Sıçanlarda Berberinin Siklofosfamide Bağli Testiküler Hasar Üzerindeki Önleme Ve / Veya Tedavi Edici Etkisi

Öz

ct: The protective and/or therapeutic effect of berberine on cyclophosphamide-induced testicular injury was investigated in rats. A total of 40 male Sprague-Dawley rats were divided into 5 groups (n=8 per group). The control group received saline and CP, BER75, BER150 and BER300 groups received single dose of intraperitoneal 200 mg/kg CP on day 8. Berberine (75 mg/kg, 150 mg/kg and 300 mg/kg) was administered orally for 7 days before and after the CP injection. At the end of the protocol, testes were removed for histological examination, immunohistochemical staining, and biochemical assessments. In our study, CP did not cause a significant change in body weight and testis weight, whereas berberine treatment significantly decreased body weight. Although no significant change was observed in terms of oxidative stress markers and cytokine levels, degenerative changes and apoptotic findings were found in the CP group; which were improved significantly with increasing doses of berberine treatment. In conclusion, we found that treatment with berberine may have anti-degenerative and anti-apoptotic potential rather than altering oxidative stress markers and/or inflammatory pathways in CP-induced testicular d

Anahtar Kelimeler

• Berberin
• Sıçan
• Siklofosfamid
• Testis hasarı

The Effect of Berberine on the Prevention and/or Treatment on Cyclophosphamide-Induced Testicular Damage in Rats

Öz

The protective and/or therapeutic effect of berberine on cyclophosphamide-induced testicular injury was investigated in rats. A total of 40 male Sprague-Dawley rats were divided into 5 groups (n=8 per group). The control group received saline and CP, BER75, BER150 and BER300 groups received single dose of intraperitoneal 200 mg/kg CP on day 8. Berberine (75 mg/kg, 150 mg/kg and 300 mg/kg) was administered orally for 7 days before and after the CP injection. At the end of the protocol, testes were removed for histological examination, immunohistochemical staining, and biochemical assessments. In our study, CP did not cause a significant change in body weight and testis weight, whereas berberine treatment significantly decreased body weight. Although no significant change was observed in terms of oxidative stress markers and cytokine levels, degenerative changes and apoptotic findings were found in the CP group; which were improved significantly with increasing doses of berberine treatment. In conclusion, we found that treatment with berberine may have anti-degenerative and anti-apoptotic potential rather than altering oxidative stress markers and/or inflammatory pathways in CP-induced testicular damage.

Anahtar Kelimeler

• berberine
• cyclophosphamide
• rat
• testicular injury

Kaynakça

1. 1. Emadi A, Jones RJ, Brodsky RA. Cyclophosphamide and cancer: golden anniversary. Nat Rev Clin Oncol. 2009;6(11):638-47.
2. 2. Ghobadi E, Moloudizargari M, Asghari MH, Abdollahi M. The mechanisms of cyclophosphamide-induced testicular toxicity and the protective agents. Expert Opin Drug Metab Toxicol. 2017;13(5):525-36.
3. 3. Vernet P, Aitken RJ, Drevet JR. Antioxidant strategies in the epididymis. Mol Cell Endocrinol. 2004;216(1-2):31-9.
4. 4. Ponticelli C, Escoli R, Moroni G. Does cyclophosphamide still play a role in glomerular diseases? Autoimmun Rev. 2018;17(10):1022-7.
5. 5. Turk G, Ceribasi AO, Sakin F, Sonmez M, Atessahin A. Antiperoxidative and anti-apoptotic effects of lycopene and ellagic acid on cyclophosphamide-induced testicular lipid peroxidation and apoptosis. Reprod Fertil Dev. 2010;22(4):587-96.
6. 6. Drumond AL, Weng CC, Wang G, Chiarini-Garcia H, Eras-Garcia L, Meistrich ML. Effects of multiple doses of cyclophosphamide on mouse testes: accessing the germ cells lost, and the functional damage of stem cells. Reprod Toxicol. 2011;32(4):395-406.
7. 7. Latta K, von Schnakenburg C, Ehrich JH. A meta-analysis of cytotoxic treatment for frequently relapsing nephrotic syndrome in children. Pediatr Nephrol. 2001;16(3):271-82.
8. 8. Selvakumar E, Prahalathan C, Mythili Y, Varalakshmi P. Beneficial effects of DL-alpha-lipoic acid on cyclophosphamide-induced oxidative stress in mitochondrial fractions of rat testis. Chem Biol Interact. 2005;152(1):59-66.

9. 9. de Lamirande E, Gagnon C. Reactive oxygen species and human spermatozoa. II. Depletion of adenosine triphosphate plays an important role in the inhibition of sperm motility. J Androl. 1992;13(5):379-86.
10. 10. Birdsall TC KG. Berberine: therapeutic potential of an alkaloid found in several medicinal plants. . Altern Med Rev. 1997 2:94–103.
11. 11. Singh J, Kakkar P. Antihyperglycemic and antioxidant effect of Berberis aristata root extract and its role in regulating carbohydrate metabolism in diabetic rats. J Ethnopharmacol. 2009;123(1):22-6.
12. 12. Kulkarni SK, Dhir A. Berberine: a plant alkaloid with therapeutic potential for central nervous system disorders. Phytother Res. 2010;24(3):317-24.
13. 13. Bhutada P, Mundhada Y Fau - Bansod K, Bansod K Fau - Dixit P, Dixit P Fau - Umathe S, Umathe S Fau - Mundhada D, Mundhada D. Anticonvulsant activity of berberine, an isoquinoline alkaloid in mice. (1525-5069 (Electronic)).
14. 14. Battu SK, Repka Ma Fau - Maddineni S, Maddineni S Fau - Chittiboyina AG, Chittiboyina Ag Fau - Avery MA, Avery Ma Fau - Majumdar S, Majumdar S. Physicochemical characterization of berberine chloride: a perspective in the development of a solution dosage form for oral delivery. (1530-9932 (Electronic)).
15. 15. Maritim AC, Sanders RA, Watkins JB, 3rd. Diabetes, oxidative stress, and antioxidants: a review. J Biochem Mol Toxicol. 2003;17(1):24-38.
16. 16. Ceballos-Picot I, Witko-Sarsat V Fau - Merad-Boudia M, Merad-Boudia M Fau - Nguyen AT, Nguyen At Fau - Thévenin M, Thévenin M Fau - Jaudon MC, Jaudon Mc Fau - Zingraff J, et al. Glutathione antioxidant system as a marker of oxidative stress in chronic renal failure. (0891-5849 (Print)).
17. 17. Cui G, Qin X, Zhang Y, Gong Z, Ge B, Zang YQ. Berberine differentially modulates the activities of ERK, p38 MAPK, and JNK to suppress Th17 and Th1 T cell differentiation in type 1 diabetic mice. J Biol Chem. 2009;284(41):28420-9.
18. 18. Lin W-HC-YL-Y. Protective effect of isoquinoline alkaloid berberine on spontaneous inflammation in the spleen, liver and kidney of non-obese diabetic mice through downregulating gene expression ratios of pro-/anti-inflammatory and Th1/Th2 cytokines. Food Chemistry 2012;131.
19. 19. Erel O. A new automated colorimetric method for measuring total oxidant status. Clin Biochem. 2005;38(12):1103-11.
20. 20. Abd El Tawab AM, Shahin NN, AbdelMohsen MM. Protective effect of Satureja montana extract on cyclophosphamide-induced testicular injury in rats. 2014(1872-7786 (Electronic)).
21. 21. Motawi TM, Sadik NA, Refaat A. Cytoprotective effects of DL-alpha-lipoic acid or squalene on cyclophosphamide-induced oxidative injury: an experimental study on rat myocardium, testicles and urinary bladder. Food Chem Toxicol. 2010;48(8-9):2326-36.
22. 22. Selvakumar E, Prahalathan C, Mythili Y, Varalakshmi P. Protective effect of DL-alpha-lipoic acid in cyclophosphamide induced oxidative injury in rat testis. Reprod Toxicol. 2004;19(2):163-7.
23. 23. Salimnejad R, Soleimani Rad J, Mohammad Nejad D, Roshangar L. Effect of ghrelin on total antioxidant capacity, lipid peroxidation, sperm parameters and fertility in mice against oxidative damage caused by cyclophosphamide. Andrologia. 2018;50(2).
24. 24. Xie R, Chen L, Wu H, Chen T, Wang F, Chen X, et al. GnRH Antagonist Improves Pubertal Cyclophosphamide-Induced Long-Term Testicular Injury in Adult Rats. Int J Endocrinol. 2018;2018:4272575.
25. 25. Myers CE, Hoelzinger DB, Truong TN, Chew LA, Myles A, Chaudhuri L, et al. Chemotherapy can induce weight normalization of morbidly obese mice despite undiminished ingestion of high fat diet. Oncotarget. 2017;8(3):5426-38.
26. 26. Hu Y, Young AJ, Ehli EA, Nowotny D, Davies PS, Droke EA, et al. Metformin and berberine prevent olanzapine-induced weight gain in rats. PLoS One. 2014;9(3):e93310.
27. 27. Lee M, McGeer EG, McGeer PL. Sodium thiosulfate attenuates glial-mediated neuroinflammation in degenerative neurological diseases. J Neuroinflammation. 2016;13:32.
28. 28. Bashir S, Gilani AH. Antiurolithic effect of berberine is mediated through multiple pathways. 2010(1879-0712 (Electronic)).
29. 29. Vladimir-Knezevic S, Blazekovic B, Kindl M, Vladic J, Lower-Nedza AD, Brantner AH. Acetylcholinesterase inhibitory, antioxidant and phytochemical properties of selected medicinal plants of the Lamiaceae family. Molecules. 2014;19(1):767-82.
30. 30. Pongkittiphan V, Chavasiri W, Supabphol R. Antioxidant Effect of Berberine and its Phenolic Derivatives Against Human Fibrosarcoma Cells. Asian Pac J Cancer Prev. 2015;16(13):5371-6.
31. 31. Laamech J, El-Hilaly J, Fetoui H, Chtourou Y, Gouitaa H, Tahraoui A, et al. Berberis vulgaris L. effects on oxidative stress and liver injury in lead-intoxicated mice. J Complement Integr Med. 2017;14(1).
32. 32. Abd El-Wahab Ae Fau - Ghareeb DA, Ghareeb DA, Sarhan Ee Fau - Abu-Serie MM, Abu-Serie Mm Fau - El Demellawy MA, El Demellawy MA. In vitro biological assessment of Berberis vulgaris and its active constituent, berberine: antioxidants, anti-acetylcholinesterase, anti-diabetic and anticancer effects. 2013(1472-6882 (Electronic)).
33. 33. Rafiee F, Nejati V, Heidari R, Ashraf H. Protective effect of methanolic extract of Berberis integerrima Bunge. root on carbon tetrachloride-induced testicular injury in Wistar rats. Int J Reprod Biomed. 2016;14(2):133-40.
34. 34. Shaker RA, Abboud SH, Assad HC, Hadi N. Enoxaparin attenuates doxorubicin induced cardiotoxicity in rats via interfering with oxidative stress, inflammation and apoptosis. BMC Pharmacol Toxicol. 2018;19(1):3.
35. 35. Korsmeyer SJ, Wei MC, Saito M, Weiler S, Oh KJ, Schlesinger PH. Pro-apoptotic cascade activates BID, which oligomerizes BAK or BAX into pores that result in the release of cytochrome c. Cell Death Differ. 2000;7(12):1166-73.
36. 36. Schwartz PS, Waxman DJ. Cyclophosphamide induces caspase 9-dependent apoptosis in 9L tumor cells. Mol Pharmacol. 2001;60(6):1268-79.
37. 37. Green DR, Reed JC. Mitochondria and apoptosis. Science. 1998;281(5381):1309-12.
38. 38. Li J, Yuan J. Caspases in apoptosis and beyond. Oncogene. 2008;27(48):6194-206.
39. 39. Potnuri AG, Allakonda L, Lahkar M. Crocin attenuates cyclophosphamide induced testicular toxicity by preserving glutathione redox system. Biomed Pharmacother. 2018;101:174-80.
40. 40. Kim JM, Ghosh SR, Weil AC, Zirkin BR. Caspase-3 and caspase-activated deoxyribonuclease are associated with testicular germ cell apoptosis resulting from reduced intratesticular testosterone. Endocrinology. 2001;142(9):3809-16.
41. 41. Ryan L, O'Callaghan YC, O'Brien NM. Generation of an oxidative stress precedes caspase activation during 7beta-hydroxycholesterol-induced apoptosis in U937 cells. J Biochem Mol Toxicol. 2004;18(1):50-9.
42. 42. Hamsa TP, Kuttan G. Protective role of Ipomoea obscura (L.) on cyclophosphamide-induced uro- and nephrotoxicities by modulating antioxidant status and pro-inflammatory cytokine levels. Inflammopharmacology. 2011;19(3):155-67.
43. 43. Yu G, Li Y, Tian Q, Liu R, Wang Q, Wang JZ, et al. Berberine attenuates calyculin A-induced cytotoxicity and Tau hyperphosphorylation in HEK293 cells. J Alzheimers Dis. 2011;24(3):525-35.
44. 44. Sakura M, Masuda H, Matsuoka Y, Yokoyama M, Kawakami S, Kihara K. Rolipram, a specific type-4 phosphodiesterase inhibitor, inhibits cyclophosphamide-induced haemorrhagic cystitis in rats. BJU Int. 2009;103(2):264-9.
45. 45. Arafa HM. Uroprotective effects of curcumin in cyclophosphamide-induced haemorrhagic cystitis paradigm. Basic Clin Pharmacol Toxicol. 2009;104(5):393-9.
46. 46. Yigitaslan S, Ozatik O, Ozatik FY, Erol K, Sirmagul B, Baseskioglu AB. Effects of tadalafil on hemorrhagic cystitis and testicular dysfunction induced by cyclophosphamide in rats. Urol Int. 2014;93(1):55-62.
47. 47. Korkmaz A, Topal T, Oter S. Pathophysiological aspects of cyclophosphamide and ifosfamide induced hemorrhagic cystitis; implication of reactive oxygen and nitrogen species as well as PARP activation. Cell Biol Toxicol. 2007;23(5):303-12.
48. 48. Li Z, Geng YN, Jiang JD, Kong WJ. Antioxidant and anti-inflammatory activities of berberine in the treatment of diabetes mellitus. Evid Based Complement Alternat Med. 2014;2014:289264.
49. 49. Chen Y, Wang Y Fau - Zhang J, Zhang J Fau - Sun C, Sun C Fau - Lopez A, Lopez A. Berberine improves glucose homeostasis in streptozotocin-induced diabetic rats in association with multiple factors of insulin resistance. 2011(2090-4649 (Electronic)).
50. 50. Shang W, Liu J, Yu X, Zhao J. [Effects of berberine on serum levels of inflammatory factors and inflammatory signaling pathway in obese mice induced by high fat diet]. Zhongguo Zhong Yao Za Zhi. 2010;35(11):1474-7.
51. 51. Lou T, Zhang Z, Xi Z, Liu K, Li L, Liu B, et al. Berberine inhibits inflammatory response and ameliorates insulin resistance in hepatocytes. Inflammation. 2011;34(6):659-67.
52. 52. Choi BH, Ahn IS, Kim YH, Park JW, Lee SY, Hyun CK, et al. Berberine reduces the expression of adipogenic enzymes and inflammatory molecules of 3T3-L1 adipocyte. Exp Mol Med. 2006;38(6):599-605.