MMSL 2022, 91(3):256-264 | DOI: 10.31482/mmsl.2022.022

THE EFFECT OF CYCLOPHOSPHAMIDE ON HIPPOCAMPAL STRUCTURE OF ADULT MALE RATS (ROLE OF ROSUVASTATIN)Original article

Luma I Al-Allaf ORCID...1, Rana KA Attarbashee ORCID...2, Jawnaa K Mammdoh ORCID...2*
1 College of Medicine, Alhadbaa Street, 41002, University of Mosul, Mosul, Ninevah Province, Iraq
2 College of Dentistry, Alhadbaa Street, 41002, University of Mosul, Mosul, Ninevah Province, Iraq

Background: Limited researchs were noticed on the histological impact of cyclophosphamide on rats’ brains and the reports on the effects of antioxidants to protect these harmful effects are scanty. Trials have assessed the effect of statins in cancer regarding the association between statins use and cancer incidence.

Aim: To investigate the protective and ameliorative effects of rosuvastatin on the brain toxicity induced by a single dose of cyclophosphamide in male rats.

Materials and methods: Twenty-four rats were divided into 3 groups (n=8 for each). The control group includes animals which were received no treatment for 15 days. The cyclophosphamide group includes rats which were received a single dose of 150 mg/kg cyclophosphamide intraperitoneally on day 8 of the experiment, then left for 7 days without treatment. The rosuvastatin+ cyclophosphamide group enrolled rats which were gavaged with rosuvastatin (20 mg/kg/day) for 7 days and then they have received an injection of cyclophosphamide and gavaged with the same dose of rosuvastatin for other 7 days. All rats were subjected to euthanasia. Brain from each case was extracted and prepared for histological examination.

Results: The hippocampal sections of rats which were belonged to group 2 showed some alterations including the presence of cells with ghost appearance and damaged neurons. Features of dense nuclei of damaged hilar cells were manifested with evidence of extracellular vacuoles besides some pyknotic nuclei in these sections. Hippocampal sections of rats of group 3 showed that the majority of pyramidal cells and granule cells manifested seminormal appearance with improvement in the thickness of both granule and pyramidal cell layers.

Conclusions: Rosuvastatin has a protective and ameliorative role against the adverse effect of cyclophosphamide on rat hippocampus which may be useful in clinical practice of cancer treatment.

Keywords: cyclophosphamide; rosuvastatin; hippocampus; dentate gyrus; rat

Received: March 3, 2022; Revised: April 17, 2022; Accepted: May 23, 2022; Prepublished online: July 20, 2022; Published: September 2, 2022  Show citation

ACS AIP APA ASA Harvard Chicago Chicago Notes IEEE ISO690 MLA NLM Turabian Vancouver
Al-Allaf, L.I., KA Attarbashee, R., & Mammdoh, J.K. (2022). THE EFFECT OF CYCLOPHOSPHAMIDE ON HIPPOCAMPAL STRUCTURE OF ADULT MALE RATS (ROLE OF ROSUVASTATIN). MMSL91(3), 256-264. doi: 10.31482/mmsl.2022.022
Download citation

References

  1. Sasaki M, Ishii N, Kikuchi Y, et al. Occupational exposures among nurses caring for chemotherapy patients-Quantitative analysis of cyclophosphamide and α-fluoro-β-alanine in urine. Sangyo Eiseigaku Zasshi= Journal of Occupational Health. 2016;58(5):164-72. https://doi.org/10.1539/sangyoeisei.2016-005-E Go to original source... Go to PubMed...
  2. Kim J, You S. Extended adverse effects of cyclophosphamide on mouse ovarian function. BMC Pharmacology and Toxicology. 2021;22(1):1-0. https://doi.org/10.1186/s40360-020-00468-5 Go to original source... Go to PubMed...
  3. Janelsins MC, Heckler CE, Thompson BD, et al. A clinically relevant dose of cyclophosphamide chemotherapy impairs memory performance on the delayed spatial alternation task that is sustained over time as mice age. Neurotoxicology. 2016;56:287-93. https://doi.org/10.1016/j.neuro.2016.06.013 Go to original source... Go to PubMed...
  4. Maragno H, Rodella P, da Silva Freitas J, et al. The effects of acute and chronic administration of phosphatidylserine on cell proliferation and survival in the dentate gyrus of adult and middle-aged rats. Brain Research. 2015;1609:72-81.https://doi.org/10.1016/j.brainres.2015.03.017 Go to original source... Go to PubMed...
  5. Batool S, Akhter B, Zaidi J, et al. Neuronal Menin Overexpression Rescues Learning and Memory Phenotype in CA1-Specific α7 nAChRs KD Mice. Cells. 2021;10(12):3286. https://doi.org/10.3390/cells10123286 Go to original source... Go to PubMed...
  6. Santos SS, Moreira JB, Costa M, et al. The Mitochondrial Antioxidant Sirtuin3 Cooperates with Lipid Metabolism to Safeguard Neurogenesis in Aging and Depression. Cells. 2022;11(1):90. https://doi.org/10.3390/cells11010090 Go to original source... Go to PubMed...
  7. Ayza MA, Zewdie KA, Tesfaye BA, et al. The role of antioxidants in ameliorating cyclophosphamide-induced cardiotoxicity. Oxidative Medicine and Cellular Longevity. 2020; 2020. https://doi.org/10.1155/2020/4965171 Go to original source... Go to PubMed...
  8. Hamzeh M, Hosseinimehr SJ, Mohammadi HR, et al. Atorvastatin attenuates the ovarian damage induced by cyclophosphamide in rat: An experimental study. International journal of reproductive biomedicine. 2018;16(5):323 Go to original source... Go to PubMed...
  9. Anderson JE, Trujillo M, McElroy T, et al. Early effects of Cyclophosphamide, Methotrexate, and 5-fluorouracil on neuronal morphology and hippocampal-dependent behavior in a murine model. Toxicological Sciences. 2020;173(1):156-70. https://doi.org/10.1093/toxsci/kfz213 Go to original source... Go to PubMed...
  10. Shaibah HS, Elsify AE, Medhat TM, et al. Histopathological and immunohistochemical study of the protective effect of triptorelin on the neurocytes of the hippocampus and the cerebral cortex of male albino rats after short-term exposure to cyclophosphamide. Journal of microscopy and ultrastructure. 2016;4(3):123-32. https://doi.org/10.1016/j.jmau.2015.12.002 Go to original source... Go to PubMed...
  11. Unsal V, Dalkiran T, Çiçek M, et al. The role of natural antioxidants against reactive oxygen species produced by cadmium toxicity: a review. Advanced pharmaceutical bulletin. 2020;10(2):184. https://doi.org/10.34172/apb.2020.023 Go to original source... Go to PubMed...
  12. Parlakgumus HA, Bolat FA, Kilicdag EB, et al. Atorvastatin for ovarian torsion: effects on follicle counts, AMH, and VEGF expression. European Journal of Obstetrics & Gynecology and Reproductive Biology. 2014;175:186-90. https://doi.org/10.1016/j.ejogrb.2014.01.017 Go to original source... Go to PubMed...
  13. Hamzeh M, Hosseinimehr SJ, Khalatbary AR, et al. Atorvastatin mitigates cyclophosphamide-induced hepatotoxicity via suppression of oxidative stress and apoptosis in rat model. Research in pharmaceutical sciences. 2018;13(5):440. https://doi.org/10.4103/1735-5362.236837 Go to original source... Go to PubMed...
  14. Althanoon Z, Faisal IM, Ahmad AA, et al. Pharmacological aspects of statins are relevant to their structural and physicochemical properties. Systematic Reviews in Pharmacy. 2020;11(7):167-71. https://doi.org/10.31838/srp.2020.7.27 Go to original source...
  15. Almukhtar HM, Faisal IM, Merkhan MM. Acute effect of atorvastatin in comparison with rosuvastatin on glucose homeostasis in hypercholesteremic patients. Pharmacology. 2021;25:25-34
  16. Baskaran G, Salvamani S, Ahmad SA, et al. HMG-CoA reductase inhibitory activity and phytocomponent investigation of Basella alba leaf extract as a treatment for hypercholesterolemia. Drug Des Devel Ther. 2015;9:509-517. https://doi.org/10.2147/DDDT.S75056 Go to original source... Go to PubMed...
  17. S Antonopoulos A, Margaritis M, Lee R, et al. Statins as anti-inflammatory agents in atherogenesis: molecular mechanisms and lessons from the recent clinical trials. Current pharmaceutical design. 2012;18(11):1519-30. https://doi.org/10.2174/138161212799504803 Go to original source... Go to PubMed...
  18. Elkady MA, Shalaby S, Fathi F, et al. Effects of quercetin and rosuvastatin each alone or in combination on cyclophosphamide-induced premature ovarian failure in female albino mice. Hum Exp Toxicol. 2019;38(11):1283-1295. https://doi.org/10.1177/0960327119865588 Go to original source... Go to PubMed...
  19. Farag MM, Mohamed MB, Youssef EA. Assessment of hepatic function, oxidant/antioxidant status, and histopathological changes in rats treated with atorvastatin: Effect of dose and acute intoxication with acetaminophen. Hum Exp Toxicol. 2015;34(8):828-37. https://doi.org/10.1177/0960327114559991 Go to original source... Go to PubMed...
  20. Almukhtar HM, Faisal IM, Merkhan MM. Effects of statins on platelet count in hyperlipidemic patients. International Journal of Pharmaceutical Research. 2020 Apr;12(2):2640-4. https://doi.org/10.31838/ijpr/2020.12.02.357 Go to original source...
  21. Almukhtar HM, Faisal IM, Merkhan MM. Short-term treatment with Atorvastatin selectively decreases Lymphocyte count. Research Journal of Pharmacy and Technology. 2022;15(2):689-4. doi: 10.52711/0974-360X.2022.00114 Go to original source...
  22. Almukhtar HM, Faisal IM, Merkhan MM. Acute effect of atorvastatin in comparison with rosuvastatin on glucose homeostasis in hypercholesteremic patients. Pharmacology. 2021;25:25-34
  23. Armando RG, Mengual Gómez DL, Gomez DE. New drugs are not enough drug repositioning in oncology: An update. International Journal of Oncology. 2020;56(3):651-84. https://doi.org/10.3892/ijo.2020.4966 Go to original source... Go to PubMed...
  24. Khalel L, Al-Ashoo HA. A histological study on the effect of imatinib on the rats' testis after early postnatal exposure. Iraqi Journal of Veterinary Sciences. 2021; 35(1):85-92. https://doi.org/10.33899/ijvs.2020.126342.1303 Go to original source...
  25. Branda RF, Chen Z, Brooks EM, et al. Diet modulates the toxicity of cancer chemotherapy in rats. J Lab Clin Med. 2002;140(5):358-68. https://doi.org/10.1067/mlc.2002.128648 Go to original source... Go to PubMed...
  26. Kamiya A, Machida T, Hirano M, et al. Administration of cyclophosphamide to rats induces pica and potentiates 5-hydroxytryptamine synthesis in the intestine without causing severe intestinal injury. Journal of Pharmacological Sciences. 2021;147(3):251-9. https://doi.org/10.1016/j.jphs.2021.07.007 Go to original source... Go to PubMed...
  27. Ibrahim HM, Zommara MA, Elnaggar ME. Ameliorating effect of selenium nanoparticles on cyclophosphamide-induced hippocampal neurotoxicity in male rats: light, electron microscopic and immunohistochemical study. Folia Morphologica. 2021;80(4):806-19. doi: 10.5603/FM.a2020.0117 Go to original source... Go to PubMed...
  28. 2Al-Allaf LK, Al-Ashoo HA. The effect of CO-Q10 on the testicular histological changes in rats induced by imatinib. Iraqi Journal of Veterinary Sciences. 2021;35(1):189-96. doi: 10.33899/ijvs.2020.126587.1347 Go to original source...
  29. Nurgali K, Jagoe RT, Abalo R. Adverse effects of cancer chemotherapy: Anything new to improve tolerance and reduce sequelae? Frontiers in pharmacology. 2018;9:245.. https://doi.org/10.3389/fphar.2018.00245 Go to original source... Go to PubMed...
  30. Abdallah HM, Abdel-Rahman RF, El Awdan SA, et al. Protective effect of some natural products against chemotherapy-induced toxicity in rats. Heliyon. 2019; 5(5):e01590. https://doi.org/10.1016/j.heliyon.2019.e01590 Go to original source... Go to PubMed...
  31. Wan L, Huang RJ, Yang C, et al. Extracranial 125I Seed Implantation Allows Non-invasive Stereotactic Radioablation of Hippocampal Adult Neurogenesis in Guinea Pigs. Frontiers in neuroscience. 2021;15. https://doi.org/10.3389/fnins.2021.756658 Go to original source...
  32. Sekeres MJ, Bradley-Garcia M, Martinez-Canabal A, Winocur G. Chemotherapy-Induced Cognitive Impairment and Hippocampal Neurogenesis: A Review of Physiological Mechanisms and Interventions. International Journal of Molecular Sciences. 2021;22(23):12697. https://doi.org/10.3390/ijms222312697 Go to original source... Go to PubMed...
  33. Lyons L, ELBeltagy M, Bennett G, et al. The effects of cyclophosphamide on hippocampal cell proliferation and spatial working memory in rat. PloS one. 2011;6(6): e21445. https://doi.org/10.1371/journal.pone.0021445 Go to original source... Go to PubMed...
  34. Koppelmans V, de Ruiter MB, van der Lijn F, et al. Global and focal brain volume in long-term breast cancer survivors exposed to adjuvant chemotherapy. Breast cancer research and treatment. 2012;132(3):1099-106. https://doi.org/10.1007/s10549-011-1888-1 Go to original source... Go to PubMed...
  35. Singh S, Kumar A. Protective effect of edaravone on cyclophosphamide induced oxidative stress and neurotoxicity in rats. Current drug safety. 2019;14(3):209-16. https://doi.org/10.2174/1574886314666190506100717 Go to original source... Go to PubMed...
  36. Alhowail AH, Almogbel YS, Abdellatif AA, et al. CMF and MET treatment induce cognitive impairment through upregulation of IL-1α in rat brain. European Review for Medical and Pharmacological Sciences. 2021;25(12):4385-93. https://doi.org/10.26355/eurrev_202106_26148 Go to original source... Go to PubMed...
  37. Wang KW, Wang HK, Chen HJ, et al. Simvastatin combined with antioxidant attenuates the cerebral vascular endothelial inflammatory response in a rat traumatic brain injury. BioMed research international. 2014;2014. https://doi.org/10.1155/2014/910260 Go to original source... Go to PubMed...
  38. Hamza RZ, EL-Megharbel SM, Altalhi T, et al. Hypolipidemic and hepatoprotective synergistic effects of selenium nanoparticles and vitamin. E against acrylamide-induced hepatic alterations in male albino mice. Applied Organometallic Chemistry. 2020;34(3):e5458. https://doi.org/10.1002/aoc.5458 Go to original source...
  39. Bhattacharjee A, Basu A, Ghosh P, et al. Protective effect of Selenium nanoparticle against cyclophosphamide induced hepatotoxicity and genotoxicity in Swiss albino mice. Journal of Biomaterials Applications. 2014;29(2):303-17. https://doi.org/10.1177/0885328214523323 Go to original source... Go to PubMed...
  40. Akomolafe SF, Olasehinde TA, Oyeleye SI, et al. Curcumin administration mitigates cyclophosphamide-induced oxidative damage and restores alteration of enzymes associated with cognitive function in rats' brain. Neurotoxicity Research. 2020;38(1):199-210. https://doi.org/10.1007/s12640-020-00205-0 Go to original source... Go to PubMed...
  41. Mamdoh J, Eman A. Evaluation of anti-inflammatory and antimicrobial effects of Iraqi propolis mouthwash in mucositis patients induced by chemotherapy. International Journal of Enhanced Research in SienceTechnology&Engineering. 2015;4:115