Alterations in the Clinical Manifestations of Cutaneous Leishmaniasis in Various Total Antioxidant Capacities: An Animal Study Using BALB/c Mice

Document Type : Research Article


1 Department of Pathobiology, Faculty of Veterinary Medicine, Bu-Ali Sina University, Hamedan, Iran.

2 Department of Clinical Sciences, Faculty of Veterinary Medicine, Bu-Ali Sina University, Hamedan, Iran.


The severity of the clinical manifestations of cutaneous leishmaniasis can vary depending on various factors, such as the Leishmania species involved as well as hosts and their immune response. This study aimed to investigate the relationship between the severity of different clinical signs, histopathological changes, and genetic indicators with TAC in mice experimentally infected with Leishmania major.A total of 105 eight-week-old BALB/c mice of both sexes were assigned to seven experimental groups (15 in each) as follows: 1) healthy mice, 2) Leishmania-infected mice treated with 100 mg/kg/day of SC glucantime until complete healing, 3) mice which received 20 IU/kg/day of vitamin E (SC for 10 days) to increase TAC prior to infection and further treatment with glucantime, 4) Leishmania-infected mice which received both vitamin E and glucantime daily until complete healing, 5) mice which received 20 IU/kg/day of vitamin E (SC for 10 days) before infection, and 6) Leishmania-infected mice which received 20 IU/kg/day of SC vitamin E up to the end of the trial, and 7) mice which received daily vitamin E until the end of the experiment. Wound size, expression of pro-inflammatory cytokines (IFN-γ and TNF-α) and healing genes (KGF and EGF), histopathological findings, and mortality rate were assessed three times on days 31, 38, and 72 post-infection. Approximately, 31 days after the parasite inoculation, dermal lesions were developed in all infected mice. In group 3, the clinical manifestations, healing time, and histopathological changes were significantly more favorable, while group 4 showed the worst situation in terms of the evaluated indicators. A high level of TAC before the onset of the disease has an effective role in the recovery indicators. However, its simultaneous elevation at the beginning of infection will decrease the body's ability to effectively clear the parasite, heal the tissue, and improve the clinical manifestations of the disease.


Main Subjects

1.    Laskay T, van Zandbergen G, Solbach W. Neutrophil granulocytes as host cells and transport vehicles for intracellular pathogens: apoptosis as infection-promoting factor. Immunobiology. 2008;213(3-4):183-91. DOI:10.1016/j.imbio.2007.11.010.
2.    Peters NC, Egen JG, Secundino N, Debrabant A, Kimblin N, Kamhawi S, et al. In vivo imaging reveals an essential role for neutrophils in leishmaniasis transmitted by sand flies. Science. 2008;321(5891):970-4. DOI:10.1126/science.1159194.
3.    Nylén S, Eidsmo L. Tissue damage and immunity in cutaneous leishmaniasis. Parasite Immunology. 2012;34(12):551-61. DOI:10.1111/pim.12007.
4.    Gantt KR, Goldman TL, McCormick ML, Miller MA, Jeronimo SM, Nascimento ET, et al. Oxidative responses of human and murine macrophages during phagocytosis of Leishmania chagasi. The Journal of Immunology. 2001;167(2):893-901. DOI:10.4049/jimmunol.167.2.893.
5.    Channon J, Roberts M, Blackwell J. A study of the differential respiratory burst activity elicited by promastigotes and amastigotes of Leishmania donovani in murine resident peritoneal macrophages. Immunology. 1984;53(2):345. PMID: 6490087 PMCID: PMC1454813.
6.    Murray H. Cell-mediated immune response in experimental visceral leishmaniasis. II Oxygen-dependent killing of intracellular Leishmania donovani amastigotes. Journal of immunology. 1982;129(1):351-7.
7.    Miller MA, McGowan SE, Gantt KR, Champion M, Novick SL, Andersen KA, et al. Inducible resistance to oxidant stress in the protozoan Leishmania chagasi. Journal of Biological Chemistry. 2000;275(43):33883-9. DOI:10.1074/jbc.M003671200.
8.    Zarley JH, Britigan BE, Wilson ME. Hydrogen peroxide-mediated toxicity for Leishmania donovani chagasi promastigotes. Role of hydroxyl radical and protection by heat shock. The Journal of clinical investigation. 1991;88(5):1511-21. DOI:10.1172/JCI115461.
9.    Panahi E, Stanisic DI, Peacock CS, Herrero LJ. Protective and Pathogenic Immune Responses to Cutaneous Leishmaniasis. 2021. DOI: 10.5772/intechopen.101160.
10.    Rodriguez NE, Chang HK, Wilson ME. Novel program of macrophage gene expression induced by phagocytosis of Leishmania chagasi. Infection and immunity. 2004;72(4):2111-22. DOI:10.1128/iai.72.4.2111-2122.2004.
11.    van Zandbergen G, Klinger M, Mueller A, Dannenberg S, Gebert A, Solbach W, et al. Cutting edge: neutrophil granulocyte serves as a vector for Leishmania entry into macrophages. The Journal of Immunology. 2004;173(11):6521-5. DOI:10.4049/jimmunol.173.11.6521.
12.    Romano A, Carneiro MB, Doria NA, Roma EH, Ribeiro-Gomes FL, Inbar E, et al. Divergent roles for Ly6C+ CCR2+ CX3CR1+ inflammatory monocytes during primary or secondary infection of the skin with the intra-phagosomal pathogen Leishmania major. PLoS pathogens. 2017;13(6): e1006479. DOI:10.1371/journal.ppat.1006479.
13.    Aga E, Katschinski DM, van Zandbergen G, Laufs H, Hansen B, Müller K, et al. Inhibition of the spontaneous apoptosis of neutrophil granulocytes by the intracellular parasite Leishmania major. The Journal of Immunology. 2002;169(2):898-905. DOI:10.4049/jimmunol.169.2.898.
14.    Almayouf MA, El-Khadragy M, Awad MA, Alolayan EM. The effects of silver nanoparticles biosynthesized using fig and olive extracts on cutaneous leishmaniasis-induced inflammation in female balb/c mice. Bioscience Reports. 2020;40(12). DOI:10.1042/BSR20202672.
15.    Almeida B, Narciso L, Melo L, Preve P, Bosco A, Lima VMFd, et al. Leishmaniasis causes oxidative stress and alteration of oxidative metabolism and viability of neutrophils in dogs. The Veterinary Journal. 2013;198(3):599-605. DOI:10.1016/j.tvjl.2013.08.024.
16.    Vieira LQ, Goldschmidt M, Nashleanas M, Pfeffer K, Mak T, Scott P. Mice lacking the TNF receptor p55 fail to resolve lesions caused by infection with Leishmania major, but control parasite replication. The Journal of Immunology. 1996;157(2):827-35. DOI:10.4049/jimmunol.157.2.827.
17.    Voronov E, Dotan S, Gayvoronsky L, White RM, Cohen I, Krelin Y, et al. IL-1-induced inflammation promotes development of leishmaniasis in susceptible BALB/c mice. International immunology. 2010;22(4):245-57. DOI:10.1093/intimm/dxq006.
18.    Baldwin T, Sakthianandeswaren A, Curtis JM, Kumar B, Smyth GK, Foote SJ, et al. Wound healing response is a major contributor to the severity of cutaneous leishmaniasis in the ear model of infection. Parasite immunology. 2007;29(10):501-13. DOI:10.1111/j.1365-3024.2007.00969.x.
19.    Akhzari S, Rezvan H, Zolhavarieh M. Expression of Pro-inflammatory Genes in Lesions and Neutrophils during Leishmania major Infection in BALB/c Mice. Iranian Journal of Parasitology. 2016;11(4):534. PMID: 28127365; PMCID: PMC5251182.
20.    Nashleanas M, Kanaly S, Scott P. Control of Leishmania major infection in mice lacking TNF receptors. The Journal of Immunology. 1998;160(11):5506-13. DOI:10.4049/jimmunol.160.11.5506.
21.    Ribeiro-Romão RP, Moreira OC, Osorio EY, Cysne-Finkelstein L, Gomes-Silva A, Valverde JG, et al. Comparative evaluation of lesion development, tissue damage, and cytokine expression in golden hamsters (Mesocricetus auratus) infected by inocula with different Leishmania (Viannia) braziliensis concentrations. Infection and immunity. 2014;82(12):5203-13. DOI:10.1128/iai.02083-14.
22.    Awasthi A, Mathur RK, Saha B. Immune response to Leishmania infection. Indian Journal of Medical Research. 2004; 119:238-58. PMID: 15243162.
23.    Scapini P, Lapinet-Vera JA, Gasperini S, Calzetti F, Bazzoni F, Cassatella MA. The neutrophil as a cellular source of chemokines. Immunological reviews. 2000; 177:195-203. DOI: 10.1034/j.1600-065X.2000.17706.x.
24.    Sakthianandeswaren A, Elso CM, Simpson K, Curtis JM, Kumar B, Speed TP, et al. The wound repair response controls outcome to cutaneous leishmaniasis. Proceedings of the National Academy of Sciences. 2005;102(43):15551-6. DOI:10.1073/pnas.0505630102.
25.    Latifynia A, Khamesipour A, Bokaie S, Khansari N. Antioxidants and proinflamatory cytokines in the sera of patients with cutaneous leishmaniasis. Iranian Journal of Immunology. 2012;9(3):208-14. DOI: ijiv9i3a8.
26.    MacKay DJ, Miller AL. Nutritional support for wound healing. Alternative medicine review. 2003;8(4). PMID: 14653765.
27.    Taş A, Karasu A, Yener Z, Yıldırım S, Atasoy N, Düz E, et al. Histopathological and Immunohistochemical Study of the Effect of Sildenafil Citrate, Vitamin A, Vitamin C and Vitamin E on Wound Healing in Alloxan-induced Diabetic Rats. West Indian Medical Journal. 2021;69(5). DOI: 10.7727/wimj.2015.596.
Volume 16, Issue 1 - Serial Number 34
This issue XML files are being prepared.
February 2024
Pages 10-18
  • Receive Date: 01 October 2023
  • Revise Date: 18 November 2023
  • Accept Date: 06 December 2023