OLANZAPİN VE L-KARNİTİNİN RAT TESTİS DOKUSU ÜZERİNDEKİ ETKİSİNİN ARAŞTIRILMASI

Abstract

Amaç Olanzapinin cinsel işlev bozukluğu üzerine olumsuz etkileri vardır. Üreme sisteminde de yapısal değişikliklere neden olduğunu gösteren sınırlı sayıda çalışma bulunmaktadır. Bu çalışmada Olanzapinin neden olduğu testis hasarı üzerine L-Karnitin'in etkilerinin histopatolojik, sperm parametreleri, biyokimyasal açıdan incelenmesi amaçlanmıştır. Gereç ve Yöntem Çalışmamızda toplam 48 adet erişkin Sprague-Dawley erkek sıçan kullanıldı. Sıçanlar, her grupta 8 sıçan olacak şekilde 6 gruba ayrıldı: Kontrol grubu (C), 200 mg/kg L-Karnitin uygulanan grup (LC), 2 mg/kg düşük doz Olanzapin verilen grup (LOZN), 2 mg/kg Olanzapin ve 200 mg/kg L-Karnitin verilen grup (LOZN+LC), 4 mg/kg Olanzapin verilen grup (HOZN), 4 mg/kg Olanzapin ve 200 mg/kg L-Karnitin verilen grup (HOZN+ LC). MDA, IL-1B, IL-6, TAS, TOS düzeylerinin belirlenmesi, histolojik değerlendirme için testis dokuları kullanıldı. Bulgular Olanzapin alan gruplarda sperm sayısında azalma, MDA, IL-1β, TOS değerlerinde artış, testis dokusunda doza bağlı histopatolojik değişiklikler gözlendi. Olanzapin ve L-Karnitin uygulanan gruplarda sadece Olanzapin verilen gruplara göre histopatolojik değişiklikler daha düşük oranda bulundu. Sonuç Yüksek doz Olanzapin uygulanan gruplarda gözlenen testis yapısındaki dejeneratif histolojik bulguların, Olanzapinin testis dokusunda oluşturduğu oksidatif stresten kaynaklanabileceği sonucuna varıldı. L-Karnitin ise oksidatif hasarı azaltarak testis dejenerasyonun azaltılmasında etkili olabileceği düşünüldü.

Keywords

• Olanzapin
• L-Karnitin
• testis
• sperm
• oksidatif stres

INVESTIGATION OF THE EFFECT OF OLANZAPINE AND L-CARNITINE ON RAT TESTIS TISSUE

Abstract

Objective Olanzapine has adverse effects on sexual dysfunction. There are a limited number of studies showing that it also causes structural changes in the reproductive system. This study aimed to examine the effects of L-Carnitine on testicular damage caused by Olanzapine in terms of histopathological, sperm parameters, and biochemical aspects. Material and Method A total of 48 adult Sprague-Dawley male rats were used in our study. Rats were divided into 6 groups, 8 rats in each group: the Control group (C), 200 mg/ kg L-Carnitine administered group (LC), 2 mg/kg low dose Olanzapine administered group (LOZN), 2 mg/kg Olanzapine, and 200 mg/kg L-Carnitine administered group (LOZN+LC), 4 mg/kg Olanzapine administered group (HOZN), 4 mg/kg Olanzapine and 200 mg/ kg L-Carnitine administered group (HOZN+LC). Testicular tissues were used for the determination of MDA, IL-1B, IL-6, TAS, TOS levels, and histological evaluation. Results In the groups receiving Olanzapine, a decrease in sperm count, an increase in MDA, IL-1β, TOS values, and dose-dependent histopathological changes in testicular tissue were observed. Histopathological changes were found at a lower rate in the Olanzapine and L-Carnitine administered groups compared to the Olanzapine-only groups. Conclusion It was concluded that the degenerative histological findings in the testicular structure observed in the high-dose Olanzapine administered groups might be caused by the oxidative stress induced by Olanzapine in the testicular tissue. L-Carnitine, on the other hand, was thought to be effective in reducing testicular degeneration by reducing oxidative damage.

Keywords

• Olanzapine
• L-Carnitine
• testis
• sperm
• oxidative stress

References

1. 1. Ardıç CM, Ilgın S, Baysal M, Karaduman AB, Kılıç V, Aydoğan- Kılıç G, Uçarcan Ş, Atlı-Eklioğlu Ö. Olanzapine induced reproductive toxicity in male rats. Sci Rep. 2021 Feb 26;11(1):4739. doi: 10.1038/s41598-021-84235-4. PMID: 33637793; PMCID: PMC7910427.
2. 2. Katzung BG. Basic and Clinical Pharmacology 14th Edition: McGraw Hill Professional; 2017.
3. 3. Byerly MJ, Nakonezny PA, Bettcher BM, Carmody T, Fisher R, Rush AJ. Sexual dysfunction associated with second-generation antipsychotics in outpatients with schizophrenia or schizoaffective disorder: an empirical evaluation of olanzapine, risperidone, and quetiapine. Schizophrenia research. 2006;86(1-3):244-50
4. 4. Bella AJ, Shamloul R. Psychotropics and sexual dysfunction. Central European journal of urology. 2013;66(4):466
5. 5. Cabello-Verrugio C, Simon F, Trollet C, Santibañez JF. Oxidative Stress in Disease and Aging: Mechanisms and Therapies 2016. Oxid Med Cell Longev. 2017; 2017:4310469. doi: 10.1155/2017/4310469.
6. 6. Reuter S, Gupta SC, Chaturvedi MM, Aggarwal BB. Oxidative stress, inflammation, and cancer: how are they linked? Free Radic Biol Med. 2010 Dec 1;49(11):1603-16. doi: 10.1016/j.freeradbiomed.2010.09.006.
7. 7. Sánchez A, Calpena AC, Clares B. Evaluating the Oxidative Stress in Inflammation: Role of Melatonin. Int J Mol Sci. 2015 Jul 27;16(8):16981-7004. doi: 10.3390/ijms160816981.
8. 8. Hussain T, Tan B, Yin Y, Blachier F, Tossou MC, Rahu N. Oxidative Stress and Inflammation: What Polyphenols Can Do for Us? Oxid Med Cell Longev. 2016; 2016:7432797. doi: 10.1155/2016/7432797.

9. 9. Medzhitov R. Inflammation 2010: new adventures of an old flame. Cell. 2010 Mar 19;140(6):771-6. doi: 10.1016/j. cell.2010.03.006.
10. 10. Seelaender M, Neto JC, Pimentel GD, Goldszmid RS, Lira FS. Inflammation in the disease: mechanism and therapies 2014. Mediators Inflamm. 2015; 2015:169852. doi: 10.1155/2015/169852.
11. 11. Lenzi A, Lombardo F, Sgrò P, Salacone P, Caponecchia L, Dondero F, et al. Use of carnitine therapy in selected cases of male factor infertility: a double-blind crossover trial. Fertility and sterility. 2003;79(2):292-300.
12. 12. Gürbüz B, Yalti S, Fiçicioğlu C, Zehi˙ r K. Relationship between semen quality and seminal plasma total carnitine in infertile men. Journal of Obstetrics and Gynaecology. 2003;23(6):653-6.
13. 13. Agarwal A, Sengupta P, Durairajanayagam D. Role of L-carnitine in female infertility. Reprod Biol Endocrinol. 2018 Jan 26;16(1):5. doi: 10.1186/s12958-018-0323-4.
14. 14. Mongioi L, Calogero A, Vicari E, Condorelli R, Russo G, Privitera S, et al. The role of carnitine in male infertility. Andrology. 2016;4(5):800-7.
15. 15. Vicari E, Calogero A. Effects of treatment with carnitines in infertile patients with prostato-vesiculo-epididymitis. Human Reproduction. 2001;16(11):2338-42.
16. 16. Jeulin C, Lewin LM. Role of free L-carnitine and acetyl-L-carnitine in post-gonadal maturation of mammalian spermatozoa. Human Reproduction Update. 1996;2(2):87-102.
17. 17. Odaci E, Bilen H, Hacimuftuoglu A, Keles ON, Can İ, Bilici M. Long-term treatments with low-and high dose olanzapine change hepatocyte numbers in rats. A stereological and histopathological study. Archives of medical research. 2009;40(3):139-45.
18. 18. Mitchell M, Riesenberg R, Bari MA, Marquez E, Kurtz D, Falk D, et al. A double-blind, randomized trial to evaluate the pharmacokinetics and tolerability of 30 or 40 mg/d oral olanzapine relative to 20 mg/d oral olanzapine in stable psychiatric subjects. Clinical therapeutics. 2006;28(6):881-92.
19. 19. de Siqueira Bringel S, de Amorim Júnior AA, Amorim MJAAL, Brito LT, Morais RN, de Torres SM, et al. Endocrine and testicular changes induced by olanzapine in adult Wistar rats. Journal of Applied Toxicology. 2013;33(1):24-31.
20. 20. Terry AV Jr, Warner SE, Vandenhuerk L, Pillai A, Mahadik SP, Zhang G, et al. Negative effects of chronic oral chlorpromazine and olanzapine treatment on the performance of tasks designed to assess spatial learning and working memory in rats. Neuroscience. 2008;156(4):1005-16.
21. 21. Yari A, Asadi MH, Bahadoran H, Dashtnavard H, Imani H, Naghii MR. Cadmium toxicity in spermatogenesis and protective effects of L-carnitine in adult male rats. Biological trace element research. 2010;137(2):216-25.
22. 22. Topcu-Tarladacalisir Y, Kanter M, Uzal MC. Role of L-carnitine in the prevention of seminiferous tubules damage induced by gamma radiation: a light and electron microscopic study. Archives of toxicology. 2009;83(8):735-46.
23. 23. Saudemont G, Prod'Homme C, Da Silva A, Villet S, Reich M, Penel N, Gamblin V. The use of olanzapine as an antiemetic in palliative medicine: a systematic review of the literature. BMC Palliat Care. 2020 Apr 22;19(1):56. doi: 10.1186/s12904-020- 00559-4.
24. 24. Soliman HM, Wagih HM, Attia GM, Algaidi SA. Light and electron microscopic study on the effect of antischizophrenic drugs on the structure of seminiferous tubules of adult male albino rats. Folia histochemica et cytobiologica. 2014;52(4):335-49.
25. 25. Deliktaş H, Gedik A, Nergiz Y, Bircan MK. The Effect of L-Carnitine on Testicular Ischemia-Reperfusion Injury due to Testicular Torsion in Rats. European Journal of General Medicine. 2012;9(3).
26. 26. Kanter M, Topcu-Tarladacalisir Y, Parlar S. Antiapoptotic effect of L-carnitine on testicular irradiation in rats. Journal of molecular histology. 2010;41(2-3):121-8.
27. 27. Coskun N, Hatipoglu MT, Ozogul C, Korkmaz C, Akyol SN, Micili SC, et al. The protective effects of acetyl L-carnitine on testis gonadotoxicity induced by Cisplatin in rats. Balkan medical journal. 2013;30(2):235-41.
28. 28. Khushboo M, Murthy MK, Devi MS, Sanjeev S, Ibrahim KS, Kumar NS, et al. Testicular toxicity and sperm quality following copper exposure in Wistar albino rats: ameliorative potentials of L-carnitine. Environmental science and pollution research international.2018;25(2):1837-62.
29. 29. Zare Z, Mohammadi M, Eimani H, Shafaroudi MM. Prevention of di (2-ethylhexyl) Phthalate-induced Testicular Disturbance in Mice by Co-administration of L-carnitine. International journal of fertility & sterility. 2011;5(3):186.
30. 30. Abo-Ghanema II, El-Nasharty M, El-Far A, Ghonium HA. Effect of ginger and L-carnitine on the reproductive performance of male rats. World Acad Sci Eng Technol. 2012; 64:980-6.
31. 31. Yüksel N. Temel Psikofarmakoloji. Ankara, Türkiye Psikiyatri Derneği. 2010.
32. 32. Albaugh VL, Judson JG, She P, Lang CH, Maresca KP, Joyal JL, et al. Olanzapine promotes fat accumulation in male rats by decreasing physical activity, repartitioning energy and increasing adipose tissue lipogenesis while impairing lipolysis. Molecular psychiatry. 2011;16(5):569.
33. 33. Pooyandjoo M, Nouhi M, Shab‐Bidar S, Djafarian K, Olyaeemanesh A. The effect of (L‐) carnitine on weight loss in adults: a systematic review and meta‐analysis of randomized controlled trials. Obesity reviews. 2016;17(10):970-6.
34. 34. Davey KJ, O’Mahony SM, Schellekens H, O’Sullivan O, Bienenstock J, Cotter PD, et al. Gender-dependent consequences of chronic olanzapine in the rat: effects on body weight, inflammatory, metabolic and microbiota parameters. Psychopharmacology.2012;221(1):155-69.
35. 35. Alahmar AT. Role of oxidative stress in male infertility: An updated review. Journal of human reproductive sciences. 2019;12(1):4.
36. 36. Mahmoud GS, El-Deek HE. Melatonin modulates inflammatory mediators and improves olanzapine-induced hepatic steatosis in rat model of schizophrenia. Int J Physiol Pathophysiol Pharmacol. 2019;11(3):64-75.
37. 37. Eftekhari A, Azarmi Y, Parvizpur A, Eghbal MA. Involvement of oxidative stress and mitochondrial/lysosomal cross-talk in olanzapine cytotoxicity in freshly isolated rat hepatocytes. Xenobiotica.2016;46(4):369-78.
38. 38. Bilgic S, Korkmaz DT, Azirak S, Güvenc AN, Kocaman N, Ozer MK. Olanzapine-induced renal damages and metabolic side effects: the protective effects of thymoquinone. Journal of Turgut Ozal Medical Center. 2018;25(1).
39. 39. Türkez H, Toğar B. The genotoxic and oxidative damage potential of olanzapine in vitro. Toxicology and industrial health. 2010;26(9):583-8.
40. 40. Samanta L, Sahoo A, Chainy G. Age-related changes in rat testicular oxidative stress parameters by hexachlorocyclohexane. Archives of toxicology. 1999;73(2):96-107.
41. 41. Abarikwu SO, Adesiyan AC, Oyeloja TO, Oyeyemi MO, Farombi EO. Changes in sperm characteristics and induction of oxidative stress in the testis and epididymis of experimental rats by a herbicide, atrazine. Archives of environmental contamination and toxicology. 2010;58(3):874-82.
42. 42. Shiraishi K, Takihara H, Matsuyama H. Elevated scrotal temperature, but not varicocele grade, reflects testicular oxidative stress-mediated apoptosis. World journal of urology. 2010;28(3):359-64.
43. 43. Aitken RJ, Baker MA. Oxidative stress and male reproductive biology. Reproduction, Fertility and development. 2004;16(5):581-8.
44. 44. Zini A, Libman J. Sperm DNA damage: clinical significance in the era of assisted reproduction. Cmaj. 2006;175(5):495-500.
45. 45. Kumar SB, Dada R, Gupta NP. Environmental Toxicants–Induced Male Reproductive Toxicity: Role of Oxidative Stress. Bioenvironmental Issues Affecting Men's Reproductive and Sexual Health: Elsevier; 2018. p. 305-22
46. 46. Ding J, Shang X, Zhang Z, Jing H, Shao J, Fei Q, et al. FDA-approved medications that impair human spermatogenesis. Oncotarget.2017;8(6):10714.
47. 47. Yanik TA, M. Sezlev, D. Kursungoz, C. Kurt, B. Akay, O. Akarsu, S. Determination of Peripheral Gonadal Hormones after the Treatment of Atypical Antipsychotics, Olanzapine and Risperidone in Wistar Male Rats. The Endocrine Society's 94th Annual Meeting and Expo. (2012);, June 23–26, Houston, TX.