The effect of co-administration of artemisinin and N-acetyl cysteine on antioxidant status, spermatological parameters and histopathology of testis in adult male mice
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Behnaz Abedi
,
Davoud Kianifard
Abstract
Objectives
This in vivo study aimed to evaluate the effect of various concentrations of artemisinin (Art) alone or together with N-acetyl cysteine (NAC) on spermatological indices, antioxidant status, and histopathological parameters of testicular tissue in adult male mice.
Methods
Six groups of five healthy male mice (25–30 g) were randomly assigned to different experimental groups. These groups received DMSO and corn oil (0.1%) as an Art solvent (Control), 50 mg kg−1 Art (Art-50), 250 mg kg−1 Art (Art-250), 50 mg kg−1 Art + 150 mg kg−1 NAC (Art-50+NAC-150), 250 mg kg−1 Art + 150 mg kg−1 NAC (Art-250+NAC-150) and 150 mg kg−1 NAC (NAC-150) for a period of 7 days. Testes and epididymis were prepared to evaluate the malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), peroxidase (POX), spermatological indices, and histological parameters.
Results
We showed that the high dose of Art (Art-250) significantly reduced the sperm count, motility, viability, and the activity of CAT and increased the levels of MDA compared to the control group. Also, the overdose of Art caused adverse changes in testicular tissue. Co-administration of NAC with Art (Art-250+NAC-150) corrected the adverse effects of Art.
Conclusions
The current study reports that a high dose of Art affects, spermatological parameters, antioxidant/stress oxidative status of the male reproductive system, and NAC is capable neutralize all adverse effects caused by Art.
Funding source: University of Tabriz
Award Identifier / Grant number: 43/124337/3
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Research funding: The authors are thankful to the Research affairs of the University of Tabriz for the financial support of this project (grant number 43/124337/3).
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Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
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Competing interests: Authors state no conflict of interest.
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Informed consent: Informed consent was obtained from all individuals included in this study.
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Ethical approval: The study protocol was approved by the Local Ethical Committee.
References
1. Agarwal, A, Sengupta, P. Oxidative stress and its association with male infertility male infertility. Cham: Springer; 2020:57–68 pp.10.1007/978-3-030-32300-4_6Search in Google Scholar
2. Bisht, S, Faiq, M, Tolahunase, M, Dada, R. Oxidative stress and male infertility. Nat Rev Urol 2017;14:470–85. https://doi.org/10.1038/nrurol.2017.69.Search in Google Scholar PubMed
3. Tulić, L, Ćurčić, M, Stojnić, J, Bulat, Z, Protić, I, Protic, I. Correlation of oxidative stress markers and semen parameters with the outcome of in vitro fertilization. Srp Arh Celok Lek 2020;148:310–4. https://doi.org/10.2298/sarh190409010t.Search in Google Scholar
4. Makker, K, Agarwal, A, Sharma, R. Oxidative stress & male infertility. Indian J Med Res 2009;129:357–67.Search in Google Scholar
5. Lam, NS, Long, X, Wong, JW, Griffin, RC, Doery, JC. Artemisinin and its derivatives: a potential treatment for leukemia. Anti Cancer Drugs 2019;30:1–18. https://doi.org/10.1097/cad.0000000000000697.Search in Google Scholar
6. Liu, Y-X, Wu, W, Liang, Y-J, Jie, Z-L, Wang, H, Wang, W, et al.. New uses for old drugs: the tale of artemisinin derivatives in the elimination of schistosomiasis japonica in China. Molecules 2014;19:15058–74. https://doi.org/10.3390/molecules190915058.Search in Google Scholar PubMed PubMed Central
7. Zyad, A, Tilaoui, M, Jaafari, A, Oukerrou, MA, Mouse, HA. More insights into the pharmacological effects of artemisinin. Phytother Res 2018;32:216–29. https://doi.org/10.1002/ptr.5958.Search in Google Scholar PubMed
8. Li, Q, Weina, PJ. Severe embryotoxicity of artemisinin derivatives in experimental animals, but possibly safe in pregnant women. Molecules 2010;15:40–57. https://doi.org/10.3390/molecules15010040.Search in Google Scholar PubMed PubMed Central
9. Efferth, T, Schöttler, U, Krishna, S, Schmiedek, P, Wenz, F, Giordano, FA. Hepatotoxicity by combination treatment of temozolomide, artesunate and Chinese herbs in a glioblastoma multiforme patient: case report review of the literature. Arch Toxicol 2017;91:1833–46. https://doi.org/10.1007/s00204-016-1810-z.Search in Google Scholar PubMed
10. Uhl, M, Schwab, S, Efferth, T. Fatal liver and bone marrow toxicity by combination treatment of dichloroacetate and artesunate in a glioblastoma multiforme patient: case report and review of the literature. Front Oncol 2016;6:204. https://doi.org/10.3389/fonc.2016.00204.Search in Google Scholar PubMed PubMed Central
11. Farombi, E, Abolaji, A, Adedara, I, Maduako, I, Omodanisi, I. Artemisinin induces hormonal imbalance and oxidative damage in the erythrocytes and uterus but not in the ovary of rats. Hum Exp Toxicol 2015;34:83–92. https://doi.org/10.1177/0960327114532385.Search in Google Scholar PubMed
12. Farombi, E, Adedara, I, Abolaji, A, Anamelechi, J, Sangodele, J. Sperm characteristics, antioxidant status and hormonal profile in rats treated with artemisinin. Andrologia 2014;46:893–901. https://doi.org/10.1111/and.12170.Search in Google Scholar PubMed
13. Ribas-Maynou, J, Yeste, M. Oxidative stress in male infertility: causes, effects in assisted reproductive techniques, and protective support of antioxidants. Biology 2020;9:77. https://doi.org/10.3390/biology9040077.Search in Google Scholar PubMed PubMed Central
14. Fazeli, F, Salimi, S. Correlation of seminal plasma total antioxidant capacity and malondialdehyde levels with sperm parameters in men with idiopathic infertility. Avicenna J Med Biochem 2016;4:e29736. https://doi.org/10.17795/ajmb-29736.Search in Google Scholar
15. Agarwal, A, Sekhon, LH. The role of antioxidant therapy in the treatment of male infertility. Hum Fertil 2010;13:217–25. https://doi.org/10.3109/14647273.2010.532279.Search in Google Scholar PubMed
16. Agarwal, A, Sharma, R, Gupta, S, Harlev, A, Ahmad, G, Du Plessis, SS, et al.. Oxidative stress in human reproduction: shedding light on a complicated phenomenon. Springer; 2017.10.1007/978-3-319-48427-3Search in Google Scholar
17. Rehman, R, Amjad, S, Tariq, H, Zahid, N, Akhter, M, Ashraf, M. Oxidative stress and male infertility: a cross sectional study. J Pakistan Med Assoc 2020;70:461–6. https://doi.org/10.5455/jpma.12992.Search in Google Scholar
18. Alvarez, JG, Storey, BT. Assessment of cell damage caused by spontaneous lipid peroxidation in rabbit spermatozoa. Biol Reprod 1984;30:323–31. https://doi.org/10.1095/biolreprod30.2.323.Search in Google Scholar PubMed
19. Palani, AF. Effect of serum antioxidant levels on sperm function in infertile male. Middle East Fertil Soc J 2018;23:19–22. https://doi.org/10.1016/j.mefs.2017.07.006.Search in Google Scholar
20. Agarwal, A, Finelli, R, Selvam, MKP, Leisegang, K, Majzoub, A, Tadros, N, et al.. A global survey of reproductive specialists to determine the clinical utility of oxidative stress testing and antioxidant use in male infertility. World J Mens Health 2021;39:470–88. https://doi.org/10.5534/wjmh.210025.Search in Google Scholar PubMed PubMed Central
21. Barik, G, Chaturvedula, L, Bobby, Z. Role of oxidative stress and antioxidants in male infertility: an interventional study. J Hum Reprod Sci 2019;12:204–9. https://doi.org/10.4103/jhrs.jhrs_135_18.Search in Google Scholar
22. Arafa, M, Agarwal, A, Majzoub, A, Panner Selvam, MK, Baskaran, S, Henkel, R, et al.. Efficacy of antioxidant supplementation on conventional and advanced sperm function tests in patients with idiopathic male infertility. Antioxidants 2020;9:219. https://doi.org/10.3390/antiox9030219.Search in Google Scholar PubMed PubMed Central
23. Terai, K, Horie, S, Fukuhara, S, Miyagawa, Y, Kobayashi, K, Tsujimura, A. Combination therapy with antioxidants improves total motile sperm counts: a Preliminary Study. Reprod Med Biol 2020;19:89–94. https://doi.org/10.1002/rmb2.12308.Search in Google Scholar PubMed PubMed Central
24. Aktaş, BK, Bulut, Ş, Bulut, S, Baykam, MM, Özden, C, Şenes, M, et al.. The effects of N-acetylcysteine on testicular damage in experimental testicular ischemia/reperfusion injury. Pediatr Surg Int 2010;26:293–8. https://doi.org/10.1007/s00383-009-2538-0.Search in Google Scholar PubMed
25. Ashoori, N, Oryan, S, Eidi, A, Roshanaei, K. Effect of N-acetylcysteine on the sperm biochemical parameters and expression of HSPA70 and caspase-3 genes in asthenoteratospermic infertile males undergoing cryopreservation. Arch Pharm Pract 2020;11:63–71.Search in Google Scholar
26. Albeltagy, RS, Mumtaz, F, Abdel Moneim, AE, El-Habit, OH. N-acetylcysteine reduces miR-146a and NF-κB p65 inflammatory signaling following cadmium hepatotoxicity in rats. Biol Trace Elem Res 2021;199:4657–65. https://doi.org/10.1007/s12011-021-02591-8.Search in Google Scholar PubMed
27. Oksay, T, Nazıroğlu, M, Ergün, O, Doğan, S, Özatik, O, Armağan, A, et al.. N-acetyl cysteine attenuates diazinon exposure-induced oxidative stress in rat testis. Andrologia 2013;45:171–7. https://doi.org/10.1111/j.1439-0272.2012.01329.x.Search in Google Scholar PubMed
28. Ciftci, H, Verit, A, Savas, M, Yeni, E, Erel, O. Effects of N-acetylcysteine on semen parameters and oxidative/antioxidant status. Urology 2009;74:73–6. https://doi.org/10.1016/j.urology.2009.02.034.Search in Google Scholar PubMed
29. Da Silva, RF, Borges, CS, Villela e Silva, P, Missassi, G, Kiguti, LRA, Pupo, AS, et al.. The coadministration of N-acetylcysteine ameliorates the effects of arsenic trioxide on the male mouse genital system. Oxid Med Cell Longev 2016;2016:1–11. https://doi.org/10.1155/2016/4257498.Search in Google Scholar PubMed PubMed Central
30. Shin, Y-J, Shannon, LJ, Bundy, A, Coll, M, Aydin, K, Bez, N, et al.. Using indicators for evaluating, comparing, and communicating the ecological status of exploited marine ecosystems. 2. Setting the scene. ICES Mar Sci Symp 2010;67:692–716. https://doi.org/10.1093/icesjms/fsp294.Search in Google Scholar
31. Reagan-Shaw, S, Nihal, M, Ahmad, N. Dose translation from animal to human studies revisited. Faseb J 2008;22:659–61. https://doi.org/10.1096/fj.07-9574lsf.Search in Google Scholar PubMed
32. Zambrano, E, Rodriguez-Gonzalez, G, Guzman, C, Garcia-Becerra, R, Boeck, L, Diaz, L, et al.. A maternal low protein diet during pregnancy and lactation in the rat impairs male reproductive development. J Physiol 2005;563:275–84. https://doi.org/10.1113/jphysiol.2004.078543.Search in Google Scholar PubMed PubMed Central
33. Jin, L, Xue, H-Y, Jin, L-J, Li, S-Y, Xu, Y-P. Antioxidant and pancreas-protective effect of aucubin on rats with streptozotocin-induced diabetes. Eur J Pharmacol 2008;582:162–7. https://doi.org/10.1016/j.ejphar.2007.12.011.Search in Google Scholar PubMed
34. Wyrobek, AJ, Gordon, LA, Burkhart, JG, Francis, MW, Kapp, RWJr, Letz, G, et al.. An evaluation of the mouse sperm morphology test and other sperm tests in nonhuman mammals: a report of the US environmental protection agency gene-tox program. Mutat Res 1983;115:1–72. https://doi.org/10.1016/0165-1110(83)90014-3.Search in Google Scholar PubMed
35. Goth, L. A simple method for determination of serum catalase activity and revision of reference range. Clin Chim Acta 1991;196:143–51. https://doi.org/10.1016/0009-8981(91)90067-m.Search in Google Scholar PubMed
36. Worthington, CC. Worthington enzyme manual: enzymes and related biochemicals. New Jersey: Worthington Biochemical Corporation; 1988.Search in Google Scholar
37. Del Maestro, R, McDonald, W. Oxidative enzymes in tissue homogenates. In: Handbook of methods for oxygen radical research. Boca Raton: CRC Press; 1985:291–6 pp.Search in Google Scholar
38. Kei, S. Serum lipid peroxide in cerebrovascular disorders determined by a new colorimetric method. Clin Chim Acta 1978;90:37–43. https://doi.org/10.1016/0009-8981(78)90081-5.Search in Google Scholar PubMed
39. Qiu, F, Liu, J, Mo, X, Liu, H, Chen, Y, Dai, Z. Immunoregulation by artemisinin and its derivatives: a new role for old antimalarial drugs. Front Immunol 2021;12:1–9. https://doi.org/10.3389/fimmu.2021.751772.Search in Google Scholar PubMed PubMed Central
40. O’Flaherty, C. Orchestrating the antioxidant defenses in the epididymis. Andrology 2019;7:662–8. https://doi.org/10.1111/andr.12630.Search in Google Scholar PubMed
41. Nwanjo, H, Iroagba, I, Nnatuanya, I, Eze, N. Antifertility activity of dihydroartemisinin in male albino rats. Internet J Endocrinol 2007;4:1–5.10.5580/282eSearch in Google Scholar
42. Aprioku, J. Testicular effects of artemisinins: are they reversible? Res J Pharmaceut Biol Chem Sci 2013;4:1152–60.Search in Google Scholar
43. Raji, Y, Gonadotoxicity evaluation of oral artemisinin derivative in male rats. J Med Sci 2005;5:303–6. https://doi.org/10.3923/jms.2005.303.306.Search in Google Scholar
44. Alahmar, AT. Role of oxidative stress in male infertility: an updated review. J Hum Reprod Sci 2019;12:4–18. https://doi.org/10.4103/jhrs.jhrs_150_18.Search in Google Scholar
45. Keshtgar, S, Fanaei, H, Bahmanpour, S, Azad, F, Ghannadi, A, Kazeroni, M. In vitro effects of α-tocopherol on teratozoospermic semen samples. Andrologia 2012;44:721–7. https://doi.org/10.1111/j.1439-0272.2011.01256.x.Search in Google Scholar PubMed
46. Basaki, M, Hashemvand, A, Tayefi-Nasrabadi, H, Panahi, Y, Dolatyarieslami, M. Artemisinin and l-carnitine combination therapy alters the erythrocytes redox status. Cell Biol Int 2022;46:1137–43. https://doi.org/10.1002/cbin.11793.Search in Google Scholar PubMed
47. Colagar, AH, Karimi, F, Jorsaraei, SGA. Correlation of sperm parameters with semen lipid peroxidation and total antioxidants levels in astheno-and oligoasheno-teratospermic men. Iran Red Crescent Med J 2013;15:780–5. https://doi.org/10.5812/ircmj.6409.Search in Google Scholar PubMed PubMed Central
48. Daikwo, OA, Kawu, MU. Evaluation of prolonged administration of artemether-lumefantrine on sperm indices and testicular testosterone concentration in adult male Wistar rats. Ann Med Biochem Sci 2015;1:52–6.Search in Google Scholar
49. Daikwo, OA, Kawu, MU, Magaji, RA, Eze, ED. Effect of prolonged administration of artemether-lumefantrine on testicular biomarkers of oxidative stress: ameliorative effect of vitamin E. Basic Sci Med 2018;7:1–6.Search in Google Scholar
50. Lysiak, J, Turner, T. Oxidative stress and testicular dysfunction. Eurekah Rep 2005;10:168–78.Search in Google Scholar
51. Izunya, A, Nwaopara, A, Aigbiremolen, A, Odike, M, Oaikhena, G, Bankole, J. Histological studies of the toxicity of artesunate on the testes in Wistar rats. Biol Med 2010;2:49–56.Search in Google Scholar
52. Jannatifar, R, Parivar, K, Roodbari, NH, Nasr-Esfahani, MH. Effects of N-acetyl-cysteine supplementation on sperm quality, chromatin integrity and level of oxidative stress in infertile men. Reprod Biol Endocrinol 2019;17:1–9. https://doi.org/10.1186/s12958-019-0468-9.Search in Google Scholar PubMed PubMed Central
53. Kunle-Alabi, OT, Akindele, OO, Odoh, MI, Oghenetega, BO, Raji, Y. Comparative effects of coconut water and N-Acetyl cysteine on the hypothalamo-pituitary-gonadal axis of male rats. Songklanakarin J Sci Technol 2017;39:759–64.Search in Google Scholar
54. Ji, Y-L, Wang, H, Zhang, C, Zhang, Y, Zhao, M, Chen, Y-H, et al.. N-acetylcysteine protects against cadmium-induced germ cell apoptosis by inhibiting endoplasmic reticulum stress in testes. Asian J Androl 2013;15:290–6. https://doi.org/10.1038/aja.2012.129.Search in Google Scholar PubMed PubMed Central
55. Rushworth, GF, Megson, IL. Existing and potential therapeutic uses for N-acetylcysteine: the need for conversion to intracellular glutathione for antioxidant benefits. Pharmacol Ther 2014;141:150–9. https://doi.org/10.1016/j.pharmthera.2013.09.006.Search in Google Scholar PubMed
56. EL-Samra, M, Aggag, SM. Effects of different antioxidants on sperm parameters in infertile males. JMSCR 2018;6:752–61.10.18535/jmscr/v6i2.117Search in Google Scholar
© 2023 Walter de Gruyter GmbH, Berlin/Boston
Articles in the same Issue
- Frontmatter
- Letter to the Editor
- The role of gut microbiota in etiopathogenesis of long COVID syndrome
- Original Articles
- Risk factors and inflammatory markers in acute coronary syndrome-ST elevation myocardial infarction (STEMI)
- Association of pro-inflammatory cytokines, inflammatory proteins with atherosclerosis index in obese male subjects
- Exploration of meteorin-like peptide (metrnl) predictors in type 2 diabetic patients: the potential role of irisin, and other biochemical parameters
- Distinct urinary progesterone metabolite profiles during the luteal phase
- Promoter methylation levels of RASSF1 and ATIC genes are associated with lung cancer in Iranian patients
- Population status of selenium in Colombia and associated factors: a cross-sectional study
- Bambusa vulgaris leaves reverse mitochondria dysfunction in diabetic rats through modulation of mitochondria biogenic genes
- Increased expression of androgen receptor and PSA genes in LNCaP (prostate cancer) cell line due to high concentrations of EGCG, an active ingredient in green tea
- The effects of endurance exercise and metformin on memory impairment caused by diabetes
- Exercise modulation in inflammation and metabolic hormonal disorders of COVID-19 to decrease risk factors in coronary heart disease
- The effect of co-administration of artemisinin and N-acetyl cysteine on antioxidant status, spermatological parameters and histopathology of testis in adult male mice
- Case Report
- Unilateral ovarian agenesis with ipsilateral tubal presence – report of a case
- Review Articles
- Brown adipose tissue as an endocrine organ: updates on the emerging role of batokines
- Zuranolone and its role in treating major depressive disorder: a narrative review
Articles in the same Issue
- Frontmatter
- Letter to the Editor
- The role of gut microbiota in etiopathogenesis of long COVID syndrome
- Original Articles
- Risk factors and inflammatory markers in acute coronary syndrome-ST elevation myocardial infarction (STEMI)
- Association of pro-inflammatory cytokines, inflammatory proteins with atherosclerosis index in obese male subjects
- Exploration of meteorin-like peptide (metrnl) predictors in type 2 diabetic patients: the potential role of irisin, and other biochemical parameters
- Distinct urinary progesterone metabolite profiles during the luteal phase
- Promoter methylation levels of RASSF1 and ATIC genes are associated with lung cancer in Iranian patients
- Population status of selenium in Colombia and associated factors: a cross-sectional study
- Bambusa vulgaris leaves reverse mitochondria dysfunction in diabetic rats through modulation of mitochondria biogenic genes
- Increased expression of androgen receptor and PSA genes in LNCaP (prostate cancer) cell line due to high concentrations of EGCG, an active ingredient in green tea
- The effects of endurance exercise and metformin on memory impairment caused by diabetes
- Exercise modulation in inflammation and metabolic hormonal disorders of COVID-19 to decrease risk factors in coronary heart disease
- The effect of co-administration of artemisinin and N-acetyl cysteine on antioxidant status, spermatological parameters and histopathology of testis in adult male mice
- Case Report
- Unilateral ovarian agenesis with ipsilateral tubal presence – report of a case
- Review Articles
- Brown adipose tissue as an endocrine organ: updates on the emerging role of batokines
- Zuranolone and its role in treating major depressive disorder: a narrative review
