FREE SHIPPING over $40
OVER 9000 FIVE-STAR REVIEWS
5% OFF ALL SUBSCRIPTIONS
100% HAPPINESS GUARANTEE
Analyze Diet
0
Home / Equine Research Bank / Trop Anim Health Prod / In vitro anti-trypanosomal effect of ivermectin on Trypanoso...
Tropical animal health and production2022; 54(4); 240; doi: 10.1007/s11250-022-03228-1

In vitro anti-trypanosomal effect of ivermectin on Trypanosoma evansi by targeting multiple metabolic pathways.

Abstract: High cytotoxicity and increasing resistance reports of existing chemotherapeutic agents against T. evansi have raised the demand for novel, potent, and high therapeutic index molecules for the treatment of surra in animals. In this regard, repurposing approach of drug discovery has provided an opportunity to explore the therapeutic potential of existing drugs against new organism. With this objective, the macrocyclic lactone representative, ivermectin, has been investigated for the efficacy against T. evansi in the axenic culture medium. To elucidate the potential target of ivermectin in T. evansi, mRNA expression profile of 13 important drug target genes has been studied at 12, 24, and 48 h interval. In the in vitro growth inhibition assay, ivermectin inhibited T. evansi growth and multiplication significantly (p < 0.001) with IC values of 13.82 μM, indicating potent trypanocidal activity. Cytotoxicity assays on equine peripheral blood mononuclear cells (PBMCs) and Vero cell line showed that ivermectin affected the viability of cells with a half-maximal cytotoxic concentration (CC) at 17.48 and 22.05 μM, respectively. Data generated showed there was significant down-regulation of hexokinase (p < 0.001), ESAG8 (p < 0.001), aurora kinase (p < 0.001), casein kinase 1 (p < 0.001), topoisomerase II (p < 0.001), calcium ATPase 1 (p < 0.001), ribonucleotide reductase I (p < 0.05), and ornithine decarboxylase (p < 0.01). The mRNA expression of oligopeptidase B remains refractory to the exposure of the ivermectin. The arginine kinase 1 and ribonucleotide reductase II showed up-regulation on treatment with ivermectin. The ivermectin was found to affect glycolytic pathways, ATP-dependent calcium ATPase, cellular kinases, and other pathway involved in proliferation and maintenance of internal homeostasis of T. evansi. These data imply that intervention with alternate strategies like nano-formulation, nano-carriers, and nano-delivery or identification of ivermectin homologs with low cytotoxicity and high bioavailability can be explored in the future as an alternate treatment for surra in animals.
© 2022. The Author(s), under exclusive licence to Springer Nature B.V.
Get Full Text
Publication Date: 2022-07-22 PubMed ID: 35869164PubMed Central: PMC9307293DOI: 10.1007/s11250-022-03228-1Google Scholar: Lookup
The Equine Research Bank provides access to a large database of publicly available scientific literature. Inclusion in the Research Bank does not imply endorsement of study methods or findings by Mad Barn.
LinkedInCopy
  • Journal Article

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

The article investigates the effectiveness of the drug ivermectin on the Trypanosoma evansi parasite, which causes the disease surra in animals. The research shows ivermectin inhibits the growth and multiplication of the parasite and affects various metabolic pathways vital for its survival, suggesting it could be explored as a treatment for surra.

Exploring the Efficacy of Ivermectin

  • The authors conducted an in vitro study to reveal how ivermectin, a well-known drug, affects T. evansi, a parasite that causes a harmful animal disease called surra.
  • The scientists assessed how ivermectin affects the growth and multiplication of the parasite in an axenic culture medium, a sterile environment free from other organisms.
  • The tests revealed that ivermectin inhibited the growth and multiplication of T. evansi significantly, meaning there’s a strong chance it could be effectively deployed as a treatment.

Molecular-level Impact on T. evansi

  • The study also investigated ivermectin’s impact on the mRNA expression of 13 important drug-target genes in T. evansi, which is crucial to understanding how the drug affects the parasite’s biological processes.
  • Data showed that several key genes, such as hexokinase and aurora kinase, which play essential roles in the metabolic activities of the organism, were significantly down-regulated by ivermectin, suggesting that the drug disrupts the normal function of the parasite.
  • However, the mRNA expression of oligopeptidase B remains unaffected by the ivermectin treatment, suggesting this pathway may be resistant to the drug’s impact.

Cytotoxicity Analysis

  • As part of this study, cytotoxicity assays were carried out to determine the potential harmful effects of ivermectin on host cells.
  • The test on equine peripheral blood mononuclear cells (PBMCs) and Vero cell line revealed that, although the drug does have a cytotoxic effect, its half-maximal cytotoxic concentration is higher than the IC50 observed for the parasite cells, indicating that the drug is more toxic to the parasite than it is to the host cells.

Future Directions

  • The research suggests that ivermectin holds significant potential as an alternative treatment for surra.
  • Given its cytotoxic effects on host cells and considering its potential application as a treatment, future research could investigate alternative strategies such as nano-formulation, nano-carriers and nano-delivery, or could focus on identifying ivermectin analogs that are less toxic and have better bioavailability.

Cite This Article

APA
Gupta S, Vohra S, Sethi K, Gupta S, Bera BC, Kumar S, Kumar R. (2022). In vitro anti-trypanosomal effect of ivermectin on Trypanosoma evansi by targeting multiple metabolic pathways. Trop Anim Health Prod, 54(4), 240. https://doi.org/10.1007/s11250-022-03228-1

Publication

Tropical animal health and production
ISSN: 1573-7438
NlmUniqueID: 1277355
Country: United States
Language: English
Volume: 54
Issue: 4
Pages: 240
PII: 240

Researcher Affiliations

Gupta, Snehil
  • Department of Veterinary Parasitology, Lala Lajpat Rai University of Veterinary and Animal Sciences, Hisar, Haryana, 125004, India.
Vohra, Sukhdeep
  • Department of Veterinary Parasitology, Lala Lajpat Rai University of Veterinary and Animal Sciences, Hisar, Haryana, 125004, India.
Sethi, Khushboo
  • Parasitology Lab, ICAR-National Research Centre on Equines, Hisar, Haryana, 125001, India.
Gupta, Surbhi
  • Department of Veterinary Physiology and Biochemistry, Lala Lajpat Rai University of Veterinary and Animal Sciences, Hisar, Haryana, 125004, India.
Bera, Bidhan Chandra
  • NCVTC, ICAR-National Research Centre on Equines, Hisar, Haryana, 125001, India.
Kumar, Sanjay
  • Parasitology Lab, ICAR-National Research Centre on Equines, Hisar, Haryana, 125001, India.
Kumar, Rajender
  • Parasitology Lab, ICAR-National Research Centre on Equines, Hisar, Haryana, 125001, India. rkg.nrce@gmail.com.

MeSH Terms

  • Animals
  • Horse Diseases
  • Horses
  • Ivermectin / pharmacology
  • Ivermectin / therapeutic use
  • Leukocytes, Mononuclear / metabolism
  • Metabolic Networks and Pathways
  • RNA, Messenger / metabolism
  • Ribonucleotide Reductases / metabolism
  • Ribonucleotide Reductases / pharmacology
  • Trypanosoma
  • Trypanosomiasis / drug therapy
  • Trypanosomiasis / veterinary

Grant Funding

  • F No 3(1)/2020-Budget- NRCE sub-scheme / Indian Council of Agricultural Research

Conflict of Interest Statement

The authors declare no competing interests.

References

This article includes 40 references
  1. Aregawi WG, Agga GE, Abdi RD, Büscher P. Systematic review and meta-analysis on the global distribution, host range, and prevalence of Trypanosoma evansi.. Parasit Vectors 2019 Jan 31;12(1):67.
    doi: 10.1186/s13071-019-3311-4pmc: PMC6357473pubmed: 30704516google scholar: lookup
  2. Baltz T, Baltz D, Giroud C, Crockett J. Cultivation in a semi-defined medium of animal infective forms of Trypanosoma brucei, T. equiperdum, T. evansi, T. rhodesiense and T. gambiense.. EMBO J 1985 May;4(5):1273-7.
    doi: 10.1002/j.1460-2075.1985.tb03772.xpmc: PMC554336pubmed: 4006919google scholar: lookup
  3. Batiha GE, Beshbishy AM, Tayebwa DS, Adeyemi OS, Yokoyama N, Igarashi I. Evaluation of the inhibitory effect of ivermectin on the growth of Babesia and Theileria parasites in vitro and in vivo.. Trop Med Health 2019;47:42.
    doi: 10.1186/s41182-019-0171-8pmc: PMC6625054pubmed: 31337949google scholar: lookup
  4. Brenndörfer M, Boshart M. Selection of reference genes for mRNA quantification in Trypanosoma brucei.. Mol Biochem Parasitol 2010 Jul;172(1):52-5.
    doi: 10.1016/j.molbiopara.2010.03.007pubmed: 20302889google scholar: lookup
  5. Brooks PA, Grace RF. Ivermectin is better than benzyl benzoate for childhood scabies in developing countries.. J Paediatr Child Health 2002 Aug;38(4):401-4.
    doi: 10.1046/j.1440-1754.2002.00015.xpubmed: 12174005google scholar: lookup
  6. Caly L, Druce JD, Catton MG, Jans DA, Wagstaff KM. The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro.. Antiviral Res 2020 Jun;178:104787.
    doi: 10.1016/j.antiviral.2020.104787pmc: PMC7129059pubmed: 32251768google scholar: lookup
  7. Campbell WC, Fisher MH, Stapley EO, Albers-Schönberg G, Jacob TA. Ivermectin: a potent new antiparasitic agent.. Science 1983 Aug 26;221(4613):823-8.
    doi: 10.1126/science.6308762pubmed: 6308762google scholar: lookup
  8. González Canga A, Sahagún Prieto AM, Diez Liébana MJ, Fernández Martínez N, Sierra Vega M, García Vieitez JJ. The pharmacokinetics and interactions of ivermectin in humans--a mini-review.. AAPS J 2008;10(1):42-6.
    doi: 10.1208/s12248-007-9000-9pmc: PMC2751445pubmed: 18446504google scholar: lookup
  9. Crump A. Ivermectin: enigmatic multifaceted 'wonder' drug continues to surprise and exceed expectations.. J Antibiot (Tokyo) 2017 May;70(5):495-505.
    pubmed: 28196978doi: 10.1038/ja.2017.11google scholar: lookup
  10. Cuypers B, Van den Broeck F, Van Reet N, Meehan CJ, Cauchard J, Wilkes JM, Claes F, Goddeeris B, Birhanu H, Dujardin JC, Laukens K, Büscher P, Deborggraeve S. Genome-Wide SNP Analysis Reveals Distinct Origins of Trypanosoma evansi and Trypanosoma equiperdum.. Genome Biol Evol 2017 Aug 1;9(8):1990-1997.
    pmc: PMC5566637pubmed: 28541535doi: 10.1093/gbe/evx102google scholar: lookup
  11. Desquesnes M, Holzmuller P, Lai DH, Dargantes A, Lun ZR, Jittaplapong S. Trypanosoma evansi and surra: a review and perspectives on origin, history, distribution, taxonomy, morphology, hosts, and pathogenic effects.. Biomed Res Int 2013;2013:194176.
    doi: 10.1155/2013/194176pmc: PMC3760267pubmed: 24024184google scholar: lookup
  12. Dias JC, Schofield CJ, Machado EM, Fernandes AJ. Ticks, ivermectin, and experimental Chagas disease.. Mem Inst Oswaldo Cruz 2005 Dec;100(8):829-32.
    doi: 10.1590/s0074-02762005000800002pubmed: 16444412google scholar: lookup
  13. Dou Q, Chen HN, Wang K, Yuan K, Lei Y, Li K, Lan J, Chen Y, Huang Z, Xie N, Zhang L, Xiang R, Nice EC, Wei Y, Huang C. Ivermectin Induces Cytostatic Autophagy by Blocking the PAK1/Akt Axis in Breast Cancer.. Cancer Res 2016 Aug 1;76(15):4457-69.
    doi: 10.1158/0008-5472.CAN-15-2887pubmed: 27302166google scholar: lookup
  14. Edwards G. Ivermectin: does P-glycoprotein play a role in neurotoxicity?. Filaria J 2003 Oct 24;2 Suppl 1(Suppl 1):S8.
    doi: 10.1186/1475-2883-2-S1-S8pmc: PMC2147658pubmed: 14975065google scholar: lookup
  15. Giordani F, Morrison LJ, Rowan TG, DE Koning HP, Barrett MP. The animal trypanosomiases and their chemotherapy: a review.. Parasitology 2016 Dec;143(14):1862-1889.
    doi: 10.1017/S0031182016001268pmc: PMC5142301pubmed: 27719692google scholar: lookup
  16. Guerrero-Hernandez A, Dagnino-Acosta A, Verkhratsky A. An intelligent sarco-endoplasmic reticulum Ca2+ store: release and leak channels have differential access to a concealed Ca2+ pool.. Cell Calcium 2010 Aug-Sep;48(2-3):143-9.
    doi: 10.1016/j.ceca.2010.08.001pubmed: 20817294google scholar: lookup
  17. Hirumi H, Hirumi K. Continuous cultivation of Trypanosoma brucei blood stream forms in a medium containing a low concentration of serum protein without feeder cell layers.. J Parasitol 1989 Dec;75(6):985-9.
    pubmed: 2614608
  18. Kumar R, Singh J, Singh R, Kumar S, Yadav SC. Comparative efficacy of different in vitro cultivation media for Trypanosoma evansi isolated from different mammalian hosts inhabiting different geographical areas of India.. J Parasit Dis 2015 Jun;39(2):174-8.
    doi: 10.1007/s12639-013-0314-5pmc: PMC4456538pubmed: 26063995google scholar: lookup
  19. Kumar R, Sharma P, Kumar Gaur D, Jain S. Recent Development in Identification of Potential Novel Therapeutic Targets Against Trypanosomatids.. Curr Top Med Chem 2016;16(20):2303-15.
    doi: 10.2174/1568026616666160413125453pubmed: 27072714google scholar: lookup
  20. Kumar R, Rani R, Kumar S, Sethi K, Jain S, Batra K, Kumar S, Tripathi BN. Drug-induced reactive oxygen species-mediated inhibitory effect on growth of Trypanosoma evansi in axenic culture system.. Parasitol Res 2020 Oct;119(10):3481-3489.
    doi: 10.1007/s00436-020-06861-7pubmed: 32869169google scholar: lookup
  21. Li N, Zhan X. Anti-parasite drug ivermectin can suppress ovarian cancer by regulating lncRNA-EIF4A3-mRNA axes.. EPMA J 2020 Jun;11(2):289-309.
    doi: 10.1007/s13167-020-00209-ypmc: PMC7272521pubmed: 32549918google scholar: lookup
  22. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method.. Methods 2001 Dec;25(4):402-8.
    doi: 10.1006/meth.2001.1262pubmed: 11846609google scholar: lookup
  23. Mendes AM, Albuquerque IS, Machado M, Pissarra J, Meireles P, Prudêncio M. Inhibition of Plasmodium Liver Infection by Ivermectin.. Antimicrob Agents Chemother 2017 Feb;61(2).
    doi: 10.1128/AAC.02447-16pmc: PMC5278742pubmed: 27895022google scholar: lookup
  24. Oldrieve G, Verney M, Jaron KS, Hébert L, Matthews KR. Monomorphic Trypanozoon: towards reconciling phylogeny and pathologies.. Microb Genom 2021 Aug;7(8).
    pmc: PMC8549356pubmed: 34397347doi: 10.1099/mgen.0.000632google scholar: lookup
  25. Ōmura S, Crump A. Ivermectin and malaria control.. Malar J 2017 Apr 24;16(1):172.
    doi: 10.1186/s12936-017-1825-9pmc: PMC5404691pubmed: 28438169google scholar: lookup
  26. Omura S, Crump A. Ivermectin: panacea for resource-poor communities?. Trends Parasitol 2014 Sep;30(9):445-55.
    doi: 10.1016/j.pt.2014.07.005pubmed: 25130507google scholar: lookup
  27. Osondu F, Ugochukwu CII, Ugochukwu EI. A comparative study of the chemotherapeutic effects of diminazene aceturate and Ivermectin on Trypanosoma brucei brucei infected rats. Asian Pacific Journal of Tropical Disease 2016;6:341–346.
    doi: 10.1016/S2222-1808(15)61043-Xgoogle scholar: lookup
  28. Panchal M, Rawat K, Kumar G, Kibria KM, Singh S, Kalamuddin M, Mohmmed A, Malhotra P, Tuteja R. Plasmodium falciparum signal recognition particle components and anti-parasitic effect of ivermectin in blocking nucleo-cytoplasmic shuttling of SRP.. Cell Death Dis 2014 Jan 16;5(1):e994.
    doi: 10.1038/cddis.2013.521pmc: PMC4040695pubmed: 24434517google scholar: lookup
  29. Pereira CA, Alonso GD, Ivaldi S, Silber AM, Alves MJ, Torres HN, Flawiá MM. Arginine kinase overexpression improves Trypanosoma cruzi survival capability.. FEBS Lett 2003 Nov 6;554(1-2):201-5.
    doi: 10.1016/s0014-5793(03)01171-2pubmed: 14596940google scholar: lookup
  30. Pinilla YT, C P Lopes S, S Sampaio V, Andrade FS, Melo GC, Orfanó AS, Secundino NFC, Guerra MGVB, Lacerda MVG, Kobylinski KC, Escobedo-Vargas KS, López-Sifuentes VM, Stoops CA, Baldeviano GC, Tarning J, Vasquez GM, Pimenta PFP, Monteiro WM. Promising approach to reducing Malaria transmission by ivermectin: Sporontocidal effect against Plasmodium vivax in the South American vectors Anopheles aquasalis and Anopheles darlingi.. PLoS Negl Trop Dis 2018 Feb;12(2):e0006221.
    doi: 10.1371/journal.pntd.0006221pmc: PMC5828505pubmed: 29444080google scholar: lookup
  31. Prichard R, Ménez C, Lespine A. Moxidectin and the avermectins: Consanguinity but not identity.. Int J Parasitol Drugs Drug Resist 2012 Dec;2:134-53.
    doi: 10.1016/j.ijpddr.2012.04.001pmc: PMC3862425pubmed: 24533275google scholar: lookup
  32. Pushpakom S, Iorio F, Eyers PA, Escott KJ, Hopper S, Wells A, Doig A, Guilliams T, Latimer J, McNamee C, Norris A, Sanseau P, Cavalla D, Pirmohamed M. Drug repurposing: progress, challenges and recommendations.. Nat Rev Drug Discov 2019 Jan;18(1):41-58.
    doi: 10.1038/nrd.2018.168pubmed: 30310233google scholar: lookup
  33. Radwanska M, Vereecke N, Deleeuw V, Pinto J, Magez S. Salivarian Trypanosomosis: A Review of Parasites Involved, Their Global Distribution and Their Interaction With the Innate and Adaptive Mammalian Host Immune System.. Front Immunol 2018;9:2253.
    doi: 10.3389/fimmu.2018.02253pmc: PMC6175991pubmed: 30333827google scholar: lookup
  34. Reis TAR, Oliveira-da-Silva JA, Tavares GSV, Mendonça DVC, Freitas CS, Costa RR, Lage DP, Martins VT, Machado AS, Ramos FF, Silva AM, Ludolf F, Antinarelli LMR, Brito RCF, Chávez-Fumagalli MA, Humbert MV, Roatt BM, Coimbra ES, Coelho EAF. Ivermectin presents effective and selective antileishmanial activity in vitro and in vivo against Leishmania infantum and is therapeutic against visceral leishmaniasis.. Exp Parasitol 2021 Feb;221:108059.
    pubmed: 33338468doi: 10.1016/j.exppara.2020.108059google scholar: lookup
  35. Rudrapal M, Khairnar JS, Jadhav GA. Drug repurposing (DR): an emerging approach in drug discovery. Drug Repurposing - Hypothesis, Molecular Aspects and Therapeutic Applications .
    doi: 10.5772/intechopen.93193google scholar: lookup
  36. Schmith VD, Zhou JJ, Lohmer LRL. The Approved Dose of Ivermectin Alone is not the Ideal Dose for the Treatment of COVID-19.. Clin Pharmacol Ther 2020 Oct;108(4):762-765.
    doi: 10.1002/cpt.1889pmc: PMC7267287pubmed: 32378737google scholar: lookup
  37. Sebaugh JL. Guidelines for accurate EC50/IC50 estimation.. Pharm Stat 2011 Mar-Apr;10(2):128-34.
    doi: 10.1002/pst.426pubmed: 22328315google scholar: lookup
  38. Sharma D, Gupta S, Sethi K, Kumar S, Kumar R. Seroprevalence and immunological characterization of Trypanosoma evansi infection in livestock of four agro-climatic zones of Himachal Pradesh, India.. Trop Anim Health Prod 2022 Jan 15;54(1):60.
    doi: 10.1007/s11250-022-03069-ypubmed: 35034203google scholar: lookup
  39. Udensi UK, Fagbenro-Beyioku AF. Effect of ivermectin on Trypanosoma brucei brucei in experimentally infected mice.. J Vector Borne Dis 2012 Sep;49(3):143-50.
    doi: 10.1002/cpt.1889pubmed: 23135008google scholar: lookup
  40. Yadav SC, Kumar P, Khurana S, Kumar R. Seroprevalence of Trypanosoma evansi Infection in Equines of North and North Western States of India.. J Equine Vet Sci 2019 Aug;79:63-67.
    doi: 10.1016/j.jevs.2019.05.019pubmed: 31405503google scholar: lookup

Citations

This article has been cited 0 times.
Subscribe to our newsletter
Join 99,357 horse owners like you who receive our email updates on horse health and nutrition.