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.
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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.
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.
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.
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.
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.
Boobis, A. R.,Fawthrop, D. J., andDavies, D. S. (1989). Mechanisms of cell death. Trends Pharmacol. Sci. 10: 275-280.
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.
Bursch, W.,Oberhammer, F., andSculte-Hermann, R. (1992). Cell death by apoptosis and its protective role against disease. Trend Pharmacol. Sci. 13: 245-251.
Carlsson, A. (1988). The current status of dopamine hypothesis of schizophrenia. Neuropsychopharmacology 1: 179-186.
Carpenter, W., andBuchana, R.W. (1994). Schizophrenia. N. Engl. J. Med. 330: 681-689.
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.
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.
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.
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.
Hait, W. N., andLee, A. (1985). Characteristics of the cytotoxic effects of the phenothiazine class of calmodulin antagonists. Bichem. Pharmacol. 14: 202-205.
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.
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.
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.
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.
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.
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.
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.
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.
Prasad, K. N., andKumarar, S. (1975). Role of cyclic AMP in differentiation of human neuroblastoma cells in culture. Cancer 36: 1338-1343.
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.
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.
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.
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.
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.
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.
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.
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.
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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
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DOI: https://doi.org/10.1023/A:1015152021192