Protective effects of Aloe vera gel on cisplatin-induced oxidative stress, ‎apoptosis and neurons structure in rat hippocampus

Document Type : Original Article

Authors

1 Department of Basic Sciences, Faculty of Veterinary Medicine, Shahid Chamran University of Ahvaz, Ahvaz, Iran

2 Stem Cells and Transgenic ‎Technology Research Center, Shahid Chamran University of Ahvaz, Ahvaz, Iran‎

3 Department of Basic Sciences, Faculty of Veterinary Medicine, Shahid Chamran University of Ahvaz, Ahvaz, Iran‎

Abstract

Cisplatin (CP) as an important chemotherapeutic drug is used for the treatment of various malignancies; but it has some side effects on central nervous system, in particular hippocampus. The present study was aimed to determine the protective effects of Aloe vera (AV) gel on CP-induced oxidative stress, apoptosis and neurons structure changes in the hippocampus of rats. Forty-eight rats were divided into six groups including control, CP (5 mg kg-1 per week; intra-peritoneally), CP + AV (400 mg kg-1 per day; orally), CP + metformin (200 mg kg-1 per day; orally), AV (400 mg kg-1 per day; orally) and metformin (200 mg kg-1 per day; orally). At the end of treatment, brain samples were obtained for analysis of apoptotic genes expression and anti-oxidant markers as well as histological study. The results showed that CP caused an increase in malondialdehyde level and a decrease in glutathione peroxidase, superoxide dismutase and catalase levels in CP group compared to control. The AV gel could diminish oxidative stress in the hippocampus of CP group and it resulted in down-regulation of Bax, caspase-3 and caspase-8 and up-regulation of Bcl-2 in CP group. It could ameliorate degenerative changes in hippocampus after exposure to CP. Our results showed that AV gel ameliorated oxidative stress, apoptosis and neuronal loss in the hippocampus of rats under CP treatment.

Keywords


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    1. Marullo R, Werner E, Degtyareva N, et al. Cisplatin induces a mitochondrial-ROS response that contributes to cytotoxicity depending on mitochondrial redox status and bioenergetic functions. PLoS One 2013; 8(11): e81162. doi: 10.1371/journal.pone.0081162.
    2. Podratz JL, Knight AM, Ta LE, et al. Cisplatin induced mitochondrial DNA damage in dorsal root ganglion neurons. Neurobiol Dis. 2011; 41(3): 661-668.
    3. Oz M, Nurullahoglu Atalik KE, Yerlikaya FH, et al. Curcumin alleviates cisplatin-induced learning and memory impairments. Neurobiol Learn Mem 2015; 123: 43-49.
    4. Choi SJ, Kim SW, Lee JB, et al. Gingko biloba extracts protect auditory hair cells from cisplatin-induced ototoxicity by inhibiting perturbation of gap junctional intercellular communication. Neuroscience 2013; 244: 49-61.
    5. Florea AM, Büsselberg D. Cisplatin as an anti-tumor drug: cellular mechanisms of activity, drug resistance and induced side effects. Cancers (Basel) 2011; 3(1): 1351-1371.
    6. Bobylev I, Joshi AR, Barham M, et al. Depletion of mitofusin-2 causes mitochondrial damage in cisplatin-induced neuropathy. Mol Neurobiol 2018; 55(2): 1227-1235.
    7. Englander EW. DNA damage response in peripheral nervous system: coping with cancer therapy-induced DNA DNA Repair (Amst). 2013; 12(8): 685-690.
    8. Sahu BD, Kuncha M, Putcha UK, et al. Effect of metformin against cisplatin induced acute renal injury in rats: a biochemical and histoarchitectural evaluation. Exp Toxicol Pathol 2013; 65(6): 933-940.
    9. Radha MH, Laxmipriya NP. Evaluation of biological properties and clinical effectiveness of Aloe vera: A systematic review. J Tradit Complement Med 2015; 5(1): 21-26.
    10. García de la Cadena S, Massieu L. Caspases and their role in inflammation and ischemic neuronal death. Focus on caspase-12. Apoptosis 2016; 21(7): 763-777.
    11. Shalini S, Dorstyn L, Dawar S, et al. Old, new and emerging functions of caspases. Cell Death Differ 2015; 22(4): 526-539.
    12. Kang MC, Kim SY, Kim YT, et al. In vitro and in vivo antioxidant activities of polysaccharide purified from Aloe vera (Aloe barbadensis) gel. Carbohydr Polym 2014; 99: 365-371.
    13. Jaggi AS, Singh N. Mechanisms in cancer-chemotherapeutic drugs-induced peripheral neuropathy. Toxicology 2012; 291(1-3): 1-9.
    14. Mohebbati R, Khazdair MR, Hedayatia M. Neuroprotective effects of medicinal plants and their constituents on different induced neurotoxicity methods. J Rep Pharm Sci 2017; 6(1): 34-50.
    15. Halliwell B. Oxidative stress and neurodegeneration: where are we now? J Neurochem 2006; 97(6):
      1634-1658.
    16. Andres AL, Gong X, Di K, et al. Low-doses of cisplatin injure hippocampal synapses: a mechanism for 'chemo' brain? Exp Neurol 2014; 255: 137-144.
    17. Manohar S, Jamesdaniel S, Salvi R. Cisplatin inhibits hippocampal cell proliferation and alters the expression of apoptotic genes. Neurotox Res 2014; 25(4): 369-380.
    18. Zhou W, Kavelaars A, Heijnen CJ. Metformin prevents cisplatin-induced cognitive impairment and brain damage in mice. PLoS One 2016; 11(3): e0151890. doi: 10.1371/journal.pone.0151890.
    19. Üstün R, Oğuz EK, Şeker A, et al. Thymoquinone prevents cisplatin neurotoxicity in primary DRG neurons. Neurotoxicology 2018; 69: 68-76.
    20. Lissoni P, Rovelli F, Brivio F et al. A randomized study of chemotherapy versus biochemotherapy with chemotherapy plus Aloe arborescens in patients with metastatic cancer. In Vivo 2009; 23(1): 171-175.
    21. Yuksel Y, Guven M, Kaymaz B, et al. Effects of Aloe vera on spinal cord ischemia–reperfusion injury of rats. J Invest Surg 2016; 29(6): 389-398.
    22. Gabriel NN, Qiang J, Ma XY, et al. Dietary Aloe vera improves plasma lipid profile, antioxidant, and hepato-protective enzyme activities in GIFT-tilapia (Oreo-chromis niloticus) after Streptococcus iniae challenge. Fish Physiol Biochem 2015; 41(5): 1321-1332.
    23. Budai MM, Varga A, Milesz S, et al. Aloe vera downregulates LPS-induced inflammatory cytokine production and expression of NLRP3 inflammasome in human macrophages. Mol Immunol 2013; 56(4): 471-479.
    24. Guven M, Gölge UH, Aslan E, et al. The effect of aloe vera on ischemia-reperfusion injury of sciatic nerve in rats. Biomed Pharmacother 2016; 79: 201-207.
    25. Halder S, Mehta AK, Mediratta PK. Aloe vera improves memory and reduces depression in mice. Nutr Neurosci 2013; 16(6): 250-254.
    26. Akaberi M, Sobhani Z, Javadi B, et al. Therapeutic effects of Aloe spp. in traditional and modern medicine. Biomed Pharmacother 2016; 84: 759-772.
    27. Redza-Dutordoir M, & Averill-Bates DA. Activation of apoptosis signalling pathways by reactive oxygen species. Biochim Biophys Acta 2016; 1863(12): 2977-2992.
    28. Liu Z, Ge X, Lu Y, et al. Effects of chitosan molecular weight and degree of deacetylation on the properties of gelatine-based films. Food Hydrocoll 2012; 26(1):
      311-317.
    29. Tabatabaei SRF, Ghaderi S, Bahrami-Tapehebur M, et al. Aloe vera gel improves behavioral deficits and oxidative status in streptozotocin-induced diabetic rats. Biomed. Pharmacother 2017; 96: 279-290.
    30. Mirshafiey A, Aghily B, Namaki S, et al. Therapeutic approach by Aloe vera in experimental model of multiple sclerosis. Immunopharmacol. Immunotoxicol 2010; 32(3): 410-415.
    31. Lomeli N, Di K, Czerniawski J, et al. Cisplatin-induced mitochondrial dysfunction is associated with impaired cognitive function in rats. Free Radic Biol Med 2017; 102: 274-286.
    32. Behmanesh MA, Erfani Majd N, Shahriari A, et al. Evaluation of antioxidant potential of Aloe vera and pituitary sexual hormones after experimental diabetes in male rats. Iran J Vet Med 2017;11(2): 165-174.
    33. Im K, Lee JY, Byeon H, et al. In vitro antioxidative and anti-inflammatory activities of the ethanol extract of eggplant (Solanum melongena) Stalks in macrophage RAW 264.7 cells. Food Agric Immunol 2016; 27(6): 758-771.
    34. Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 1976; 72: 248-254.
    35. Buege JA, Aust SD. Microsomal lipid peroxidation. Methods Enzymol 1978; 52: 302-310.
    36. Koroliuk MA, Ivanova LI, Maĭorova IG, et al. A method of determining catalase activity [Russian]. Lab Delo 1988; (1): 16-19.
    37. Kakkar P, Das B, & Viswanathan PN. A modified spectrophotometric assay of superoxide dismutase. Indian J Biochem Biophys1984; 21(2): 130-132.
    38. Gulec M, Oral E, Dursun OB, et al. Mirtazapine protects against cisplatin‐induced oxidative stress and DNA damage in the rat brain. Psychiatry Clin Neurosci 2013; 67(1): 50-58.
    39. Tuncer S, Dalkilic N, Akif Dunbar M, et al. Comparative effects of α lipoic acid and melatonin on cisplatin-induced neurotoxicity. Int J Neurosci 2010; 120(10): 655-663.
    40. Saritha V, Anilakumar KR, Khanum F. Antioxidant and antibacterial activity of Aloe vera gel extracts. Int J Pharm Biol Arch 2010; 1: 376-384.
    41. Pace A, Giannarelli D, Galiè, E, et al. Vitamin E neuroprotection for cisplatin neuropathy: a randomized, placebo-controlled trial. Neurology 2010; 74(9): 762-766.
    42. Tilyek A, Chai C, Hou X, et al. The protective effects of Ribes diacanthum Pall on cisplatin-induced nephron-toxicity in mice. J Ethnopharmacol 2016; 178: 297-306.
    43. Mustafa S, Walker A, Bennett G, et al. 5‐Fluorouracil chemotherapy affects spatial working memory and newborn neurons in the adult rat hippocampus. Eur J Neurosci 2008; 28(2): 323-330.
    44. Lee S, Moon SO, Kim W, et al. Protective role of L-2-oxothiazolidine-4-carboxylic acid in cisplatin-induced renal injury. Nephrol Dial Transplant 2006; 21(8): 2085-2095.
    45. Wang Y, Cao L, Du G. Protective effects of Aloe vera extract on mitochondria of neuronal cells and rat brain. [Chinese] Zhongguo Zhong Yao Za Zhi 2010; 35(3): 364-368.
    46. Zheng H, Xiao WH, Bennett GJ. Mitotoxicity and bortezomib-induced chronic painful peripheral neuropathy. Exp Neurol 2012; 238(2): 225-234.
    47. Patki G, Solanki N, Atrooz F, et al. Depression, anxiety-like behavior and memory impairment are associated with increased oxidative stress and inflammation in a rat model of social stress. Brain Res 2013; 1539: 73-86.
    48. Negi G, Kumar A, Sharma SS. Melatonin modulates neuroinflammation and oxidative stress in experimental diabetic neuropathy: effects on NF‐κb and Nrf2 cascades. J Pineal Res 2011; 50(2): 124-131.
Volume 13, Issue 1
March 2022
Pages 111-119
  • Receive Date: 25 January 2020
  • Revise Date: 14 April 2020
  • Accept Date: 03 May 2020
  • First Publish Date: 15 December 2021