IMPACT OF GERANIOL ON CYCLOPHOSPHAMIDE PROVOKED CARDIOTOXIC PROPERTIESâ€“AN IN VIVO STUDY
Objective: Toxicity profiles of diverse anti-neoplastic drugs are extensively documented in past decades and the protective role of natural products against such toxic drugs plays a vital role in the evolution of chemoprevention. Globally, Cyclophosphamide (CYP) is used as an anticancer drug, but now it has been limited due to its acute and chronic cardio toxicity. Hence the present study was designed to investigate the protective role of Geraniol (GOH) against CYP induced cardio toxicity.
Methods: The activity of serum marker enzymes and lipoprotein fractions, cardiac marker enzymes and lipid profiles as well as antioxidant status was done using standard procedures in vivo. In addition, optimum dosage of GOH was determined as obtained by the levels of serum marker enzymes for tissue damage and the pathological changes were assessed by histology.
Results: Administration of CYP to rats results in hoisted levels of marker enzymes (in both serum and heart tissue) and reduced levels of antioxidants. GOH (200 mg/kg body weight) restrained the elevation of marker enzymes (in both serum and heart tissue) and augmented the levels of antioxidants. Moreover, histological observations added proofs to the protective role of GOH against cardiac damage.
Conclusion: CYP administered pathological changes were attenuated by the oral treatment of GOH at a dose of 200 mg/kg body weight of rat and suggests that the cardioprotective effects could be related to up regulation of antioxidant mechanism. Conclusive outcome from our findings suggests that GOH might be a potential chemo preventive agent in attenuating drug induced cardio toxicity.
2. Colombo P, Gunnarsson K, Latropoulos M, Brugera M. Toxicological testing of cytotoxic drugs (Review). Int J Oncol 2001;19:1021-8.
3. Sulkowska M, Skrzydlewska E, Sobamee-Lotowska M, Famulski W, Terlikowski S, Reszee J. Effect of cyclophosphamide induced generation forms on ultrastructure of the liver and lung. Bull Vet Inst Pulawy 2002;46:239-46.
4. Dollery C, Cyclophosphamide. In: Dollery C. Ed. Therapeutic Drugs. Churchill Livingstone, Edinburg; 1999. p. 349â€“53.
5. Goldberg MA, Antin JH, Guinan EC, Rappeport JM. Cyclophosphamide cardiotoxicity: an analysis of doing as a risk factor. Blood 1986;68:1114â€“8.
6. Bukowski R. The need for cytoprotection. Eur J Cancer 1999;32A Suppl 4:S2â€“4.
7. Fraiser LH, Kanekel S, Kehrer JP. Cyclophosphamide toxicity. Characterizing and avoiding the problem. Drugs 1991;42:781â€“95.
8. Sladek N. Metabolism of cyclophosphamide by rat hepatic microsomes. Cancer Res 1971;1:901â€“8.
9. Sladek NE. Metabolism of oxazaphosphorines. Pharmacol Ther 1988;37:301â€“55.
10. Shanholtz C. Acute life-threatening toxicity of cancer treatment. Crit Care Clin 2001;17:483-502.
11. Schimmel KJ, Richel DJ, van den Brink RB, Guchelaar HJ. Cardiotoxicity of cytotoxic drugs. Cancer Treat Rev 2004;30:181-91.
12. Loudet AM, Dousset N, Carton M, Douste-Blazy L. Effects of an antimitotic agent (cyclophosphamide) on plasma lipoproteins. Biochem Pharmacol 1984;33:2961-5.
13. Lespine A, Chap H, Perret B. Impaired secretion of heart lipoprotein lipase in cyclophosphamide-treated rabbit. Biochem Biophys Acta 1997;1345:77-85.
14. Al-Nasser IA. In vivo prevention of cyclophosphamide induced Ca2+dependent damage of rat heart and liver mitochondria by cyclosporin A. Comp Biochem Physiol Part A: Mol Integr Physiol 1998;121:209â€“14.
15. Mythili Y, Sudharsan PT, Varalakshmi P. DL-Î±-lipoic acid ameliorates cyclophosphamide induced cardiac mitochondrial injury. Toxicology 2005;215:108â€“14.
16. Santos GW, Sensenbrenner LL, Burke PJ. The use of cyclophosphamide for clinical marrow transplantation. Transplant Proc 1972;4:559â€“64.
17. Gottdiener JS, Applebaum ER, Ferrans VJ, Deisseroth A, Ziegler J. Cardiotoxicity associated with high-dose cyclophosphamide therapy. Arch Intern Med 1981;141:758â€“63.
18. Goldberg MA, Antin JH, Guiman EC, Rappeport JM. Cyclophosphamide cardiotoxicity: an analysis of dosing as a risk factor. Blood 1986;68:1114â€“8.
19. Birchall IW, Lalani Z, Venner P, Hugh J. Fatal haemorrhagic myocarditis secondary to cyclophosphamide therapy. Br J Radiol 2000;73:1112â€“4.
20. Kamezaki K, Fukuda T, Makino S, Harada M. Cyclophosphamide induced cardiomyopathy in a patient with seminoma and a history of mediastinal irradiation. Intern Med 2005;44:120-3.
21. Rajendran R, Ganesan N, Balu SK, Alagar S, Thandavamoorthy P, Thiruvengadam D. Green synthesize, characterization, antimicrobial and cytotoxic effects of silver nanoparticles using O. heracleoticumL. leaf extract. Int J Pharm Pharm Sci 2015;7:288-93.
22. Balan R, Rajendran R, Thandavamoorthy P, Thiruvengadam D. Carvacrol attenuates N-nitrosodiethylamine induced liver injury in experimental Wistar rats. Food Sci Hum Wellness 2015. doi.org/10.1016/j.fshw.2015.04.002. [Article in Press]
23. Kalemda D, Kunicka A. Antibacterial and antifungal properties of essential oils. Curr Med Chem 2003;10:813â€“29.
24. Edris AE. Pharmaceutical and therapeutic potentials of essential oils and their individual volatile constituents: a review. Phytother Res 2007;21:308â€“23.
25. Thandavamoothy P, Balan R, Subramaniyan J, Arumugam M, John B, Krishnan G, et al. Alleviative role of rutin against 4-Nitroquinoline-1-Oxide (4-NQO) provoked oral squamous cell carcinoma in experimental animal model. J Pharm Res 2014;8:899-906.
26. Arumugam M, Thiruvengadam D. Geraniol, a component of plant essential oilsâ€“a review of its pharmacological activities. Int J Pharm Pharm Sci 2015;7:67-70.
27. AridoÄŸan BC, Baydar H, Kaya S, Demirci M, OzbaÅŸar D, Mumcu E. Antimicrobial activity and chemical composition of some essential oils. Arch Pharmacal Res 2002;25:860-4.
28. Mesa Arango AC, Montiel-Ramos J, Zapata B, DurÃ¡n C, Betancur-Galvis L, Stashenko E. Citral and carvonechemotypes from the essential oils of Colombian Lippiaalba (Mill.) NE Brown: composition, cytotoxicity and antifungal activity. Mem Inst Oswaldo Cruz 2009;104:878-84.
29. Boukhatem MN, Kameli A, Ferhat MA, Saidi F, Mekarnia M. Rose geranium essential oil as a source of new and safe anti-inflammatory drugs. Libyan J Med 2013;8:22520. doi: 10.3402/ljm.v8i0.22520. [Article in Press]
30. Madankumar A, Jayakumar S, Devaki T. Geraniol, a component of plant essential oils prevents experimental oral carcinogenesis by modulating glycoprotein abnormalities and membrane bound ATPaseâ€™s. Int J Pharm Pharm Sci 2013;5:416-21.
31. De Carvalho KI, Bonamin F, Dos Santos RC, PÃ©rico LL, Beserra FP, de Sousa DP, et al. Geraniol-a flavoring agent with multifunctional effects in protecting the gastric and duodenal mucosa. Naunyn-Schmiedeberg's Arch Pharmacol 2014;387:355-65.
32. Prasad SN, Muralidhara. Neuroprotective effect of geraniol and curcumin in an acrylamide model of neurotoxicity in Drosophila melanogaster: relevance to neuropathy. J Insect Physiol 2014;60:7-16.
33. Singh BK, Tripathi M, Chaudhari BP, Pandey PK, Kakkar P. Natural terpenes prevent mitochondrial dysfunction, oxidative stress and release of apoptotic proteins during nimesulide-hepatotoxicity in rats. PLoS One 2012;7:e34200. doi: 10.1371/journal.pone.0034200. [Article in Press]
34. Viswanatha Swamy HM, Patel UM, Koti BC, Gadad PC, Patel NL, Thippeswamy AHM. Cardioprotective effective of Saracaindica against cyclophosphamide induced cardiotoxicity in rats: A bio chemical, electromicrograph and histophathology study. Indian J Pharmacol 2013;45:44-8.
35. Okinaka S, Sugita H, Mamoi T. Cysteine-stimulated serum creatine kinase in health and disease. J Lab Clin Med 1964;64:299â€“305.
36. King J. The dehydrogenases or oxidoreductases-lactate dehydrogense. In: Van D. editor. Practical clinical enzymology. London: Nostrand; 1965. p. 83â€“93.
37. Mohun AF, Cook LJ. Simple method for measuring serum level of glutamateoxaloacetate and glutamate-pyruvate transaminases in laboratories. J Clin Chem 1957;10:394â€“9.
38. King J. In: D Van. editor. Practical clinical enzymology. London: Nostrand; 1965. p. 363.
39. Misra HP, Fridovich J. The role of superoxide anion in the auto-oxidation of epinephrine and a simple assay for superoxide dismutase. J Biol Chem 1972;247:3170â€“5.
40. Bergmeyer HV, Gowehn K, Grassel M. Methods of enzymatic analysis. New York: Academic; 1974. p. 438.
41. Rotruck JT, Pope AL, Ganther HE. Selenium: biochemical role as a component of glutathione peroxidase, purification and assay. Science 1973;179:588â€“90.
42. Habig WH, Pabs Jakoby. Glutathione-S-transferase. J Biol Chem 1974;249:7130â€“9.
43. Beutler E, Matsumoto F. Ethinic variation in red cell glutathione peroxidase activity. Blood 1975;46:103-10.
44. Omaye ST, Turbull TP, Sauberchich HC. Selected methods for determination of ascorbic acid in cells, tissues and fluids. Methods Enzymol 1979;6:3-11.
45. Desai ID. Vitamin E analysis methods for animal tissues. Methods Enzymol 1984;105:138-47.
46. Bayfield RF, Cole ER. Colorimetric estimation of vitamin A with trichloroacetic acid. Methods Enzymol 1980;67:189-203.
47. Staal GEJ, Visser J, Veger C. Purification and properties of glutathione reductase of human erythrocytes. Biochim Biophys Acta 1969;185:39â€“48.
48. Wilson DF, Spiger MJ. A dual precipitation method for quantitative plasma lipoprotein measurement without ultracentrifugation. J Lab Clin Med 1973;82:473-82.
49. Sperry WM, Webb A. A revision of schoenhemer-sperry method for cholesterol determination. J Biol Chem 1950;187:97-106.
50. Barlett GR. Phosphorous assay in column chromatography. J Biol Chem 1959;234:466-8.
51. Rouser, George, Sidney Fleischer, Akira Yamamoto. Two dimensional thin layer chromatographic separation of polar lipids and determination of phospholipids by phosphorus analysis of spots. Lipids 1970:494-96.
52. Horn WT and Menahan IA. A sensitive method for the determination of the fatty acids in plasma. J Lipid Res 1981;22:377-81.
53. Rice EW. Triglycerides ("neutral fats") in serum. In: Standard methods of clinical chemistry. MacDonald RP. Ed. Academic press: New York; 1970;6:215-22.
54. Asiri, Yousif A. Probucol attenuates cyclophosphamide-induced oxidative apoptosis, P53 and bax signal expression in rat cardiac tissues. Oxid Med Cell Longevity 2010;308-16.
55. Nagi, Mahmoud N. Thymoquinone supplementation attenuates cyclophosphamide-induced cardiotoxicity in rats. J Biochem Mol Toxicol 2010;25:135-42.
56. Senthilkumar, Subramanian. Attenuation of cyclophosphamide induced toxicity by squalene in experimental rats. Chem Biol Interact 2006;160:252-60.
57. Yogeeta, Surinder Kumar. Synergistic interactions of ferulic acid with ascorbic acid: its cardioprotective role during isoproterenol induced myocardial infarction in rats. Mol Cell Biochem 2006;283:139-46.
58. Singh, Ravinder J. Glutathione: a marker and antioxidant for aging. J Lab Clin Med 2002;140:380-1.
59. Halliwell B, Gutteridge JMC. Lipid peroxidation, oxygen radicals, cell damage and antioxidant therapy. Lancet 1984;1:1396â€“7.
60. Mantawy, Eman M. Chrysin alleviates acute doxorubicin cardiotoxicity in rats via suppression of oxidative stress, inflammation and apoptosis'. Eur J Pharmacol 2014;728:107-18.