Antileishmanial effect and immunomodulatory activity of Tinospora cordifolia and Withania somnifera against experimental BALB/c mice
Abstract
Visceral leishmaniasis (VL) is a vector-borne disease that progress mainly by lowering of immune protective cells Th1 and the appearance of cells Th2 that promote illness therefore the treatment of this disease relies on improving the immune condition of the host. Currently used treatment options of VL are Amphotericin B (AmB) and its liposomal formulation i.e., Ambisome. But these treatment options are not safe as these drugs have many side effects and limitations like hepatotoxicity, nephrotoxicity, VL relapse and PKDL conversion. This has prompted the search for alternative treatment options amongst herbal drugs; Thus, This study investigated Tinospora cordifolia and Withania somnifera's antileishmanial potentia, either in combination or alone. In vivo experiments demonstrated a substantial decrease in BALB/c mice in the spleen parasitic burden. Moreover, the treatment effectively modulated immune response of the host, leading to Th1 polarization, crucial for eliminating Leishmania donovani. This method not only targets the parasite but also fortifies the immune system, offering a safer, cost-effective alternative to current therapies for Visceral leishmaniasis, which are often limited by toxicity and resistance.
Keywords:
Visceral leishmaniasis, Nitric oxide, Reactive oxygen species, Cytokines, Herbal extracts, ImmunomodulatoryDOI
https://doi.org/10.25004/IJPSDR.2025.170401References
McCall LI, Zhang WW, Matlashewski G. Determinants for the Development of Visceral Leishmaniasis Disease. Chitnis CE, editor. PLoS Pathog. 2013 Jan 3;9(1):e1003053. Available from: https://dx.plos.org/10.1371/journal.ppat.1003053
Kaur S, Chauhan K, Sachdeva H. Protection against experimental visceral leishmaniasis by immunostimulation with herbal drugs derived from Withania somnifera and Asparagus racemosus. J Med Microbiol. 2014;63:1328–38. Available from: https://doi.org/10.1099/jmm.0.072694-0
Bhunia GS, Kesari S, Chatterjee N, Kumar V, Das P. The Burden of Visceral Leishmaniasis in India: Challenges in Using Remote Sensing and GIS to Understand and Control. ISRN Infect Dis. 2013 Nov 4;2013:1–14. Available from: https://doi.org/10.5402/2013/675846
Torres-Guerrero E, Quintanilla-Cedillo MR, Ruiz-Esmenjaud J, Arenas R. Leishmaniasis: a review. F1000Res. 2017 May 26; 6:750. Available from: /pmc/articles/PMC5464238
Taslimi Y, Zahedifard F, Rafati S. Leishmaniasis and various immunotherapeutic approaches. Parasitology. 2018 Apr 1;145(4):497–507. Available from: https://pubmed.ncbi.nlm.nih.gov/27974063
Andargie TE, Diro Ejara E. Pro- and Anti-inflammatory Cytokines in Visceral Leishmaniasis. J Cell Sci Ther. 2016;06(02). Available from: https://www.omicsonline.org/open-access/pro-and-antiinflammatory-cytokines-in-visceral-leishmaniasis-2157-7013-1000206.php?aid=51612
Utsugi M, Dobashi K, Ishizuka T, Endou K, Hamuro J, Murata Y, et al. c-Jun N-Terminal Kinase Negatively Regulates Lipopolysaccharide-Induced IL-12 Production in Human Macrophages: Role of Mitogen-Activated Protein Kinase in Glutathione Redox Regulation of IL-12 Production. The Journal of Immunology. 2003 Jul 15;171(2):628–35. Available from: https://doi.org/10.4049/jimmunol.171.2.628
Salih MAM, Fakiola M, Abdelraheem MH, Younis BM, Musa AM, ElHassan AM, et al. Insights into the possible role of IFNG and IFNGR1 in Kala-azar and Post Kala-azar Dermal Leishmaniasis in Sudanese patients. BMC Infect Dis. 2014 Dec 3;14(1). Available from: /pmc/articles/PMC4265480/
Murray HW. Targeting IL-27 and/or IL-10 in Experimental Murine Visceral Leishmaniasis. Am J Trop Med Hyg. 2020 Nov 4;103(5):1938–41. Available from: https://www.ajtmh.org/view/journals/tpmd/103/5/article-p1938.xml
Stevens TL, Bossie A, Sanders VM, Fernandez-Botran R, Coffman RL, Mosmann TR, et al. Regulation of antibody isotype secretion by subsets of antigen-specific helper T cells. Nature. 1988;334(6179):255–8. Available from: https://pubmed.ncbi.nlm.nih.gov/2456466/
Shadab M, Jha B, Asad M, Deepthi M, Kamran M, Ali N. Apoptosis-like cell death in Leishmania donovani treated with KalsomeTM10, a new liposomal amphotericin B. PLoS One. 2017 Feb 1;12(2). Available from: 10.1371/journal.pone.0171306
Laniado-Laborín R, Cabrales-Vargas MN. Amphotericin B: side effects and toxicity. Rev Iberoam Micol. 2009 Dec 31;26(4):223–7. Available from: https://linkinghub.elsevier.com/retrieve/pii/S1130140609000291
Sundar S, Chakravarty J. Liposomal amphotericin B and leishmaniasis: dose and response. J Glob Infect Dis. 2010 May;2(2):159–66. Available from: http://www.jgid.org/text.asp?2010/2/2/159/62886
Kumar P, Kumar P, Singh N, Khajuria S, Patel R, Rajana VK, et al. Limitations of current chemotherapy and future of nanoformulation-based AmB delivery for visceral leishmaniasis-An updated review. Front Bioeng Biotechnol. 2022 Dec 14;10. Available from: https://pubmed.ncbi.nlm.nih.gov/36588956/
Jamal F, Altaf I, Ahmed G, Asad S, Ahmad H, Zia Q, et al. Amphotericin B Nano-Assemblies Circumvent Intrinsic Toxicity and Ensure Superior Protection in Experimental Visceral Leishmaniasis with Feeble Toxic Manifestation. Vaccines (Basel). 2023 Jan 1;11(1). Available from: 10.3390/vaccines11010100
Kaur R, Kaur S. Evaluation of in vitro and in vivo antileishmanial potential of bergenin rich Bergenia ligulata (Wall.) Engl. root extract against visceral leishmaniasis in inbred BALB/c mice through immunomodulation. J Tradit Complement Med. 2018;8(1):251–60. Available from: http://dx.doi.org/10.1016/j.jtcme.2017.06.006
Agarwal R, Diwanay S, Patki P, Patwardhan B. Studies on immunomodulatory activity of Withania somnifera (Ashwagandha) extracts in experimental immune inflammation. J Ethnopharmacol. 1999;67(1):27–35. Available from: doi: 10.1016/s0378-8741(99)00065-3
Singh N, Kumar A, Gupta P, Chand K, Samant M, Maurya R, et al. Evaluation of antileishmanial potential of Tinospora sinensis against experimental visceral leishmaniasis. Parasitol Res. 2008;102(3). Available from: doi: 10.1007/s00436-007-0822-2
Kushwaha S, Roy S, Maity R, Mallick A, Soni VK, Singh PK, et al. Chemotypical variations in Withania somnifera lead to differentially modulated immune response in BALB/c mice. Vaccine. 2012;30(6):1083–93. Available from: http://dx.doi.org/10.1016/j.vaccine.2011.12.031
Ahmed G, Jamal F, Tiwari RK, Singh V, Rai SN, Chaturvedi SK, et al. Arsenic exposure to mouse visceral leishmaniasis model through their drinking water linked to the disease exacerbation via modulation in host protective immunity: a preclinical study. Sci Rep. 2023 Dec 1;13(1). Available from: 10.1038/s41598-023-48642-z
Ahmed G, Thakur AK, Pushpanjali, Snehil, Chaturvedi SK, Shivam P, et al. Modulation of the immune response and infection pattern to Leishmania donovani in visceral leishmaniasis due to arsenic exposure: An in vitro study. Afrin F, editor. PLoS One. 2019 Feb 5;14(2):e0210737. Available from: https://dx.plos.org/10.1371/journal.pone.0210737
Späth GF, Beverley SM. A lipophosphoglycan-independent method for isolation of infective Leishmania metacyclic promastigotes by density gradient centrifugation. Exp Parasitol. 2001 Oct;99(2):97–103. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0014489401946569
Cambridge EL, Mcintyre Z, Clare S, Arends MJ, Goulding D, Isherwood C, et al. The AMP-activated protein kinase beta 1 subunit modulates erythrocyte integrity. Exp Hematol. Available from: doi: 10.1016/j.exphem.2016.09.006
Silva‐Santana G, Bax JC, Fernandes DCS, Bacellar DTL, Hooper C, Dias AASO, et al. Clinical hematological and biochemical parameters in Swiss, BALB/c, C57BL/6 and B6D2F1 Mus musculus. Animal Model Exp Med. 2020;3(4):304–15. Available from: doi: 10.1002/ame2.12139
Pushpanjali, Thakur AK, Purkait B, Jamal F, Singh MK, Ahmed G, et al. Direct evidence for role of anti-saliva antibodies against salivary gland homogenate of P. argentipes in modulation of protective Th1-immune response against Leishmania donovani. Cytokine. 2016 Oct;86:79–85. Available from: http://dx.doi.org/10.1016/j.cyto.2016.07.017
Ranneh Y, Ali F, Akim AM, Hamid HA, Khazaai H, Fadel A. Crosstalk between reactive oxygen species and pro-inflammatory markers in developing various chronic diseases: a review. Appl Biol Chem. 2017 Jun 1;60(3):327–38. Available from: doi: https://doi.org/10.1007/s13765-017-0285-9
Gaurav H, Yadav D, Maurya A, Yadav H, Yadav R, Shukla AC, Sharma M, Gupta VK, Palazon J. Biodiversity, Biochemical Profiling, and Pharmaco-Commercial Applications of Withania somnifera: A Review. Molecules. 2023 Jan 26;28(3):1208. Available from: doi: 10.3390/molecules28031208. PMID: 36770874; PMCID: PMC9921868.
Sharma U, Bala M, Kumar N, Singh B, Munshi RK, Bhalerao S. Immunomodulatory active compounds from Tinospora cordifolia. J Ethnopharmacol. 2012;141(3). Available from: doi: 10.1016/j.jep.2012.03.027
Sachdeva H, Sehgal R, Kaur S. Tinospora cordifolia as a protective and immunomodulatory agent in combination with cisplatin against murine visceral leishmaniasis. Exp Parasitol. 2014 Feb; Gaurav H, Yadav D, Maurya A, Yadav H, Yadav R, Shukla AC, et al. Biodiversity, Biochemical Profiling, and Pharmaco-Commercial Applications of Withania somnifera: A 137:53–65. Available from: http://dx.doi.org/10.1016/j.exppara.2013.12.006
Dayakar A, Chandrasekaran S, Veronica J, Sundar S, Maurya R. In vitro and in vivo evaluation of anti-leishmanial and immunomodulatory activity of Neem leaf extract in Leishmania donovani infection. Exp Parasitol. 2015;153:45–54. Available from: http://dx.doi.org/10.1016/j.exppara.2015.02.011
Mann S, Frasca K, Scherrer S, Henao-Martínez AF, Newman S, Ramanan P, et al. A Review of Leishmaniasis: Current Knowledge and Future Directions. Vol. 8, Current Tropical Medicine Reports. 2021. Available from: doi: 10.1007/s40475-021-00232-7
Ghosh A, Zhang WW, Matlashewski G. Immunization with A2 protein results in a mixed Th1/Th2 and a humoral response which protects mice against Leishmania donovani infections. Vaccine. 2001;20(1–2). Available from: doi: 10.1016/s0264-410x(01)00322-x
Afrin F, Chouhan G, Islamuddin M, Want MY, Ozbak HA, Hemeg HA. Cinnamomum cassia exhibits antileishmanial activity against Leishmania donovani infection in vitro and in vivo. Oliveira F, editor. PLoS Negl Trop Dis. 2019 May 9;13(5):e0007227. Available from: https://dx.plos.org/10.1371/journal.pntd.0007227
Cláudio Nascimento Da Silva L, Carolina Accioly Brelaz De M, Afrin afrin F, Chouhan G, Islamuddin M, Want MY, et al. Leishmanicidal Activity of Piper nigrum Bioactive Fractions is Interceded via Apoptosis In Vitro and Substantiated by Th1 Immunostimulatory Potential In Vivo. 2015; Available from: www.frontiersin.org
Arunachalam K, Yang X, San TT. Tinospora cordifolia (Willd.) Miers: Protection mechanisms and strategies against oxidative stress-related diseases. Vol. 283, Journal of Ethnopharmacology. 2022. Available from: doi: 10.1016/j.jep.2021.114540
Melcon-Fernandez E, Galli G, García-Estrada C, Balaña-Fouce R, Reguera RM, Pérez-Pertejo Y. Miltefosine and Nifuratel Combination: A Promising Therapy for the Treatment of Leishmania donovani Visceral Leishmaniasis. Int J Mol Sci. 2023;24(2). Available from: doi: 10.3390/ijms24021635
He J, Chipot C, Shao X, Cai W. Cyclodextrin-Mediated Recruitment and Delivery of Amphotericin B. The Journal of Physical Chemistry C. 2013 Jun 6;117(22):11750–6. Available from: https://pubs.acs.org/doi/10.1021/jp3128324
Roatt BM, de Oliveira Cardoso JM, De Brito RCF, Coura-Vital W, de Oliveira Aguiar-Soares RD, Reis AB. Recent advances and new strategies on leishmaniasis treatment. Vol. 104, Applied Microbiology and Biotechnology. 2020. Available from: doi: 10.1007/s00253-020-10856-w
Ponte-Sucre A, Gamarro F, Dujardin JC, Barrett MP, López-Vélez R, García-Hernández R, et al. Drug resistance and treatment failure in leishmaniasis: A 21st century challenge. Maes L, editor. PLoS Negl Trop Dis. 2017 Dec 14;11(12):e0006052. Available from: https://dx.plos.org/10.1371/journal.pntd.0006052
Published
Abstract Display: 876
PDF Downloads: 392 How to Cite
Issue
Section
Copyright (c) 2025 Ritesh Kumar tiwari, Gaurav Kumar Pandit, Ashish Kumar, Kundan Kunal, Veer Singh, Gufran Ahmed, Meenakshi Singh

This work is licensed under a Creative Commons Attribution 4.0 International License.

