Protective Effect of Edaravone on Cyclophosphamide Induced Oxidative Stress and Neurotoxicity in Rats

Author(s): Sanjiv Singh*, Abhishek Kumar.

Journal Name: Current Drug Safety

Volume 14 , Issue 3 , 2019

Become EABM
Become Reviewer

Graphical Abstract:


Background: Cyclophosphamide (CPA) is the most widely prescribed cancer chemotherapeutic agent which shows serious neurotoxic side effect. Generation of reactive oxygen species at the cellular level is the basic mechanism of cyclophosphamide induced neurotoxicity. Edaravone is the synthetic drug used for brain stroke and has potent antioxidant property.

Objective: This study aimed to investigate the effect of edaravone on neurobehavioral and neuropathological alteration induced by cyclophosphamide in male rats.

Methods: Twenty eight Sprague-Dawley rats were equally divided into four groups of seven rats in each. The control group received saline, and other groups were given CPA intraperitoneally (100 mg/kg), CPA (100 mg/kg) intraperitoneally + Edaravone (10 mg/kg) orally, or Edaravone (10 mg/kg) orally for one month.

Results: Our data showed that CPA significantly elevated brain AChE activity in the hippocampal region. A decrease in the total antioxidant capacity and a reduction in the CAT, SOD, and GPX activity occurred in the brains of the rats exposed to CPA. CPA-treated rats showed a significant impairment in long-termmemory and motor coordination. These results were supported by histopathological observations of the brain. Results revealed that administration of edaravone reversed AChE activity alternation and ameliorated behavioral and histopathological changes induced by CPA.

Conclusion: This study suggests that co-administration of edaravone with cyclophosphamide may be a useful intriguing therapeutic approach to overcome cyclophosphamide induced neurotoxicity.

Keywords: Cyclophosphamide, edaravone, neurotoxicity, oxidative stress, neuroprotective, AChE.

Olayinka ET, Ore A, Ola OS, et al. Ameliorative effect of gallic acid on cyclophosphamide-induced oxidative injury and hepatic dysfunction in rats. Med Sci (Basel) 2015; 3: 78-92.
Roy SS, Chakraborty P, Bhattacharya S. Intervention in cyclophosphamide induced oxidative stress and DNA damage by a flavonyl-thiazolidinedione based organoselenocyanate and evaluation of its efficacy during adjuvant therapy in tumor bearing mice. Eur J Med Chem 2014; 73: 195-209.
Kim SH, Lee IC, Baek HS, et al. Mechanism for the protective effect of diallyl disulfide against cyclophosphamide acute urotoxicity in rats. Food Chem Toxicol 2014; 64: 110-8.
Song J, Liu L, Li L, et al. Protective effects of lipoic acid and mesna on cyclophosphamide-induced haemorrhagic cystitis in mice. Cell Biochem Funct 2014; 32: 125-32.
Kuhlen M, Bleckmann K, Moricke A, et al. Neurotoxic side effects in children with refractory or relapsed T-cell malignancies treated with nelarabine based therapy. Br J Haematol 2017; 179: 272-83.
Senthilkumar S, Yogeeta SK, Subashini R, et al. Attenuation of cyclophosphamide induced toxicity by squalene in experimental rats. Chem Biol Interact 2006; 160: 252-60.
Mythili Y, Sudharsan PT, Selvakumar E, et al. Protective effect of DL-alpha-lipoic acid on cyclophosphamide induced oxidative cardiac injury. Chem Biol Interact 2004; 151: 13-9.
Rzeski W, Pruskil S, Macke A, et al. Anticancer agents are potent neurotoxins in vitro and in vivo. Ann Neurol 2004; 56: 351-60.
Nagarajan R, Peters C, Orchard P, et al. Report of severe neurotoxicity with cyclophosphamide. J Pediatr Hematol Oncol 2000; 22: 544-6.
Chen L, Xiong X, Hou X, et al. Wuzhi capsule regulates chloroacetaldehyde pharmacokinetics behaviour and alleviates high-dose cyclophosphamide-induced nephrotoxicity and neurotoxicity in rats. Basic Clin Pharmacol Toxicol 2019. [Epub ahead of print].
Seo EJ, Klauck SM, Efferth T, et al. Adaptogens in chemobrain (Part II): Effect of plant extracts on chemotherapy-induced cytotoxicity in neuroglia cells. Phytomedicine 2018; 58: 152743.
Asiri YA. Probucol attenuates cyclophosphamide-induced oxidative apoptosis, p53 and Bax signal expression in rat cardiac tissues. Oxid Med Cell Longev 2010; 3: 308-16.
Zhang P, Li W, Li L, et al. Treatment with edaravone attenuates ischemic brain injury and inhibits neurogenesis in the subventricular zone of adult rats after focal cerebral ischemia and reperfusion injury. Neuroscience 2012; 201: 297-306.
Kaur C, Ling EA. Antioxidants and neuroprotection in the adult and developing central nervous system. Curr Med Chem 2008; 15: 3068-80.
Wu CY, Zha H, Xia QQ, et al. Expression of angiotensin II and its receptors in activated microglia in experimentally induced cerebral ischemia in the adult rats. Mol Cell Biochem 2013; 382: 47-58.
Mishima K, Egashira N, Hirosawa N, et al. Characteristics of learning and memory impairment induced by delta9-tetrahydrocan nabinol in rats. Jpn J Pharmacol 2001; 87: 297-308.
Monville C, Torres EM, Dunnett SB. Comparison of incremental and accelerating protocols of the rotarod test for the assessment of motor deficits in the 6-OHDA model. J Neurosci Methods 2006; 158: 219-23.
Hussein MM, Ali HA, Ahmed MM. Ameliorative effects of phycocyanin against gibberellic acid induced hepatotoxicity. Pestic Biochem Physiol 2015; 119: 28-32.
Nair V, Turner GA. The thiobarbituric acid test for lipid peroxidation: Structure of the adduct with malondialdehyde. Lipids 1984; 19: 804-5.
Beutler E. Effect of flavin compounds on glutathione reductase activity: in vivo and in vitro studies. J Clin Invest 1969; 48: 1957-66.
Sinha AK. Colorimetric assay of catalase. Anal Biochem 1972; 47: 389-94.
Misra HP, Fridovich I. The role of superoxide anion in the autoxidation of epinephrine and a simple assay for superoxide dismutase. J Biol Chem 1972; 247: 3170-5.
Paglia DE, Valentine WN. Studies on the quantitative and qualitative characterization of erythrocyte glutathione peroxidase. J Lab Clin Med 1967; 70: 158-69.
Nagy A, Delgado-Escueta AV. Rapid preparation of synaptosomes from mammalian brain using nontoxic isoosmotic gradient material (Percoll). J Neurochem 1984; 43: 1114-23.
Ellman GL, Courtney KD, Andres V Jr, et al. A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol 1961; 7: 88-95.
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: e21445.
Yang M, Kim JS, Song MS, et al. Cyclophosphamide impairs hippocampus-dependent learning and memory in adult mice: Possible involvement of hippocampal neurogenesis in chemotherapy-induced memory deficits. Neurobiol Learn Mem 2010; 93: 487-94.
Kitamura Y, Hattori S, Yoneda S, et al. Doxorubicin and cyclophosphamide treatment produces anxiety-like behavior and spatial cognition impairment in rats: Possible involvement of hippocampal neurogenesis via brain-derived neurotrophic factor and cyclin D1 regulation. Behav Brain Res 2015; 292: 184-93.
Christie LA, Acharya MM, Parihar VK, et al. Impaired cognitive function and hippocampal neurogenesis following cancer chemotherapy. Clin Cancer Res 2012; 18: 1954-65.
Shakil S, Khan R, Tabrez S, et al. Interaction of human brain acetylcholinesterase with cyclophosphamide: A molecular modeling and docking study. CNS Neurol Disord Drug Targets 2011; 10: 845-8.
Al-Jafari AA, Shakil S, Reale M, et al. Human platelet acetylcholinesterase inhibition by cyclophosphamide: A combined experimental and computational approach. CNS Neurol Disord Drug Targets 2011; 10: 928-35.
Oboh G, Ogunruku OO. Cyclophosphamide-induced oxidative stress in brain: Protective effect of hot short pepper (Capsicum frutescens L. var. abbreviatum). Exp Toxicol Pathol 2010; 62: 227-33.
Oyagbemi AA, Omobowale TO, Saba AB, et al. Gallic acid ameliorates cyclophosphamide-induced neurotoxicity in wistar rats through free radical scavenging activity and improvement in antioxidant defense system. J Diet Suppl 2016; 13: 402-19.
Gonzalez EJ, Peterson A, Malley S, et al. The effects of tempol on cyclophosphamide-induced oxidative stress in rat micturition reflexes. Scientific World Journal 2015; 2015: 545048.
Cetik S, Ayhanci A, Sahinturk V. Protective effect of carvacrol against oxidative stress and heart injury in cyclophosphamide-induced cardiotoxicity in rat. Braz Arch Biol Technol 2015; 58: 569-76.
Shinohara Y, Inoue S. Cost-effectiveness analysis of the neuroprotective agent edaravone for noncardioembolic cerebral infarction. J Stroke Cerebrovasc Dis 2013; 22: 668-74.
Kikuchi K, Miura N, Kawahara KI, et al. Edaravone (Radicut), a free radical scavenger, is a potentially useful addition to thrombolytic therapy in patients with acute ischemic stroke. Biomed Rep 2013; 1: 7-12.
Hassan MQ, Akhtar MS, Akhtar M, et al. Edaravone protects rats against oxidative stress and apoptosis in experimentally induced myocardial infarction: Biochemical and ultrastructural evidence. Redox Rep 2015; 20: 275-81.
Yang R, Wang Q, Li F, et al. Edaravone injection ameliorates cognitive deficits in rat model of Alzheimer’s disease. Neurol Sci 2015; 36: 2067-72.
Pirinccioglu AG, Gokalp D, Pirinccioglu M, et al. Malondialdehyde (MDA) and protein carbonyl (PCO) levels as biomarkers of oxidative stress in subjects with familial hypercholesterolemia. Clin Biochem 2010; 43: 1220-4.
Jomova K, Vondrakova D, Lawson M, et al. Metals, oxidative stress and neurodegenerative disorders. Mol Cell Biochem 2010; 345: 91-104.
Lee HS, Kim BK, Nam Y, et al. Protective role of phosphatidylcholine against cisplatin-induced renal toxicity and oxidative stress in rats. Food Chem Toxicol 2013; 58: 388-93.
Areti A, Yerra VG, Naidu V, et al. Oxidative stress and nerve damage: Role in chemotherapy induced peripheral neuropathy. Redox Biol 2014; 2: 289-95.
Espinosa-Diez C, Miguel V, Mennerich D, et al. Antioxidant responses and cellular adjustments to oxidative stress. Redox Biol 2015; 6: 183-97.
Kurutas EB. The importance of antioxidants which play the role in cellular response against oxidative/nitrosative stress: Current state. Nutr J 2016; 15: 71.
Kapoor S. Edaravone and its protective effects against disease progression in neurological conditions besides strokes. J Stroke Cerebrovasc Dis 2017; 26: 3031.
Yoshida H, Yanai H, Namiki Y, et al. Neuroprotective effects of edaravone: A novel free radical scavenger in cerebrovascular injury. CNS Drug Rev 2006; 12: 9-20.
Kraus RL, Pasieczny R, Lariosa-Willingham K, et al. Antioxidant properties of minocycline: Neuroprotection in an oxidative stress assay and direct radical-scavenging activity. J Neurochem 2005; 94: 819-27.
Banno M, Mizuno T, Kato H, et al. The radical scavenger edaravone prevents oxidative neurotoxicity induced by peroxynitrite and activated microglia. Neuropharmacology 2005; 48: 283-90.
Lee BJ, Egi Y, van Leyen K, et al. Edaravone, a free radical scavenger, protects components of the neurovascular unit against oxidative stress in vitro. Brain Res 2010; 1307: 22-7.
Miyamoto N, Maki T, Pham LD, et al. Oxidative stress interferes with white matter renewal after prolonged cerebral hypoperfusion in mice. Stroke 2013; 44: 3516-21.
Watanabe T, Morita I, Nishi H, et al. Preventive effect of MCI-186 on 15-HPETE induced vascular endothelial cell injury in vitro. Prostaglandins Leukot Essent Fatty Acids 1988; 33: 81-7.
Yuan Y, Zha H, Rangarajan P, et al. Anti-inflammatory effects of Edaravone and Scutellarin in activated microglia in experimentally induced ischemia injury in rats and in BV-2 microglia. BMC Neurosci 2014; 15: 125.
Reeta KH, Singh D, Gupta YK. Edaravone attenuates intracerebroventricular streptozotocin-induced cognitive impairment in rats. Eur J Neurosci 2017; 45: 987-97.
Li X, Lu F, Li W, et al. Edaravone injection reverses learning and memory deficits in a rat model of vascular dementia. Acta biochimica et biophysica Sinica 2017; 49: 83-9.

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2019
Page: [209 - 216]
Pages: 8
DOI: 10.2174/1574886314666190506100717

Article Metrics

PDF: 21
PRC: 2