Abstract
The use of chemotherapeutic drugs is associated with oxidative damage, cognitive dysfunction, and brain damage. This study sought to investigate the neuroprotective effect of curcumin against cognitive problems associated with treatment with cyclophosphamide via assessment of biomolecules associated with cognitive function in rats’ brain homogenates. Rats were divided in to five groups: Control (vehicle), CUR (curcumin [20 mg/kg]), CPA (cyclophosphamide [150 mg/kg]), CUR1 + CPA (curcumin [20 mg/kg] and cyclophosphamide [150 mg/kg]), and CPA + CUR2 (cyclophosphamide [150 mg/kg] and curcumin [20 mg/kg]). After the treatment, cognitive behavior was assessed and enzymes [cholinesterases, purinergic enzymes, arginase, and angiotensin I-converting enzyme] associated with cognitive function were examined. Oxidative stress parameters [total thiol, non-protein thiol, malondialdehyde, and nitric oxide] including the expression of caspase-3 were also assessed in rats’ brain. Our results showed that curcumin improved cognitive behavior, attenuated cholinergic deficit as revealed by the inhibition of cholinesterases, and improved purinergic signaling in cyclophosphamide-treated rats. Furthermore, curcumin reduced angiotensin-I-converting enzyme and arginase activities before and after treatment with cyclophosphamide. Curcumin also improved redox balance and showed protection against cyclophosphamide-induced oxidative damage to rats’ brain via an increase in protein and non-protein thiols and nitric oxide levels as well as a significant reduction in malondialdehyde levels. Curcumin also prevented neuronal degeneration in different brain regions and reduced caspase-3 expression. Hence this study suggests that pre and post-treatment with curcumin improved neurobehavior, modulates some biomarkers associated with cognitive function and exhibit neuroprotection against cyclophosphamide-induced neurotoxicity in rats.
Similar content being viewed by others
References
Abdallah HM, Abdel-Rahman RF, El Awdan SA, Allam RM, El-Mosallamy AE, Selim MS, Mohamed SS, Arbid MS, Farrag ARH (2019) Protective effect of some natural products against chemotherapy-induced toxicity in rats. Heliyon 5(5):01590
Adeniyi PA, Ishola AO, Laoye BJ, Olatunji BP, Bankole OO, Shallie PD, Ogundele OM (2016) Neural and behavioural changes in male periadolescent mice after prolonged nicotine-MDMA treatment. Metab Brain Dis 31(1):93–107
Akinyemi AJ, Onyebueke N, Faboya OA, Onikanni SA, Fadaka A, Olayide I (2017a) Curcumin inhibits adenosine deaminase and arginase activities in cadmium-induced renal toxicity in rat kidney. J Food Drug Anal 25(2):438–446
Akinyemi AJ, Oboh G, Oyeleye SI, Ogunsuyi O (2017b) Anti-amnestic effect of curcumin in combination with donepezil, an anticholinesterase drug: involvement of cholinergic system. Neurotox Res 31(4):560–569
Anand P, Thomas SG, Kunnumakkara AB, Sundaram C, Harikumar KB, Sung B, Aggarwal BB (2008) Biological activities of curcumin and its analogues (congeners) made by man and Mother Nature. Biochem Pharmacol 76(11):1590–1611
Avci H, Epikmen ET, Ipek E, Tunca R, Birincioglu SS, Akşit H, Sekkin S, Akkoc AN, Boyacioglu M (2017) Protective effects of silymarin and curcumin on cyclophosphamide-induced cardiotoxicity. Exp Toxicol Pathol 69(5):317–327
Baba SP, Bhatnagar A (2018) Role of thiols in oxidative stress. Curr Opin Toxicol 7:133–139
Bagatini MD, dos Santos AA, Cardoso AM, Mânica A, Reschke CR, Carvalho FB (2018) The impact of purinergic system enzymes on noncommunicable, neurological and degenerative diseases. J Immunol Res 2018:4892473
Barai P, Raval N, Acharya S, Acharya N (2018) Bergenia ciliata ameliorates streptozotocin-induced spatial memory deficits through dual cholinesterase inhibition and attenuation of oxidative stress in rats. Biomed Pharmacother 102:966–980
Briones TL, Woods J (2011) Chemotherapy-induced cognitive impairment is associated with decreases in cell proliferation and histone modifications. BMC Neurosci 12(1):124
Caldwell RB, Toque HA, Narayanan SP, Caldwell RW (2015) Arginase: an old enzyme with new tricks. Trends Pharmacol Sci 36(6):395–405
Chainani-Wu N (2003) Safety and anti-inflammatory activity of curcumin: a component of tumeric (Curcuma longa). J Alternative Complement Med 9:161–168
Cushman DW, Cheung SH (1971) Spectrophotometric assay and properties of the angiotensin-converting enzyme of rabbit lung. Biochem Pharmacol 20:1637–1648
Dikalov SI, Nazarewicz RR (2013) Angiotensin II-induced production of mitochondrial reactive oxygen species: potential mechanisms and relevance for cardiovascular disease. Antioxid Redox Signal 19(10):1085–1094
Ellman GL (1959) Tissue sulfurhydryl groups. Arch Biochem Biophys 82:70–77
Ellman GL, Courtney KD, Andres Jr V, Featherstone RM (1961) A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol 7(2): 88–95
Farrer LA, Sherbatich T, Keryanov SA, Korovaitseva GI, Rogaeva EA, Petruk S, Sato C (2000) Association between angiotensin-converting enzyme and Alzheimer disease. Arch Neurol 57(2):210–214
García-Ayllón MS, Small DH, Avila J, Sáez-Valero J (2011) Revisiting the role of acetylcholinesterase in Alzheimer’s disease: cross-talk with P-tau and β-amyloid. Front Mol Neurosci 4:22
Gomes CV, Kaster MP, Tomé AR, Agostinho PM, Cunha RA (2011) Adenosine receptors and brain diseases: neuroprotection and neurodegeneration. Biochimica et Biophysica Acta (BBA)-Biomembranes 1808(5):1380–1399
Heymann D, Reddington M, Kreutzberg GW (1984) Subcellular localization of 5′-nucleotidase in rat brain. J Neurochem 43:971–978
Ijomone OM, Olatunji SY, Owolabi JO, Naicker T, Aschner M (2018) Nickel-induced neurodegeneration in the hippocampus, striatum and cortex; an ultrastructural insight, and the role of caspase-3 and α-synuclein. J Trace Elements in Med and Bio 50:16–23
Ijomone OK, Shallie PD, Naicker T (2019) Nco-nitro-L-arginine methyl model of pre-eclampsia elicits differential Iba1 and EAAT1 expressions in brain. J Chem Neuroanat 100:101660
Khan MB, Khan MM, Khan A, Ahmed ME, Ishrat T, Tabassum R, Vaibhav K, Ahmad A, Islam F (2012) Naringenin ameliorates Alzheimer’s disease (AD)-type neurodegeneration with cognitive impairment (AD-TNDCI) caused by the intracerebroventricular-streptozotocin in rat model. Neurochem Int 61(7):1081–1093
Khan S, Ahmad K, Alshammari EM, Adnan M, Baig MH, Lohani M, Somvanshi P, Haque S (2015) Implication of caspase-3 as a common therapeutic target for multineurodegenerative disorders and its inhibition using nonpeptidyl natural compounds. Biomed Res Int 2015, 379817
Kim JH, Bugaj LJ, Oh YJ, Bivalacqua TJ, Ryoo S, Soucy KG, Nyhan D (2009) Arginase inhibition restores NOS coupling and reverses endothelial dysfunction and vascular stiffness in old rats. J Appl Physiol 107(4):1249–1257
Kim KS, Lim HJ, Lim JS, Son JY, Lee J, Lee BM, Chang S, Kim HS (2018) Curcumin ameliorates cadmium-induced nephrotoxicity in Sprague-Dawley rats. Food Chem Toxicol 114:34–40
Labandeira-García JL, Garrido-Gil P, Rodriguez-Pallares J, Valenzuela R, Borrajo A, Rodríguez-Perez AI (2014) Brain renin-angiotensin system and dopaminergic cell vulnerability. Front Neuroanat 8:67
Maheshwari RK, Singh AK, Gaddipati J, Srimal RC (2006) Multiple biological activities of curcumin: a short review. Life Sci 78(18):2081–2087
Melekoglu R, Ciftci O, Eraslan S, Cetin A, Basak N (2018) Beneficial effects of curcumin and capsaicin on cyclophosphamide-induced premature ovarian failure in a rat model. J Ovarian Res 11(1):33
Miranda KM, Espay MG, Wink DA (2001) A rapid, simple spectrophotometric method for simultaneous detection of nitrate and nitrite. Nitric Oxide 5:62–71
Mufson EJ, Counts SE, Perez SE, Ginsberg SD (2008) Cholinergic system during the progression of Alzheimer’s disease: therapeutic implications. Expert Rev Neurother 8(11):1703–1718
Oboh G, Adewuni TM, Ademosun AO, Olasehinde TA (2016) Sorghum stem extract modulates Na+/K+-ATPase, ecto-5′-nucleotidase, and acetylcholinesterase activities. Comp Clin Pathol 25(4):749–756
Oboh G, Oyeleye SI, Akintemi OA, Olasehinde TA (2018) Moringa oleifera supplemented diet modulates nootropic-related biomolecules in the brain of STZ-induced diabetic rats treated with acarbose. Metab Brain Dis 33(2):457–466
Ohkawa H, Ohishi N, Yagi K (1979) Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 95:351–358
Olasehinde TA, Olaniran AO, Okoh AI (2017) Therapeutic potentials of microalgae in the treatment of Alzheimer’s disease. Molecules 22(3)
Olasehinde TA, Olaniran AO, Okoh AI (2019a) Phenolic composition, antioxidant activity, anticholinesterase potential and modulatory effects of aqueous extracts of some seaweeds on β-amyloid aggregation and disaggregation. Pharmaceutical Bio 57(1):460–469
Olasehinde TA, Olaniran AO, Okoh AI (2019b) Neuroprotective effects of some seaweeds against Zn–induced neuronal damage in HT-22 cells via modulation of redox imbalance, inhibition of apoptosis and acetylcholinesterase activity. Metab Brain Dis 34(6):1615–1627
Philpot RM, Ficken M, Wecker L (2016) Doxorubicin and cyclophosphamide lead to long-lasting impairment of spatial memory in female, but not male mice. Behav Brain Res 307:165–175
Pimentel-Gutiérrez HJ, Bobadilla-Morales L, Barba-Barba CC, Ortega-De-La-Torre C, Sánchez-Zubieta FA, Corona-Rivera JR, Corona-Rivera A (2016) Curcumin potentiates the effect of chemotherapy against acute lymphoblastic leukemia cells via downregulation of NF-κB. Oncol Lett 12(5):4117–4124
Polis B, Samson AO (2018) Arginase as a potential target in the treatment of Alzheimer’s disease. Adv Alzheimer’s Dis 7:119–140
Robson SC, Sévigny J, Zimmermann H (2006) The E-NTPDase family of ectonucleotidases: structure function relationships and pathophysiological significance. Purinergic Signal 2(2):409–430
Salas-Ramirez KY, Bagnall C, Frias L, Abdali SA, Ahles TA, Hubbard K (2015) Doxorubicin and cyclophosphamide induce cognitive dysfunction and activate the ERK and AKT signaling pathways. Behav Brain Res 292:133–141
Schagen SB, van Dam FS, Muller MJ, Boogerd W, Lindeboom J, Bruning PF (1999) Cognitive deficits after postoperative adjuvant chemotherapy for breast carcinoma. Cancer Interdiscipl Int J Am Cancer Soc 85(3):640–650
Schagen SB, Wefel JS (2013) Chemotherapy-related changes in cognitive functioning. EJC Suppl 11(2):225–232
Schetinger MR, Morsch VM, Bonan CD, Wyse AT (2007) NTPDase and 5′-nucleotidase activities in physiological and disease conditions: new perspectives for human health. Biofactors. 31(2):77–98
Seigers R, Fardell JE (2011) Neurobiological basis of chemotherapy-induced cognitive impairment: a review of rodent research. Neurosci Biobehav Rev 35(3):729–741
Swamy AV, Patel UM, Koti BC, Gadad PC, Patel NL, Thippeswamy AHM (2013) Cardioprotective effect of Saraca indica against cyclophosphamide induced cardiotoxicity in rats: a biochemical, electrocardiographic and histopathological study. Indian J Pharm 45(1):4
Valko M, Leibfritz D, Moncol J, Cronin MTD, Mazur M, Telser J (2007) Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol 39: 44–84
Van Dam FS, Boogerd W, Schagen SB, Muller MJ, Droogleever Fortuyn ME, Wall EV, Rodenhuis S (1998) Impairment of cognitive function in women receiving adjuvant treatment for high-risk breast cancer: high-dose versus standard-dose chemotherapy. J National Cancer Institute 90(3):210–218
Virarkar M, Alappat L, Bradford PG, Awad AB (2013) L-arginine and nitric oxide in CNS function and neurodegenerative diseases. Crit Rev Food Sci Nutr 53(11):1157–1167
Wieneke MH, Dienst ER (1995) Neuropsychological assessment of cognitive functioning following chemotherapy for breast cancer. Psycho-Oncology 4(1):61–66
Wigmore P (2012) The effect of systemic chemotherapy on neurogenesis, plasticity and memory. In Neurogenesis and neural plasticity (pp. 211-240). Springer, Berlin, Heidelberg
Yang HY, Lee TH (2015) Antioxidant enzymes as redox-based biomarkers: a brief review. BMB Rep 48(4):200–208
Zhang C, Hein TW, Wang W, Chang CI, Kuo L (2001) Constitutive expression of arginase in microvascular endothelial cells counteract nitric oxide-mediated vasodilatory function. FASEB J 15:1264–1266
Zhang QY, Wang FX, Jia KK, Kong LD (2018) Natural product interventions for chemotherapy and radiotherapy-induced side effects. Front Pharmacol 9:1253
Zhou L, Sun CB, Liu C, Fan Y, Zhu HY, Wu XW, Li QP (2015) Upregulation of arginase activity contributes to intracellular ROS production induced by high glucose in H9c2 cells. Int J Clin Exp Pathol 8(3):2728–2736
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of Interest
The authors declare that they have no conflict of interest.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Akomolafe, S.F., Olasehinde, T.A., Oyeleye, S.I. et al. Curcumin Administration Mitigates Cyclophosphamide-Induced Oxidative Damage and Restores Alteration of Enzymes Associated with Cognitive Function in Rats’ Brain. Neurotox Res 38, 199–210 (2020). https://doi.org/10.1007/s12640-020-00205-0
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12640-020-00205-0