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Evaluation of the Anti-Trypanosoma Cruzi Effects of the Antipsychotic Drug Levomepromazine

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DOI: 10.4236/ijcm.2012.35067    3,755 Downloads   5,293 Views   Citations

ABSTRACT

Chagas disease, caused by the protozoan Trypanosoma cruzi, is a relevant parasitic disease in the Americas. Current chemotherapy relies on Nifurtimox and Benznidazole, which present serious drawbacks, including high toxicity, low efficiency and the emergence of resistant strains. In the present work, the perspectives of levomepromazine, a tri-cyclic compound belonging to the family of phenotiazines with well-known properties as antipsychotics were evaluated as a potential anti-T. cruzi drug. We show that this drug is able to inhibit the proliferation of epimastigotes (IC50 = 0.41 ± 0.01 mM) and to interfere with the infection of the host cells (IC50 = 0.34 ± 0.01 mM). Interestingly, the treatment with levomepromazine affected the ability of metabolites such as glucose, proline and glutamate to fuel the recovery of epi-mastigotes after being submitted to metabolic stress. These findings prompt levomepromazine as a promising leader drug to obtain new trypanocidal activities.

Conflicts of Interest

The authors declare no conflicts of interest.

Cite this paper

I. Lange, E. Pral, A. Magdaleno and A. Silber, "Evaluation of the Anti-Trypanosoma Cruzi Effects of the Antipsychotic Drug Levomepromazine," International Journal of Clinical Medicine, Vol. 3 No. 5, 2012, pp. 344-351. doi: 10.4236/ijcm.2012.35067.

References

[1] S. B. Boscardin, A. C. Torrecilhas, R. Manarin, S. Revelli, E. G. Rey, R. R. Tonelli and A. M. Silber "Chagas' disease: an update on immune mechanisms and therapeutic strategies". Journal of Cellular and Molecular Medicine, Vol. 14, 2010, pp. 1373-1384.
[2] G. Sudeshna and K. Parimal "Multiple non-psychiatric effects of phenothiazines: a review". European Journal of Pharmacology, Vol. 648, 2010, pp. 6-14.
[3] M. J. Ohlow and B. Moosmann "Phenothiazine: the seven lives of pharmacology's first lead structure". Drug Discovery Today, Vol. 16, 2011, pp. 119-131.
[4] A. P. Feinberg and S. H. Snyder "Phenothiazine drugs: structure-activity relationships explained by a conformation that mimics dopamine". Proceedings of the National Academy of Science - U S A, Vol. 72, 1975, pp. 1899-1903.
[5] S. Sammut, K. E. Bray and A. R. West "Dopamine D2 receptor-dependent modulation of striatal NO synthase activity". Psychopharmacology (Berl), Vol. 191, 2007, pp. 793-803.
[6] T. Silverstone "Clinically relevant differences between antipsychotic compounds". Acta Psychiatrica Scandi-navica Suppl, Vol. 358, 1990, pp. 88-91.
[7] S. H. Snyder, S. P. Banerjee, H. I. Yamamura and D. Greenberg "Drugs, neurotransmitters, and schizophrenia". Science, Vol. 184, 1974, pp. 1243-1253.
[8] F. L. Schuster and N. Mandel "Phenothiazine compounds inhibit in vitro growth of pathogenic free-living amoebae". Antimicrobials Agents and Chemotherapy, Vol. 25, 1984, pp. 109-112.
[9] A. Makioka, M. Kumagai, S. Kobayashi and T. Takeuchi "Possible role of calcium ions, calcium channels and calmodulin in excystation and metacystic development of Entamoeba invadens". Parasitology Research, Vol. 88, 2002, pp. 837-843.
[10] R. D. Pearson, A. A. Manian, J. L. Harcus, D. Hall and E. L. Hewlett "Lethal effect of phenothiazine neuroleptics on the pathogenic protozoan Leishmania donovani". Science, Vol. 217, 1982, pp. 369-371.
[11] N. C. Wood and K. M. Nugent "Inhibitory effects of chlorpromazine on Candida species". Antimicrobial Agents and Chemotherapy, Vol. 27, 1985, pp. 692-694.
[12] D. Ordway, M. Viveiros, C. Leandro, M. Jorge Arroz, J. Molnar, J. E. Kristiansen and L. Amaral "Chlorpromazine has intracellular killing activity against phagocytosed Staphylococcus aureus at clinical concentrations". Journal of Infection and Chemotherapy, Vol. 8, 2002, pp. 227-231.
[13] A. J. Crowle, E. R. Ross, D. L. Cohn, J. Gilden and M. H. May "Comparison of the abilities of Mycobacterium avium and Mycobacterium intracellulare to infect and multiply in cultured human macrophages from normal and human immunodeficiency virus-infected subjects". Infection and Immunity, Vol. 60, 1992, pp. 3697-3703.
[14] P. Ratnakar and P. S. Murthy "Antitubercular activity of trifluoperazine, a calmodulin antagonist". FEMS Microbiology Letters, Vol. 76, 1992, pp. 73-76.
[15] H. Most "Studies on the effectiveness of phenothiazine in human nematode infections". American Journal of Tropical Medicine and Hygiene, Vol. s1, 1943, pp. 459-464.
[16] Z. Brener and E. Chiari "Morphological variations observed in different strains of Trypanosoma cruzi.". Revista do Instituto de Medicina Tropical de Sao Paulo, Vol. 19, 1963, pp. 220-224.
[17] E. P. Camargo "Growth and differentiation in Trypanosoma cruzi. I. Origin of metacyclic trypanosomes in liquid media". Revista do Instituto de Medicina Tropical de Sao Paulo, Vol. 12, 1964, pp. 93-100.
[18] V. T. Contreras, J. M. Salles, N. Thomas, C. M. Morel and S. Goldenberg "In vitro differentiation of Trypanosoma cruzi under chemically defined conditions". Molecular and Biochemical Parasitology, Vol. 16, 1985, pp. 315-327.
[19] R. R. Tonelli, A. M. Silber, M. Almeida-de-Faria, I. Y. Hirata, W. Colli and M. J. Alves "L-proline is essential for the intracellular differentiation of Trypanosoma cruzi". Cellular Microbiol, Vol. 6, 2004, pp. 733-741.
[20] I. Stolic, K. Miskovic, A. Magdaleno, A. M. Silber, I. Piantanida, M. Bajic and L. Glavas-Obrovac "Effect of 3,4-ethylenedioxy-extension of thiophene core on the DNA/RNA binding properties and biological activity of bis-benzimidazole amidines". Bioorganic and Medicinal Chemistry, Vol. 17, 2009, pp. 2544-2554.
[21] A. Magdaleno, I. Y. Ahn, L. S. Paes and A. M. Silber "Actions of a proline analogue, L-thiazolidine-4-carboxylic acid (T4C), on Trypanosoma cruzi". PLoS ONE, Vol. 4, 2009, pp. e4534.
[22] A. Magdaleno, B. Suarez Mantilla, S. C. Rocha, E. M. Pral and A. M. Silber "The involvement of glutamate metabolism in the resistance to thermal, nutritional, and oxidative stress in Trypanosoma cruzi". Enzyme Research, Vol. 2011, 2011, pp. 486928.
[23] B. K. Slinker "The statistics of synergism". Journal of Molecular and Cellular Cardiology, Vol. 30, 1998, pp. 723-731.
[24] A. M. Silber, W. Colli, H. Ulrich, M. J. Alves and C. A. Pereira "Amino acid metabolic routes in Trypanosoma cruzi: possible therapeutic targets against Chagas' disease". Current Drug Targets - Infectious Disorders, Vol. 5, 2005, pp. 53-64.
[25] P. Lisvane Silva, B. S. Mantilla, M. J. Barison, C. Wrenger and A. M. Silber "The uniqueness of the Trypanosoma cruzi mito-chondrion: opportunities to identify new drug target for the treatment of Chagas disease". Current Pharmaceutical Design, Vol. 17, 2011, pp. 2074-2099.
[26] J. J. Cazzulo "Energy metabolism in Trypanosoma cruzi". Subcellular Biochemistry, Vol. 18, 1992, pp. 235-257.
[27] P. Paglini-Oliva, A. R. Fernandez, R. Fretes and A. Peslman "Structural, ultrastructural studies and evolution of Trypanosoma cruzi-infected mice treated with thioridazine". Experimental and Molecular Pathology, Vol. 65, 1998, pp. 78-86.
[28] M. S. Lo Presti, H. W. Rivarola, J. M. Bustamante, A. R. Fernandez, J. E. Enders, R. Fretes, S. Gea and P. A. Paglini-Oliva "Thioridazine treatment prevents cardiopathy in Trypanosoma cruzi infected mice". International Journal of Antimicrobial Agents, Vol. 23, 2004, pp. 634-636.
[29] H. W. Rivarola, A. R. Fernandez, J. E. Enders, R. Fretes, S. Gea, M. Suligoy, J. A. Palma and P. Paglini-Oliva "Thioridazine treatment modifies the evolution of Trypanosoma cruzi infection in mice". Annals of Tropical Medicine and Parasitology, Vol. 93, 1999, pp. 695-702.

  
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