Abstract
Cisplatin, a chemotherapy drug containing platinum, is considered a neurotoxic agent. On the other hand, crocin, the primary component of saffron, possesses neuroprotective and antioxidant properties. In this study, 28 healthy adult male Wistar rats weighing 200–250 g were used (6–7 weeks old). Rats were divided into a control group (Ctr), a crocin group (Cro), a cisplatin group (Cis), and a crocin with cisplatin group (Cro + Cis). Rotarod, open field, and shuttle box tests were performed to assess balance, explorative behavior, and avoidance memory. After behavioral testing, the hippocampus was extracted to analyze oxidative stress parameters such as GPx (glutathione peroxidase), SOD (superoxide dismutase), CAT (catalase), and MDA (malondialdehyde) activity. Shuttle box, rotarod, and open field results showed that crocin can substantially mitigate the deleterious effects of cisplatin on avoidance memory, explorative behavior, motor coordination, and balance. Crocin was also able to effectively avoid the negative effects of cisplatin on MDA, GPx, and CAT during the assessment of oxidative indicators, while the beneficial effect of crocin on cisplatin was not statistically significant in terms of SOD level. In conclusion, since free radicals produced by cisplatin are a contributing factor to memory loss and movement disorders, crocin, owing to its antioxidant properties, improved passive avoidance learning as well as motor activity.
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Data Availability
The datasets generated for this study are available on request to the corresponding author.
References
Alfarouk KO, Stock C-M, Taylor S, Walsh M, Muddathir AK, Verduzco D, Bashir AH, Mohammed OY, Elhassan GO, Harguindey S (2015) Resistance to cancer chemotherapy: failure in drug response from ADME to P-gp. Cancer Cell Int 15:1–13
Taillibert S, Le Rhun E, Chamberlain MC (2016) Chemotherapy-related neurotoxicity. Curr Neurol Neurosci Rep 16:1–14
Oun R, Moussa YE, Wheate NJ (2018) The side effects of platinum-based chemotherapy Drugs: a review for chemists. Dalton Trans 47:6645–6653
Zhu J, Carozzi VA, Reed N, Mi R, Marmiroli P, Cavaletti G, Hoke A (2016) Ethoxyquin provides neuroprotection against cisplatin-induced neurotoxicity. Sci Rep 6:28861
Hoebers FJ, Pluim D, Verheij M, Balm AJ, Bartelink H, Schellens JH, Begg AC (2006) Prediction of treatment outcome by cisplatin-DNA adduct formation in patients with stage III/IV head and neck squamous cell carcinoma, treated by concurrent cisplatin‐radiation (RADPLAT). Int J Cancer 119:750–756
Köberle B, Tomicic MT, Usanova S, Kaina B (2010) Cisplatin resistance: preclinical findings and clinical implications. Biochim et Biophys Acta (BBA)-Reviews Cancer 1806:172–182
Sears CR, Turchi JJ (2012) Complex cisplatin-double strand break (DSB) lesions directly impair cellular non-homologous end-joining (NHEJ) Independent of downstream damage response (DDR) pathways. J Biol Chem 287:24263–24272
Peng B, Tilby M, English M, Price L, Pearson A, Boddy A, Newell D (1997) Platinum-DNA adduct formation in leucocytes of children in relation to pharmacokinetics after cisplatin and carboplatin therapy. Br J Cancer 76:1466–1473
Li Y, Zheng M, Sah SK, Mishra A, Singh Y (2019) Neuroprotective influence of sitagliptin against cisplatin-induced neurotoxicity, biochemical and behavioral alterations in Wistar rats. Mol Cell Biochem 455:91–97
Zhang A, Shen Y, Cen M, Hong X, Shao Q, Chen Y, Zheng B (2019) Polysaccharide and crocin contents, and antioxidant activity of saffron from different origins. Ind Crops Prod 133:111–117
Ighodaro O, Akinloye O (2018) First line defence antioxidants-superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX): their fundamental role in the entire antioxidant defence grid. Alexandria J Med 54:287–293
Leone S, Recinella L, Chiavaroli A, Orlando G, Ferrante C, Leporini L, Brunetti L, Menghini L (2018) Phytotherapic use of the Crocus sativus L.(Saffron) and its potential applications: a brief overview. Phytother Res 32:2364–2375
Srivastava R, Ahmed H, Dixit RK, Saraf S (2010) Crocus sativus L.: a comprehensive review. Pharmacogn Rev 4:200
Kapucu A (2021) Crocin ameliorates oxidative stress and suppresses renal damage in streptozotocin induced diabetic male rats. Biotech Histochem 96:153–160
Chen Y, Zhang H, Tian X, Zhao C, Cai L, Liu Y, Jia L, Yin H-X, Chen C (2008) Antioxidant potential of crocins and ethanol extracts of Gardenia jasminoides ELLIS and Crocus sativus L.: a relationship investigation between antioxidant activity and crocin contents. Food Chem 109:484–492
Wang K, Zhang L, Rao W, Su N, Hui H, Wang L, Peng C, Tu Y, Zhang S, Fei Z (2015) Neuroprotective effects of crocin against traumatic brain injury in mice: involvement of notch signaling pathway. Neurosci Lett 591:53–58
Mehri S, Abnous K, Mousavi SH, Shariaty VM, Hosseinzadeh H (2012) Neuroprotective effect of crocin on acrylamide-induced cytotoxicity in PC12 cells. Cell Mol Neurobiol 32:227–235
Morelli S, Salerno S, Piscioneri A, Tasselli F, Drioli E, De Bartolo L (2016) Neuronal membrane bioreactor as a tool for testing crocin neuroprotective effect in Alzheimer’s Disease. Chem Eng J 305:69–78
Vakili A, Einali MR, Bandegi AR (2014) Protective effect of crocin against cerebral ischemia in a dose-dependent manner in a rat model of ischemic Stroke. J Stroke Cerebrovasc Dis 23:106–113
Asadi F, Jamshidi AH, Khodagholi F, Yans A, Azimi L, Faizi M, Vali L, Abdollahi M, Ghahremani MH, Sharifzadeh M (2015) Reversal effects of crocin on amyloid β-induced memory deficit: modification of autophagy or apoptosis markers. Pharmacol Biochem Behav 139:47–58
Khalili M, Hamzeh F (2010) Effects of active constituents of Crocus sativus L., crocin on streptozocin-induced model of sporadic Alzheimer’s Disease in male rats. Iran Biomed J 14:59
Wang J, Xiao B, Han F, Shi Y (2017) Metformin alleviated the neuronal oxidative stress in hippocampus of rats under single prolonged stress. J Mol Neurosci 63:28–35
Delkhosh-Kasmaie F, Farshid AA, Tamaddonfard E, Imani M (2018) The effects of safranal, a constitute of saffron, and metformin on spatial learning and memory impairments in type-1 diabetic rats: behavioral and hippocampal histopathological and biochemical evaluations. Biomed Pharmacother 107:203–211
Bandegi AR, Rashidy-Pour A, Vafaei AA, Ghadrdoost B (2014) Protective effects of Crocus sativus L. extract and crocin against chronic-stress induced oxidative damage of brain, liver and kidneys in rats. Adv Pharm Bull 4:493
Oz M, Atalik KEN, Yerlikaya FH, Demir EA (2015) Curcumin alleviates cisplatin-induced learning and memory impairments. Neurobiol Learn Mem 123:43–49
Shabani M, Nazeri M, Parsania S, Razavinasab M, Zangiabadi N, Esmaeilpour K, Abareghi F (2012) Walnut consumption protects rats against cisplatin-induced neurotoxicity. Neurotoxicology 33:1314–1321
Ghotbeddin Z, Moazedi AA, Parham GA (2007) Effect of combined administration of zinc chloride and aluminum chloride on memory and motor activity of young rats. Physiol Pharmacol 11:146–152
Aliheydari M, Ghotbeddin Z, Khazaeil K, Tabandeh MR (2020) Effect of fish oil treatment during chronic hypoxia in pregnancy on memory impairment, brain morphometry changes and oxidative stress in adult male rat offspring. KAUMS J (FEYZ) 24:170–180
Nooraei A, Khazaeel K, Darvishi M, Ghotbeddin Z, Basir Z (2022) Dimorphic evaluation of hippocampal changes in rat model of demyelination: a comparative functional, morphometric, and histological study. Brain and Behavior 12:e32723
Ghotbeddin Z, Khazaeel K, Tabandeh M-R, Aliheydari M, Yaghoubi H (2022) Effects of omega-3 fatty acid supplementation during chronic maternal hypoxia on behavioral disorders in male rat offspring: the role of trk family and oxidative stress. Metab Brain Dis 37:1959–1967
Zhou JY, Prognon P (2006) Raw material enzymatic activity determination: a specific case for validation and comparison of analytical methods—the example of superoxide dismutase (SOD). J Pharm Biomed Anal 40:1143–1148
Buege JA, Aust SD (1978) Microsomal lipid peroxidation. Methods in enzymology. Elsevier, Amsterdam, pp 302–310
Anderson-Hanley C, Sherman ML, Riggs R, Agocha VB, Compas BE (2003) Neuropsychological effects of treatments for adults with cancer: a meta-analysis and review of the literature. J Int Neuropsychol Soc 9:967–982
Rzeski W, Pruskil S, Macke A, Felderhoff-Mueser U, Reiher AK, Hoerster F, Jansma C, Jarosz B, Stefovska V, Bittigau P (2004) Anticancer agents are potent neurotoxins in vitro and in vivo. Ann Neurol 56:351–360
Mustafa S, Walker A, Bennett G, Wigmore PM (2008) 5-Fluorouracil chemotherapy affects spatial working memory and newborn neurons in the adult rat hippocampus. Eur J Neurosci 28:323–330
Correa DD, Ahles TA (2008) Neurocognitive changes in cancer survivors. Cancer J 14:396–400
Krarup-Hansen A, Helweg-Larsen S, Schmalbruch H, Rørth M, Krarup C (2007) Neuronal involvement in cisplatin neuropathy: prospective clinical and neurophysiological studies. Brain 130:1076–1088
Callizot N, Andriambeloson E, Glass J, Revel M, Ferro P, Cirillo R, Vitte P-A, Dreano M (2008) Interleukin-6 protects against paclitaxel, cisplatin and vincristine-induced neuropathies without impairing chemotherapeutic activity. Cancer Chemother Pharmacol 62:995–1007
Hosseinzadeh M, Alizadeh A, Heydari P, Kafami M, Hosseini M, Beheshti F, Marefati N, Ghanbarabadi M (2021) Effect of vitamin E on cisplatin-induced memory impairment in male rats. Acta Neuropsychiatrica 33:43–48
Chen C, Zhang H, Xu H, Zheng Y, Wu T, Lian Y (2019) Ginsenoside Rb1 ameliorates cisplatin-induced learning and memory impairments. J Ginseng Res 43:499–507
Moradi M, Goodarzi N, Faramarzi A, Cheraghi H, Hashemian AH, Jalili C (2021) Melatonin protects rats testes against bleomycin, etoposide, and cisplatin-induced toxicity via mitigating nitro-oxidative stress and apoptosis. Biomed Pharmacother 138:111481
Tredici G, Tredici S, Fabbrica D, Minoia C, Cavaletti G (1998) Experimental cisplatin neuronopathy in rats and the effect of retinoic acid administration. J Neurooncol 36:31–40
Pace A, Giannarelli D, Galie E, Savarese A, Carpano S, Della Giulia M, Pozzi A, Silvani A, Gaviani P, Scaioli V (2010) Vitamin E neuroprotection for cisplatin neuropathy: a randomized, placebo-controlled trial. Neurology 74:762–766
Melli G, Taiana M, Camozzi F, Triolo D, Podini P, Quattrini A, Taroni F, Lauria G (2008) Alpha-lipoic acid prevents mitochondrial damage and neurotoxicity in experimental chemotherapy neuropathy. Exp Neurol 214:276–284
Tahvilian N, Masoodi M, Faghihi Kashani A, Vafa M, Aryaeian N, Heydarian A, Hosseini A, Moradi N, Farsi F (2021) Effects of saffron supplementation on oxidative/antioxidant status and severity of Disease in ulcerative Colitis patients: a randomized, double-blind, placebo‐controlled study. Phytother Res 35:946–953
Samarghandian S, Samini F, Azimi-Nezhad M, Farkhondeh T (2017) Anti-oxidative effects of safranal on immobilization-induced oxidative damage in rat brain. Neurosci Lett 659:26–32
Tuberoso CI, Rosa A, Montoro P, Fenu MA, Pizza C (2016) Antioxidant activity, cytotoxic activity and metabolic profiling of juices obtained from saffron (Crocus sativus L.) floral by-products. Food Chem 199:18–27
Pan P, Qiao L, Wen X (2016) Safranal prevents rotenone-induced oxidative stress and apoptosis in an in vitro model of Parkinson’s Disease through regulating Keap1/Nrf2 signaling pathway. Cell Mol Biol 62:11–17
Liou J-C, Yang S-L, Wang P-H, Wu J-L, Huang Y-P, Chen B-Y, Lee M-C (2018) Protective effect of crocin against the declining of high spatial frequency-based visual performance in mice. J Funct Foods 49:314–323
Boussabbeh M, Salem IB, Belguesmi F, Bacha H, Abid-Essefi S (2016) Tissue oxidative stress induced by patulin and protective effect of crocin. Neurotoxicology 53:343–349
Weber F, Laskawy G, Grosch W (1974) Co-oxidation of carotene and crocin by soyabean lipoxygenase isoenzymes. Z für Lebensmittel-Untersuchung und Forschung 155:142–150
Thushara R, Hemshekhar M, Santhosh MS, Jnaneshwari S, Nayaka S, Naveen S, Kemparaju K, Girish K (2013) Crocin, a dietary additive protects platelets from oxidative stress-induced apoptosis and inhibits platelet aggregation. Mol Cell Biochem 373:73–83
Yoshino F, Yoshida A, Umigai N, Kubo K, Masaichi C-iL (2011) Crocetin reduces the oxidative stress induced reactive oxygen species in the stroke-prone spontaneously hypertensive rats (SHRSPs) brain. J Clin Biochem Nutr 49:182–187
Yüce A, Ateşşahin A, Çeribaşı AO, Aksakal M (2007) Ellagic acid prevents cisplatin-induced oxidative stress in liver and heart tissue of rats. Basic Clin Pharmacol Toxicol 101:345–349
Avgerinos KI, Vrysis C, Chaitidis N, Kolotsiou K, Myserlis PG, Kapogiannis D (2020) Effects of saffron (Crocus sativus L.) on cognitive function. A systematic review of RCTs. Neurol Sci 41:2747–2754
Sadeghnia HR, Shaterzadeh H, Forouzanfar F, Hosseinzadeh H (2017) Neuroprotective effect of safranal, an active ingredient of Crocus sativus, in a rat model of transient cerebral ischemia. Folia Neuropathol 55:206–213
Acknowledgements
We are grateful to the Research Council of Shahid Chamran University of Ahvaz for financial supports and Dr. Mina Jahangiri for the detailed and accurate statistical analysis of the data.
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We are grateful to the Research Council of Shahid Chamran University of Ahvaz for financial support.
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ZG participated in study design, data collection, evaluation and contributed to behavioral experiments and was responsible for overall supervision. MP, AMD and MAI contributed to all experimental work and data statistical analysis. All the authors reviewed and approved the final manuscript.
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Animal studies were conducted according to the protocols and guidelines approved by the Institutional Ethics Committee of Shahid Chamran University of Ahvaz (EE/97.24.3.49914/scu.ac.ir) and were conducted under the Guide for the Care and Use of Laboratory Animals (NIH).
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Ghotbeddin, Z., Peysokhan, M., Dezfouli, A.M. et al. Nutritional Support of Crocin on Neurobehavioral Disabilities Induced by Cisplatin-Based Chemotherapy in Rats. Neurochem Res 49, 649–659 (2024). https://doi.org/10.1007/s11064-023-04059-8
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DOI: https://doi.org/10.1007/s11064-023-04059-8