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Infectious Disorders - Drug Targets

Author(s): Lima Asgharpour Sarouey, Parvaneh Rahimi-Moghaddam, Fatemeh Tabatabaie* and Khadijeh Khanaliha*

DOI: 10.2174/1871526518666181113114820

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Evaluating the Effect of Cinnarizine on Promastigotes and Amastigotes forms of Leishmania major

Page: [550 - 555] Pages: 6

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Abstract

As an important global disease, cutaneous leishmaniasis is associated with complications such as secondary infections and atrophic scars. The first line treatment with antimonials is expensive and reported to have serious side effects and enhance resistance development. The main objective of this study was to evaluate the effect of Cinnarizine on standard strains of Leishmania major because of paucity of information on this subject.

Methods: In this experimental study, four concentrations of the drug (5, 10, 15 and 20 μg/ml) were added to Leishmania major cultures at 24, 48 and 72 hours intervals. MTT assays were performed to determine parasite viability and drug toxicity. Leishmania major promastigotes were augmented to the in vitro cultured macrophages (J774 cells) and then incubated for 72 hours. Half maximal inhibitory concentration (IC50) was ascertained by counting parasites. The inhibitory effect of the drug was compared with that of Glucantime. Flow-cytometry was performed to investigate apoptosis. Each test was repeated thrice.

Results: The IC50 values of Cinnarizine after 72 hours were calculated to be 34.76 μg/ml and 23.73 μg/ml for promastigotes and amastigotes, respectively. The results of MTT assays showed 48 % promastigote viability after 72 hour-exposure to Cinnarizine at 20 μg/ml concentration. Programmed cell death in promastigote- and amastigote-infected macrophages was quantified to be 13.66 % and 98.7 %, respectively. Flow- cytometry analysis indicated that Cinnarizine induced early and late apoptosis in parasites. All treatments produced results which differed significantly from control group (P<0.05).

Conclusion: Cinnarizine showed low toxicity with anti-leishmanial and apoptosis effects on both promastigote and intracellular amastigote forms. Therefore, we may suggest further assessment on animal models of this drug as candidates for cutaneous leishmaniasis therapy.

Keywords: Cinnarizine, MTT, apoptosis, IC50, cutaneous leishmaniasis, Leishmania major, promastigote, amastigote.

[1]
Savoia, D. Recent updates and perspectives on leishmaniasis. J. Infect. Dev. Ctries., 2015, 9(6), 588-596.
[http://dx.doi.org/10.3855/jidc.6833] [PMID: 26142667]
[2]
Desjeux, P. Leishmaniasis: current situation and new perspectives. Comp. Immunol. Microbiol. Infect. Dis., 2004, 27(5), 305-318.
[http://dx.doi.org/10.1016/j.cimid.2004.03.004] [PMID: 15225981]
[3]
Khodadadi, S.; Dakhili, M.; Akhlaghi, L.; Haeri, M.; Tabatabaie, F. Three-year epidemiological evaluation of Cutaneous Leishmaniasis in Qom province (2007-2009). Health Med, 2012, 6, 3056.
[4]
Kwakye-Nuako, G.; Mosore, M.T.; Duplessis, C.; Bates, M.D.; Puplampu, N.; Mensah-Attipoe, I.; Desewu, K.; Afegbe, G.; Asmah, R.H.; Jamjoom, M.B.; Ayeh-Kumi, P.F.; Boakye, D.A.; Bates, P.A. First isolation of a new species of Leishmania responsible for human cutaneous leishmaniasis in Ghana and classification in the Leishmania enriettii complex. Int. J. Parasitol., 2015, 45(11), 679-684.
[http://dx.doi.org/10.1016/j.ijpara.2015.05.001] [PMID: 26099650]
[5]
Quero Reimão, J.; Gustavo Tempone, A. Investigation into in vitro anti-leishmanial combinations of calcium channel blockers and current anti-leishmanial drugs. Mem. Inst. Oswaldo Cruz, 2011, 16(8)
[6]
Diro, E.; Lynen, L.; Ritmeijer, K.; Boelaert, M.; Hailu, A.; van Griensven, J. Visceral Leishmaniasis and HIV coinfection in East Africa. PLoS Negl. Trop. Dis., 2014, 8(6)e2869
[http://dx.doi.org/10.1371/journal.pntd.0002869] [PMID: 24968313]
[7]
Rezaei, F.; Ebrahimzadeh, M.A.; Daryani, A.; Sharif, M.; Ahmadpour, E.; Sarvi, S. The inhibitory effect of cromolyn sodium and ketotifen on Toxoplasma gondii entrance into host cells in vitro and in vivo. J. Parasit. Dis., 2016, 40(3), 1001-1005.
[http://dx.doi.org/10.1007/s12639-014-0623-3] [PMID: 27605827]
[8]
Pinto, E.G. da costa-silva TA, Tempone AG. Histamine H1-rceptor antagonsts against Leishmania infantum an in vitro and in vivo eraluation using phosphatidyl serine-liposomes. Acta Trop., 2014, 137, 206-210.
[http://dx.doi.org/10.1016/j.actatropica.2014.05.017] [PMID: 24905294]
[9]
Ebrahimisadr, P.; Ghaffarifar, F.; Mohammad Hassan, Z. In-vitro Evaluation of Antileishmanial Activity and Toxicity of Artemether with Focus on its Apoptotic Effect. Iran. J. Pharm. Res., 2013, 12(4), 903-909.
[PMID: 24523770]
[10]
Ganguly, S.; Bandyopadhyay, S.; Sarkar, A.; Chatterjee, M. Development of a semi-automated colorimetric assay for screening anti-leishmanial agents. J. Microbiol. Methods, 2006, 66(1), 79-86.
[http://dx.doi.org/10.1016/j.mimet.2005.10.011] [PMID: 16316700]
[11]
Ghaffarifar, F.; Esavand Heydari, F.; Dalimi, A.; Hassan, Z.M.; Delavari, M.; Mikaeiloo, H. Evaluation of Apoptotic and Antileishmanial Activities of Artemisinin on Promastigotes and BALB/C Mice Infected with Leishmania major. Iran. J. Parasitol., 2015, 10(2), 258-267.
[PMID: 26246824]
[12]
Milner, E.; Sousa, J.; Pybus, B.; Auschwitz, J.; Caridha, D.; Gardner, S.; Grauer, K.; Harris, E.; Hickman, M.; Kozar, M.P.; Lee, P.; Leed, S.; Li, Q.; Melendez, V.; Moon, J.; Ngundam, F.; O’Neil, M.; Parriott, S.; Potter, B.; Sciotti, R.; Tangteung, A.; Dow, G.S. Ketotifen is an antimalarial prodrug of norketotifen with blood schizonticidal and liver-stage efficacy. Eur. J. Drug Metab. Pharmacokinet., 2012, 37(1), 17-22.
[http://dx.doi.org/10.1007/s13318-012-0080-2] [PMID: 22314893]
[13]
Ibrahim, A.M.; Elhag, E.R.; Mustafa, S.E. Ketotifen in treatment of uncomplicated falciparum malaria. Saudi Med. J., 2000, 21(3), 257-265.
[PMID: 11533794]
[14]
Delavari, M.; Dalimi Asl, A.; Ghaffarifar, F.; Sadraei, J. Effect of aloe- emodin on growth and induction of apoptosis in Leishmania major promastigotes in vitro. Feyz, 2013, 17, 422-428.
[15]
Daryani, A; Ebrahimzadeh, M.A; Sharif, M; Rezaei, F; Ahmadpour, E; Sarvi, Sh; Ajami, A; Ziaei, H; Khalilian, A. The inhibitory effect of ketotifen on entrance of Toxoplasma gondii tachyzoites into macrophages of mouse J mazand Univ Med 2014, 23, 75-80.
[16]
Montazeri, M.; Rezaei, K.; Ebrahimzadeh, M.A.; Sharif, M.; Sarvi, S.; Ahmadpour, E.; Rahimi, M.T.; Pagheh, A.S.; Mehrzadi, S.; Daryani, A. Survey on synergism effect of ketotifen in combination with pyrimethamine in treatment of acute murine toxoplasmosis. Trop. Med. Health, 2017, 45, 39.
[http://dx.doi.org/10.1186/s41182-017-0079-0] [PMID: 29200930]