Beneficial effects of ascorbic acid on ivermectin repeated high-dose therapy in rabbits: biochemical and histopathological investigations

  • Makhlouf Chahrazed Department of Biology, Faculty of Nature and Life Sciences, University Blida 1, BP 270, Soumaa, Blida, Algeria; Natural Resources Laboratory, University Mouloud Mammeri, BP 15017, Tizi-Ouzou, Algeria
  • Khaldoun Oularbi Hassina Department of Biology, Faculty of Nature and Life Sciences, University Blida 1, BP 270, Soumaa, Blida, Algeria; Natural Resources Laboratory, University Mouloud Mammeri, BP 15017, Tizi-Ouzou, Algeria
  • Bokreta Soumya Department of Biology, Faculty of Nature and Life Sciences, University Blida 1, BP 270, Soumaa, Blida, Algeria; Natural Resources Laboratory, University Mouloud Mammeri, BP 15017, Tizi-Ouzou, Algeria
  • Tarzali Dalila Department of Biology, Faculty of Nature and Life Sciences, University Blida 1, BP 270, Soumaa, Blida, Algeria
  • Boukrid Asma Department of Biology, Faculty of Nature and Life Sciences, University Blida 1, BP 270, Soumaa, Blida, Algeria
  • Boulahia Meriem Department of Biology, Faculty of Nature and Life Sciences, University Blida 1, BP 270, Soumaa, Blida, Algeria
  • Daoudi Zerrouki Nacira Natural Resources Laboratory, University Mouloud Mammeri, BP 15017, Tizi-Ouzou, Algeria
Keywords: Ivermectin, Ascorbic acid, Biochemical parameters, Histopathology, Rabbit

Abstract

Ivermectin (IVM) is a lipophilic anthelmintic drug widely used for the control of internal and external parasites in both human and veterinary medicine. Conversely, overdoses of IVM are associated with resistance and efficacy problems. The present study aimed to evaluate the effects of repeated administration of a high dose of IVM alone or with combination of ascorbic acid (AA) in male young rabbits (Oryctolagus cuniculus) via biochemical and histological investigations. Twenty rabbits were divided into four groups (n=5) and treated for three consecutive weeks: Control group; IVM group (2 mg/kg of body weight subcutaneously, 3 times a week); IVM + AAg (20 mg/mL) group and IVM + AAf (200 mg/kg of diet) group. IVM induced a disruption of hepatic biochemical parameters and lipid profile with a statistically significant (p < 0.05) increase in glucose, ALT, AST, GGT, HDL-C and a significant decrease of TC, TG, LDL-C, VLDL-C in IVM group compared to control group. Co-administration of AA moderately improved those biochemical parameters. Histopathological changes following IVM treatment in liver comprised loss of normal hepatocytes structure, central vein dilation and portal vein congestion. The lung showed abnormal structure of intrapulmonary bronchus, dilated bronchioles and alveoli and congested pulmonary artery. Nevertheless, the AA treatment groups revealed significant improvement when co-administered orally with IVM. This study suggested that AA has a beneficial ameliorative role against toxic effects induced by repeated high-dose of IVM.

DOI: http://dx.doi.org/10.5281/zenodo.4116306

Downloads

Download data is not yet available.

References

1. Omondi EO, Nyabadza F, Bonyah E, Badu K. Modeling the infection dynamics of onchocerciasis and its treatment. J Biol Systems. 2017; 25(02): 247-277.

2. Campbell WC. Ivermectin: a reflection on simplicity (Nobel lecture). Angewandte Chemie Int Edn. 2016; 55(35): 10184-10189.

3. Danaher M, Howells LC, Crooks SR, Cerkvenik-Flajs V, O’Keeffe M. Review of methodology for the determination of macrocyclic lactone residues in biological matrices. J Chromatogr B. 2006; 844(2): 175-203.

4. Campbel CW. History of avermectin and ivermectin, with notes on the history of other macrocyclic lactone antiparasitic agents. Curr Pharmac Biotechnol. 2012; 13(6): 853-865.

5. Qureshi S. Biochemical toxicity of ivermectin in Wistar albino rats. Am-Euras J Toxicol Sci. 2013; 5(1): 15-19.

6. Batiha GE, El-Far AH, El-Mleeh AA, Alsenosy AA, Abdelsamei EK, Abdel-Daim MM, et al. In vitro study of ivermectin efficiency against the cattle tick, Rhipicephalus (Boophilus) annulatus, among cattle herds in El-Beheira, Egypt. Vet World. 2019; 12(8): 1319-1326.

7. Liu Y, Fang S, Sun Q, Liu B. Anthelmintic drug ivermectin inhibits angiogenesis, growth and survival of glioblastoma through inducing mitochondrial dysfunction and oxidative stress. Biochem Biophys Res Commun. 2016; 480(3): 415-421.

8. Wang J, Xu Y, Wan H, Hu J. Antibiotic ivermectin selectively induces apoptosis in chronic myeloid leukemia through inducing mitochondrial dysfunction and oxidative stress. Biochem Biophys Res Commun. 2018; 497(1): 241-247.

9. Dou Q, Chen HN, Wang K, Yuan K, Lei Y, Li K, et al. Ivermectin induces cytostatic autophagy by blocking the PAK1/Akt axis in breast cancer. Cancer Res. 2016; 76(15): 4457-4469.

10. Hansen JM, Coleman RL, Sood AK. Targeting the tumour microenvironment in ovarian cancer. Eur J Cancer. 2016; 56: 131-143.

11. Zhu M, Li Y, Zhou Z. Antibiotic ivermectin preferentially targets renal cancer through inducing mitochondrial dysfunction and oxidative damage. Biochem Biophys Res Commun. 2017; 492(3): 373-378.

12. 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; 104787.

13. Lu M, Xiong D, Sun W, Yu T, Hu Z, Ding J, et al. Sustained release ivermectin-loaded solid lipid dispersion for subcutaneous delivery: in vitro and in vivo evaluation. Drug Delivery. 2017; 24(1): 622-631.

14. Gokbulut C, Biligili A, Kart A, Turgut C. Plasma dispositions of ivermectin, doramectin and moxidectin following subcutaneous administration in rabbits. Lab Animals. 2010; 44(2): 138-142.

15. Guzzo CA, Furtek CI, Porras AG, Chen C, Tipping R, Clineschmidt CM, et al. Safety, tolerability, and pharmacokinetics of escalating high doses of ivermectin in healthy adult subjects. J Clin Pharmacol. 2002; 42(10): 1122-1133.

16. Laing R, Gillan V, Devaney E. Ivermectin–old drug, new tricks? Trends Parasitol. 2017; 33(6): 463-472.

17. Merola VM, Paul AE. Toxicology of avermectins and milbemycins (macrocyclic lactones) and the role of P-glycoprotein in dogs and cats. Vet Clinics Small Animal Practice. 2018; 48(6): 991-1012.

18. Al-Jassim KB, Jawad AADH, Al-Masoudi EA. Effects of ivermectin on lipid profiles, antioxidant enzymes and proteins with the beneficial effects of vitamin C in rabbits. Int J Sci Technol. 2015; 143(2495): 1-13.

19. Al-Jassim KB, Jawad AADH, Al-Masoudi EA, Majeed SK. Histopathological and biochemical effects of ivermectin on kidney functions, lung and the ameliorative effects of vitamin c in rabbits (Lupus cuniculus). Basrah J Vet Res. 2016; 14: 110-24.

20. El Zoghby RR, Amin A, Hamouda AF, Ali AF. Toxicological and pathological studies of ivermectin on male albino rats. J Am Sci. 2015; 11(3): 73- 83.

21. Li M, You TZ, Zhu WJ, Qu JP, Liu C, Zhao B, et al. Antioxidant response and histopathological changes in brain tissue of pigeon exposed to avermectin. Ecotoxicol. 2013; 22(8): 1241-1254.

22. Abdel-Daim MM, Abdellatief SA. Attenuating effects of caffeic acid phenethyl ester and betaine on abamectin-induced hepatotoxicity and nephrotoxicity. Environ Sci Pollut Res. 2018; 25(16): 15909-15917.

23. Omshi FS, Abbasalipourkabir R, Abbasalipourkabir M, Nabyan S, Bashiri A, Ghafourikhosroshahi A. Effect of vitamin A and vitamin C on attenuation of ivermectin-induced toxicity in male Wistar rats. Environ Sci Pollut Res. 2018; 25(29): 29408-29417.

24. Ali BH. The effect of ivermectin on some haematological indices in rabbits: influence of vitamin K treatment. Clin Exp Pharmacol Physiol. 1990; 17(10): 735-738.

25. Behera SK, Dimri U, Singh SK, Mohanta RK. The curative and antioxidative efficiency of ivermectin and ivermectin+ vitamin E-selenium treatment on canine Sarcoptes scabiei infestation. Vet Res Commun. 2011; 35(4): 237-244.

26. Singh R, Verma PK, Singh G. Total phenolic, flavonoids and tannin contents in different extracts of Artemisia absinthium. J Complem Med Res. 2012; 1(2): 101-104.

27. Jurczuk M, Brzóska MM, Moniuszko-Jakoniuk J. Hepatic and renal concentrations of vitamins E and C in lead-and ethanol-exposed rats. An assessment of their involvement in the mechanisms of peroxidative damage. Food Chem Toxicol. 2007; 45(8): 1478-1486.

28. Halliwell B, Gutteridge JM. Free radicals in biology and medicine. Oxford University Press, USA; 2015.

29. Mandl J, Szarka A, Banhegyi G. Vitamin C: update on physiology and pharmacology. British J Pharmacol. 2009; 157(7): 1097-1110.

30. Khaldoun Oularbi H, Richeval C, Lebaili N, Zerrouki-Daoudi N, Baha M, Djennas N, et al. Ameliorative effect of vitamin C against hepatotoxicity induced by emamectin benzoate in rats. Human Exp Toxicol. 2017; 36(7): 709-717.

31. Derelanko MJ, Auletta CS, eds. Handbook of toxicology. CRC Press, 2014.

32. Fetoui H, Makni M, Garoui EM, Zeghal N. Toxic effects of lambda-cyhalothrin, a synthetic pyrethroids pesticide, on the rat kidney: involvement of oxidative stress and protective role of ascorbic acid. Exp Toxicol Pathol. 2010; 62: 593-599.

33. Króliczewska B, Miśta D, Ziarnik A, Żuk M, Szopa J, Pecka-Kiełb E, et al. The effects of seed from Linum usitatissimum cultivar with increased phenylpropanoid compounds and hydrolysable tannin in a high cholesterol-fed rabbit. Lipids Health Disease. 2018; 17(1): 76.

34. Millán J, Pintó X, Muñoz A, Zúñiga M, Rubiés-Prat J, Pallardo LF, et al. Lipoprotein ratios: physiological significance and clinical usefulness in cardiovascular prevention. Vascular Health Risk Manag. 2009; 5: 757.

35. Gonzalez-Canga A, Fernandez-Martinez N, Sahagun-Prieto A, Diez-Liébana MJ, Sierra-Vega M, Garcia-Vieitez JJ. A review of the pharmacological interactions of ivermectin in several animal species. Curr Drug Metab. 2009; 10(4): 359-368.

36. Bentounsi B, Ouksel M, Kachtarzi B. Compared efficacy of twelve registered preparations of ivermectin on the digestive and respiratory nematodes in Algerian sheep. Revue Méd Vét. 2009; 160(7): 329-334.

37. Kaplan RM, Vidyashankar AN. An inconvenient truth: global warming and anthelmintic resistance. Vet Parasitol. 2012; 186(1-2):70-78.

38. Zhang Y, Luo M, Xu W, Yang M, Wang B, Gao J, et al. Avermectin confers its cytotoxic effects by inducing DNA damage and mitochondria-associated apoptosis. J Agricult Food Chem. 2016; 64(36): 6895-6902.

39. Khaldoun-Oularbi H, Richeval C, Djenas N, Lhermitte M, Humbert L, Baz A. Effect of sub-acute exposure to abamectin “insecticide” on liver rats (Rattus norvegicus). Ann Toxicol Anal. 2013; 25(2): 63-70.

40. Arise RO, Malomo SO. Effects of ivermectin and albendazole on some liver and kidney function indices in rats. Afr J Biochem Res. 2009; 3(5): 190-197.

41. El-Far AH. Effect of therapeutic and double therapeutic doses of ivermectin on oxidative status and reproductive hormones in male rabbits. Am J Animal Vet Sci. 2013; 8(3): 128-133.

42. Hsu DZ, Hsu CH, Huang BM, Liu MY. Abamectin effects on aspartate aminotransferase and nitric oxide in rats. Toxicology. 2001; 165(2-3):189-193.

43. Miyajima A, Komoda M, Akagi K, Yuzawa K, Yoshimasu T, Yamamoto Y, et al. Experimental study of pharmacokinetics of external, whole body bathing application of ivermectin. J Dermatol. 2015; 42(1): 87-89.

44. Jin L, Feng X, Rong H, Pan Z, Inaba Y, Qiu L, et al. The antiparasitic drug ivermectin is a novel FXR ligand that regulates metabolism. Nature Commun. 2013; 4(1): 1-8.

45. Abd-Elhady HK, Abou-Elghar GE. Abamectin induced biochemical and histopathological changes in the albino rat, Rattus norvegicus. J Plant Protect Res. 2013; 53(3): 263-270.
Published
2020-10-21
How to Cite
(1)
Chahrazed, M.; Hassina, K.; Soumya, B.; Dalila, T.; Asma, B.; Meriem, B.; Nacira, D. Z. Beneficial Effects of Ascorbic Acid on Ivermectin Repeated High-Dose Therapy in Rabbits: Biochemical and Histopathological Investigations. European Journal of Biological Research 2020, 11, 1-13.
Section
Research Articles