EPS) and tardive dyskinesia (TD). Recent reports reveal neurotoxic activity in some neuroleptics. We hypothesized that neurotoxicity might be implicated in EPS. This study aims to evaluate the neurotoxic activity of typical and atypical neuroleptics and to determine the possible role of neurotoxicity in neuroleptic-induced EPS. Perphenazine, haloperidol, clozapine, sulpiride, and risperidone (10–100 μM) were administered, either alone or combined with dopamine, to primary mouse neuronal or intact brain culture and to a human neuroblastoma (NB) cell line (SK-N-SH). Cell viability (measured by neutral red and alamar blue), DNA fragmentation (flow cytometry–NB) were determined. Neuroblastoma: perphenazine, clozapine, and haloperidol (100 μM) decreased viability by 87, 43, and 34% respectively. Sulpiride and risperidone were not toxic. At 10 μM, toxicity decreased markedly. Dopamine (125 μM) potentiated the perphenazine-induced toxicity. Flow cytometry of NB cells treated with perphenazine (2.5–40 μM) showed an increase (perphenazine 20 μM, 40 μM, 48 h) in fragmented DNA (74.7% and 95.0% vs. 8.7% in controls). Lower concentrations increased the G1 phase and decreased S phase in the cell cycle. In primary neurons, perphenazine, haloperidol, and clozapine, but not risperidone and sulpiride, induced a significant neurotoxic effect, which, in intact brain culture, was absent (haloperidol and clozapine) or lowered (perphenazine). Dopamine (0.5 mM) did not modify the effect of the drugs in the primary cultures. Neuroleptics possess differential neurotoxic activity with higher sensitivity of neoplasm tissue (NB compared to primary cultures). The order of toxicity was perphenazine > haloperidol = clozapine; sulpiride and risperidone were not toxic. Neurotoxicity is independent of dopamine and is associated with cell cycle arrest and apoptosis. With the exception of clozapine, neurotoxicity seems relevant to neuroleptic-induced EPS and TD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

REFERENCES

  • Barancik, M.,Palekova, L.,Mrazova, T.,Breier, A.,Stankovicova, T., andSlejak, J. (1994). Reversal effects of several Ca (2C) entry blockers, neuroleptics and local anesthetics on p-glycoproteinmediated vincristine resistance of L1210/VCR mouse leukaemic cell line. Drugs Exp. Clin. Res. 20: 13-18.

    Google Scholar 

  • Behl, C.,Rupprecht, R.,Skutelia, T., andHolsboer, F. (1995). Haloperidol induced cell death-mechanism and protection with vitamin E “in vitro.” Neuroreport 7: 360-364.

    Google Scholar 

  • Ben Shachar, D.,Livne, E.,Spanier, I.,Zur, R., andYoudim, M. B. (1993). Iron modulates neuroleptic induced effects related to the dopaminergic system. Isr. J. Med. Sci. 29: 587-592.

    Google Scholar 

  • Ben Shahar, D.,Livne, E.,Spanier, I.,Zur, R., andYoudim, M. B. (1994). Typical and atypical neuroleptics induce alteration in blood brain barrier and brain 59Fe c13 uptake. J. Neurochem. 62: 112-118.

    Google Scholar 

  • Bloomquist, J.,King, E.,Wright, A.,Mytilineou, C.,Kimura, K.,Castagnoli, K., andCastagnoli, N. (1994). 1-methyl-4-phenylpyridinium-like neurotoxicity of a pyridinium metabolite derived from haloperidol; cell culture and neurotransmitter uptake studies. J. Pharmacol. Exp. Ther. 270: 822-830.

    Google Scholar 

  • Boobis, A. R.,Fawthrop, D. J., andDavies, D. S. (1989). Mechanisms of cell death. Trends Pharmacol. Sci. 10: 275-280.

    Google Scholar 

  • Borenfreund, E., andPuerner, J. A. (1984). A simple quantitave procedure using monolayer cultures for cytotoxicity assays (HTD/NR-90). J. Tissue Cult. Methods 9: 7-9.

    Google Scholar 

  • Bursch, W.,Oberhammer, F., andSculte-Hermann, R. (1992). Cell death by apoptosis and its protective role against disease. Trend Pharmacol. Sci. 13: 245-251.

    Google Scholar 

  • Carlsson, A. (1988). The current status of dopamine hypothesis of schizophrenia. Neuropsychopharmacology 1: 179-186.

    Google Scholar 

  • Carpenter, W., andBuchana, R.W. (1994). Schizophrenia. N. Engl. J. Med. 330: 681-689.

    Google Scholar 

  • Chiueh, C. C.,Miyake, H., andPeng, T. (1993). Role of dopamine autooxidation, hydroxyl radical generation and calcium overload in underlying mechanisms involved in MPTP induced Parkinsonism. Adv. Neurol. 60: 251-258.

    Google Scholar 

  • Deutsch, S. I.,Weizman, A.,Goldman, M. E., andMorihisa, J. M. (1988). The sigma receptor: A novel site implicated in psychosis and antipsychotic drug efficacy. Clin. Neuropharmacol. 11: 105-119.

    Google Scholar 

  • Galili-Mosberg, R.,Gil-ad, I.,Weizman, A.,Melamed, E., andOffen, D. (1999). Haloperidol-induced neurotoxicity-possible implication for tardive dyskinesia. J. Neural. Transm. 107: 479-490.

    Google Scholar 

  • Gil-ad, I.,Offen, D.,Shtaif, B.,Galili-Mosberg, R., andWeizman, A. (1998). Haloperidol induces neurotoxicity in mouse embryo brain tissue. Evidence for oxidative damage mechanism, and implication for tardive dyskinesia. In Fisher, A.,Yoshida, M., andHanin, I. (eds.), Progress in Alzheimer's and Parkinson's Diseases. Plenum Press, New York, pp. 163-169.

    Google Scholar 

  • Hait, W. N., andLee, A. (1985). Characteristics of the cytotoxic effects of the phenothiazine class of calmodulin antagonists. Bichem. Pharmacol. 14: 202-205.

    Google Scholar 

  • Henderson, C. E.,Philips, H. S.,Pollock, R. A.,Davies, A. M.,Lemeulle, C.,Armanini, M.,Simpson, L. C.,Moffet, B.,Vandlen, R. A.,Koliatsos, V. E., andRosenthal, A. (1995). GDNF:Apotent survival factor for motoneurons present in peripheral nerve and muscle. Nature 266: 1062-1064.

    Google Scholar 

  • Makar, T. K.,Nedergraad, M.,Preuss, A.,Gelbard, A.,Perumal, A. S., andCooper, A. J. L. (1994). Vitamin E, Ascorbate, Glutathion disulfide and enzymes of glutathione metabolism in cultures of chick astrocytes and neurons: Evidence that astrocytes play an important role in antioxidative processes in the brain. J. Neurochem. 62: 45-53.

    Google Scholar 

  • Motohashi, N.,Kurihara, T.,Satoh, K.,Sakagami, H., andMolnar, J. (1997). Correlation between structure and diverse biological activities of “half mustard type” phenothiazines. Anticancer Res. 17: 4403-4406.

    Google Scholar 

  • Nicolletti, I.,Migliorato, G.,Pagliacci, M. C.,Grimsani, F., andRiccardi, C. (1991). A rapid and simple method for measuring thymocyte apoptosis by propidium-iodide staining and flow cytometry. J. Immunol. Methods 139: 271-279.

    Google Scholar 

  • Nociari, M. M.,Shalev, A.,Benias, P., andRusso, C. (1998). A novel one-step highly sensitive fluorimetric assay to evaluate cell-mediated cytotoxicity. J. Immunol. Methods 15(213): 157-167.

    Google Scholar 

  • Nordenberg, J.,Fenig, E.,Landau, M.,Weizman, R., andWeizman, A. (1999). Effect of psychotrophic drugs on cell proliferation and differentiation. Biochem. Pharmacol. 58: 1229-1236.

    Google Scholar 

  • Offen, D.,Ziv, I.,Gorodin, S.,Barzilai, A.,Malik, Z., andMelamed, E. (1995). Dopamine-induced programmed cell death in mouse thymocytes. Biochem. Biophys. Acta 1268: 171-177.

    Google Scholar 

  • Offen, D.,Ziv, I.,Sternin, H.,Melamed, E., andHochman, A. (1996). Prevention of dopamine-induced cell death by thiol antioxidants: Possible implication for treatment of Parkinson's disease. Exp. Neurobiol. 141: 32-39.

    Google Scholar 

  • Prasad, K. N., andKumarar, S. (1975). Role of cyclic AMP in differentiation of human neuroblastoma cells in culture. Cancer 36: 1338-1343.

    Google Scholar 

  • Rollema, H.,Skolnik, M.,D'Engelbronner, J.,Igarashi, K.,Usuki, E., andCastagnoli, N. (1994). MPP(C)-like neurotoxicity of a pyridinium metabolite derived from haloperidol: In vivo microanalysis and in vitro mitochondrial studies. J. Pharmacol. Exp. Ther. 268: 380-387.

    Google Scholar 

  • Sidi, Y.,Beery, E.,Panet, C.,Wasserman, L.,Novogrodsky, A., andNordenberg, J. (1989). Growth inhibition and induction of phenotyping alterations by tiazofurin: Differential effects on breast cancer and HB-100 breast cell-line. Eur. J. Cancer Clin. Oncol. 25: 883-889.

    Google Scholar 

  • Silver, M. A.,Yang, Z.W.,Ganguli, R., andNimgaonkar, V. L. (1994). An inhibitory effect of psychoactive drugs on a human neuroblastoma cell line. Biol. Psychiatry 35: 824-826.

    Google Scholar 

  • Vilner, B. J., and Bowen,W. D. (1993). Sigma receptor-active neuroleptics are cytotoxic to C6 glioma cells in culture. Eur. J. Pharmacol. 244: 199-201.

    Google Scholar 

  • Vilner, B. J.,John, C. S., and Bowen,W. D. (1995). Sigma-1 and sigma-2 receptors are expressed in a wide variety of human and rodent tumor cell-lines. Cancer Res. 15: 408-413.

    Google Scholar 

  • Vindelov, L. L.,Christiensen, I. J., andNissen, N. I. (1983). Adetergent trypsin method for the preparation of nuclei for flow cytometric DNA analysis. Cytometry 5: 323-327.

    Google Scholar 

  • Wounola, M. A.,Palfreyman, M. G.,Motohashi, N.,Kawase, M.,Gabay, S.,Gupta, R. R., andMolnar, J. (1998). The primary in vitro anticancer activity of “half mustard type” Phenothiazines in NCI's revised anticancer screening paradigm. Anticancer Res. 18: 337-348.

    Google Scholar 

  • Ziv, I.,Melamed, E.,Nardi, N.,Luria, D.,Achiron, A.,Offen, D., andBarzilai, A. (1994). Dopamine induces apoptosis-like cell death in cultured chick sympathetic neurons-a possible novel pathogenic mechanism in Parkinson's disease. Neurosci. Lett. 170: 136-140.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Laboratory of Biological Psychiatry, Felsenstein Medical Research Center, Tel-Aviv University, Campus Rabin, Petah-Tiqva, 49100, Israel

    Irit Gil-ad, Biana Shtaif, Roni Shiloh & Abraham Weizman

Authors
  1. Irit Gil-ad
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Biana Shtaif
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Roni Shiloh
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Abraham Weizman
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gil-ad, I., Shtaif, B., Shiloh, R. et al. Evaluation of the Neurotoxic Activity of Typical and Atypical Neuroleptics: Relevance to Iatrogenic Extrapyramidal Symptoms. Cell Mol Neurobiol 21, 705–716 (2001). https://doi.org/10.1023/A:1015152021192

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1015152021192

Search

Navigation