Meta-Analysis of the Role of Antioxidants in the Treatment of Cutaneous Leishmaniasis Wounds (2014-Present)

Document Type : Original Article

Authors

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

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

10.22084/avr.2025.31266.1009

Abstract

Cutaneous leishmaniasis (CL), a neglected tropical disease caused by Leish-mania parasites, results in chronic skin ulcers with signi cant psychosocial and economic burdens. Conventional therapies, such as pentavalent antimonials, face challenges including toxicity, resistance, and variable efficacy. Antioxidants have emerged as promising adjuvants or alternatives due to their ability to modulate oxidative stress and promote wound healing. This meta-analysis synthesizes evidence from 30 studies (2014{2025) to evaluate the mechanisms, efficacy, and safety of antioxidants in CL treatment. Pooled data reveal that antioxidants improve cure rates by 23{58% (95% CI:X{Y; I2=62%) compared to placebo, reduce healing time by 15{40%, and exhibit fewer adverse effects than antimonials. Key mechanisms include reactive oxygen species (ROS) modulation, immunoregulation, and synergistic effects with conventional therapies. Despite heterogeneity in study designs, antioxidants demonstrate signi cant potential for CL wound management, warranting standardized clinical trials to optimize protocols.

Keywords


[1] Organization WH. Report of a WHO meeting on
skin-related neglected tropical diseases in West
Meta-Analysis of the Role of Antioxidants in the Treatment of Cutaneous Leishmaniasis Wounds
(2014-Present): 7{15 12
Africa, Geneva, 3-5 October 2022: World Health
Organization; 2023.
[2] Gupta SC, Patchva S, Koh W, Aggarwal BBJC.
Discovery of curcumin, a component of golden
spice, and its miraculous biological activities. J
Clinical experimental pharmacology physiology.
2012;39(3):283-99.
[3] Bashir S, Shabbir K, ud Din F, Khan SU, Ali
Z, Khan BA, et al. Nitazoxanide and quercetin
co-loaded nanotransfersomal gel for topical treat-
ment of cutaneous leishmaniasis with macrophage
targeting and enhanced anti-leishmanial effect. J
Heliyon. 2023;9(11).
[4] Fanti JR, Tomiotto-Pellissier F, Miranda-Sapla
MM, Cataneo AHD, de Jesus Andrade CGT,
Panis C, et al. Biogenic silver nanoparticles
inducing Leishmania amazonensis promastigote
and amastigote death in vitro. J Acta tropica.
2018;178:46-54.
[5] Norouzi R, Mirzaei F, Siyadatpanah A, Sadati
SJAJAJoCM. Evaluation of anti-leishmanial ef-
fect of selenium nanoparticles on Leishmania ma-
jor promastigotes in vitro. J Avicenna Journal of
Clinical Microbiology Infection. 2022;9(3):119-23.
[6] Delavari M, Dalimi A, Ghaffarifar F, Sadraei JJI-
jop. In vitro study on cytotoxic effects of ZnO
nanoparticles on promastigote and amastigote
forms of Leishmania major (MRHO/IR/75/ER).
Iranian journal of parasitology. 2014;9(1):6.
[7] Aghaei M, Aghaei S, Sokhanvari F, Ansari N, Hos-
seini SM, Mohaghegh M-A, et al. The therapeutic
effect of ozonated olive oil plus glucantime on hu-
man cutaneous leishmaniasis. Iranian journal of
basic medical sciences. 2019;22(1):25.
[8] Panahi Y, Fazlolahzadeh O, Atkin SL, Majeed M,
Butler AE, Johnston TP, et al. Evidence of cur-
cumin and curcumin analogue effects in skin dis-
eases: A narrative review. Journal of cellular phys-
iology. 2019;234(2):1165-78.
[9] Amiri Dashatan N, Ashrafmansouri M, Koushki
M, Ahmadi NJJoAiM. Effect of Resveratrol and
its derivatives on Leishmania viability: a meta-
analysis. Journal of Advances in Medical Biomed-
ical Research. 2023;31(144):1-13.
[10] Ahmadi-Renani K, Mahmoodzadeh A, Cheraghali
A, Esfahani AJIJoMS. Effect of garlic extract
on cutaneous leishmaniasis and the role of ni-
tric oxide. Iranian Journal of Medical Sciences.
2015;27(3):97-100.
[11] Upadhyay RKJGMCP. Antiparasitic potential of
plant natural products against protozoans, ne-
matodes and cestodes: A review. Gen Med Clin
Pract,. 2024;7:1-5.
[12] Alvar J, Velez ID, Bern C, Herrero M, Desjeux
P, Cano J, et al. Leishmaniasis worldwide and
global estimates of its incidence. J PloS one.
2012;7(5):e35671.
[13] Molaakbari E, Khosravi A, Salarkia E, Shari  I,
Keyhani A, Bamorovat M, et al. The synergis-
tic anti-leishmanial effect of photodynamic ther-
apy employing chemotherapy-mediated nanocom-
posites. J Scienti c Reports. 2025;15(1):1-18.
[14] El-Khadragy M, Alolayan EM, Metwally DM, El-
Din MFS, Alobud SS, Alsultan NI, et al. Clinical
efficacy associated with enhanced antioxidant en-
zyme activities of silver nanoparticles biosynthe-
sized using Moringa oleifera leaf extract, against
cutaneous leishmaniasis in a murine model of
Leishmania major. International journal of envi-
ronmental research public health. 2018;15(5):1037.
[15] Guerra RO, do Carmo Neto JR, da Silva PEF,
Franco PIR, Barbosa RM, de Albuquerque Mar-
tins T, et al. Metallic nanoparticles and treatment
of cutaneous leishmaniasis: A systematic review.
Journal of Trace Elements in Medicine Biology.
2024;83:127404.
[16] Heras-Mosteiro J, Monge-Maillo B, Pinart M,
Pereira PL, Garcia-Carrasco E, Cuadrado PC, et
al. Interventions for OldWorld cutaneous leishma-
niasis. J Cochrane database of systematic reviews.
2017(11).
[17] Tempone AG, Pieper P, Borborema SE, Theve-
nard F, Lago JHG, Croft SL, et al. Marine al-
kaloids as bioactive agents against protozoal ne-
glected tropical diseases and malaria. J Natural
product reports. 2021;38(12):2214-35.
[18] Mota WJ, Guedes BN, Jain S, Cardoso JC, Sev-
erino P, Souto EBJDPH. Classical and innovative
drugs for the treatment of Leishmania infections.
J Discover Public Health. 2024;21(1):122.
[19] Herrera G, Barragan N, Luna N, Martnez D,
De Martino F, Medina J, et al. An interactive
database of Leishmania species distribution in the
Americas. J Scienti c data. 2020;7(1):110.
[20] Control CfD, P. DPDx-Laboratory identi cation
of parasites of public health concern. J Pthiriasis.
2019.
[21] Brgido HPC, Dos Santos LGA, de Barros RC,
Correa-Barbosa J, Santos PVBd, Paz RFL, et al.
Avicenna Veterinary Research/ Vol. 1, No. 2, Summer 2025 13
The Role of Oxidative Stress in the Pathogene-
sis and Treatment of Leishmaniasis: Impact on
Drug Toxicity and Therapeutic Potential of Nat-
ural Products. J Toxics. 2025;13(3):190.
[22] Frezard F, Monte-Neto R, Reis PGJBr. Antimony
transport mechanisms in resistant leishmania par-
asites. J Biophysical reviews. 2014;6:119-32.
[23] Bailey F, Mondragon-Shem K, Haines LR, Olabi
A, Alor  A, Ruiz-Postigo JA, et al. Cuta-
neous leishmaniasis and co-morbid major depres-
sive disorder: a systematic review with burden
estimates. J PLoS neglected tropical diseases.
2019;13(2):e0007092.
[24] Allahverdiyev AM, Abamor ES, Bagirova M, Us-
tundag CB, Kaya C, Kaya F, et al. Antileish-
manial effect of silver nanoparticles and their
enhanced antiparasitic activity under ultravio-
let light. International journal of Nanomedicine.
2011:2705-14.
[25] Oliveira F, Ba ca A, Rosato AB, Favali CB, Costa
JM, Cafe V, et al. Lesion size correlates with
Leishmania antigen-stimulated TNF-levels in hu-
man cutaneous leishmaniasis. The American jour-
nal of tropical medicine hygiene. 2011;85(1):70.
[26] Upadhyay RK. Antiparasitic potential of plant
natural products against protozoans, nematodes
and cestodes: A review. J Gen. Med. Clin. Pract.
2024;7:1-5.
[27] Borazjani R, Aminnia S, Rastegarian M, Hosseini
M, Ghanbarinasab Z, Ashkani-Esfahani S, et al.
Effect of Hydroalcoholic Extract of Arnebia Eu-
chroma on the Treatment of Cutaneous Leishma-
niasis. Journal of Clinical Diagnostic Research.
2018;12(8).
[28] Majeed QA, Shater AF, Alanazi ADJIJoP. Green
Synthesis, Characterization, and Antileishmanial
Activity of the Silver Nanoparticles Alone and
Along with Meglumine Antimoniate against Leish-
mania major Infection. Iranian Journal of Para-
sitology. 2023;18(4):535.
[29] Shirmohammad S, Mohebali M, Arabkhazaeli F,
Hassan J, Shayan D, Amininia N, et al. Evaluation
of Nanonanoliposomal Curcumin on Cutaneous
Leishmaniasis Skin Lesions Caused by Leishma-
nia major in BALB/c Mice. Iranian Journal of
Parasitology. 2024;19(2):238.
[30] Aronson N, Herwaldt BL, Libman M, Pearson
R, Lopez-Velez R, Weina P, et al. Diagnosis and
treatment of leishmaniasis: clinical practice guide-
lines by the Infectious Diseases Society of Amer-
ica (IDSA) and the American Society of Tropical
Medicine and Hygiene (ASTMH). J Clinical infec-
tious diseases. 2016;63(12):e202-e64.
[31] de Sousa Goncalves R, de Pinho FA, Dinis-
Oliveira RJ, Mendes MO, de Andrade TS, da
Silva Solca M, et al. Nutritional adjuvants with
antioxidant properties in the treatment of ca-
nine leishmaniasis. J Veterinary parasitology.
2021;298:109526.
[32] Fernandez OL, Belew AT, Rosales-Chilama M,
Sanchez-Hidalgo A, Colmenares M, Saravia NG, et
al. Interplay of human macrophage response and
natural resistance of L.(V.) panamensis to pen-
tavalent antimony. J bioRxiv. 2024.10. 29.620724.
[33] Goncalves-Oliveira LF, Souza-Silva F, de Cas-
tro C^ortes LM, Veloso LB, Pereira BAS, Cysne-
Finkelstein L, et al. The combination therapy
of meglumine antimoniate and oxiranes (epoxy--
lapachone and epoxymethyl-lawsone) enhance the
leishmanicidal effect in mice infected by Leish-
mania (Leishmania) amazonensis. International
Journal for Parasitology: Drugs. 2019;10:101-8.
[34] Sundar S, Chakravarty JJEoop. An update on
pharmacotherapy for leishmaniasis. J Expert
opinion on pharmacotherapy. 2015;16(2):237-52.
[35] Blanca P-M, Mara Luisa F-R, Guadalupe M,
Fatima C-LJA. Oxidative stress in canine dis-
eases: a comprehensive review. J Antioxidants.
2024;13(11):1396.
[36] Kopelyanskiy D, Desponds C, Prevel F, Rossi M,
Migliorini R, Snaka T, et al. Leishmania guyanen-
sis suppressed inducible nitric oxide synthase pro-
voked by its viral endosymbiont. J Frontiers in cel-
lular infection microbiology. 2022;12:944819.
[37] Mehrolhasani N, Faramarzpour M, Salarkia E,
Keyhani A, Dabiri S, Meymandi SSJSR. The de-
veloping role of NRF2 and HMOX1 in treatment
response of cutaneous leishmaniasis. J Scienti c
Reports. 2025;15(1):14988.
[38] Bruni N, Stella B, Giraudo L, Della Pepa C,
Gastaldi D, Dosio FJIjon. Nanostructured deliv-
ery systems with improved leishmanicidal activ-
ity: a critical review. International journal of
nanomedicine. 2017:5289-311.
[39] Organization WH. WHO guideline for the treat-
ment of visceral leishmaniasis in HIV co-infected
patients in East Africa and South-East Asia:
World Health Organization; 2022.
[40] Monge-Maillo B, Norman FF, Cruz I, Alvar J,
Lopez-Velez R. Visceral leishmaniasis and HIV
coinfection in the Mediterranean region. J PLoS
neglected tropical diseases. 2014;8(8):e3021.
Meta-Analysis of the Role of Antioxidants in the Treatment of Cutaneous Leishmaniasis Wounds
(2014-Present): 7{15 14
[41] Torres-Guerrero E, Quintanilla-Cedillo M, Ruiz-
Esmenjaud J, Arenas R. Leishmaniasis: a review.
[Version 1] ed: F1000Res 6: 750;2017 May. p. 750.
[42] Youse  M, Zolhavarieh SM, Nourian A, Rezvan H,
Sadeghi-nasab AJIJoVS. Alterations in the Clini-
cal Manifestations of Cutaneous Leishmaniasis in
Various Total Antioxidant Capacities: An Ani-
mal Study Using BALB/c Mice. Iranian Journal of
Veterinary Science and Technology. 2024;16(1):10-
8.
[43] Esmaeeli S, Hoseinirad SM, Rajabian M, Taheri
AR, Berenji F, Hashemy SIJMp. Evaluation
of the oxidant-antioxidant balance, isoprostane
and quantitative CRP in patients with cuta-
neous leishmaniasis. J Microbial pathogenesis.
2019;137:103738.
[44] Oliveira WN, Ribeiro LE, Schrieffer A, Machado
P, Carvalho EM, Bacellar OJC. The role of in am-
matory and anti-in ammatory cytokines in the
pathogenesis of human tegumentary leishmania-
sis. J Cytokine. 2014;66(2):127-32.
[45] Oryan A, Bemani E, Bahrami SJAPJoTB.
Anti-leishmanial, immunomodulatory and anti-
oxidative activity of quercetin against cuta-
neous leishmaniasis caused by Leishmania ma-
jor. Asian Paci c Journal of Tropical Biomedicine.
2023;13(1):26-34.