Skip to main content

Advertisement

Log in

Nutritional Support of Crocin on Neurobehavioral Disabilities Induced by Cisplatin-Based Chemotherapy in Rats

  • Original Paper
  • Published:
Neurochemical Research Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

Data Availability

The datasets generated for this study are available on request to the corresponding author.

References

  1. 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

    Article  CAS  Google Scholar 

  2. Taillibert S, Le Rhun E, Chamberlain MC (2016) Chemotherapy-related neurotoxicity. Curr Neurol Neurosci Rep 16:1–14

    Article  CAS  Google Scholar 

  3. Oun R, Moussa YE, Wheate NJ (2018) The side effects of platinum-based chemotherapy Drugs: a review for chemists. Dalton Trans 47:6645–6653

    Article  CAS  PubMed  Google Scholar 

  4. 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

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  5. 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

    Article  CAS  PubMed  Google Scholar 

  6. 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

    Article  Google Scholar 

  7. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. 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

    Article  CAS  PubMed  Google Scholar 

  10. 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

    Article  CAS  Google Scholar 

  11. 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

    Article  Google Scholar 

  12. 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

    Article  CAS  PubMed  Google Scholar 

  13. Srivastava R, Ahmed H, Dixit RK, Saraf S (2010) Crocus sativus L.: a comprehensive review. Pharmacogn Rev 4:200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Kapucu A (2021) Crocin ameliorates oxidative stress and suppresses renal damage in streptozotocin induced diabetic male rats. Biotech Histochem 96:153–160

    Article  CAS  PubMed  Google Scholar 

  15. 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

    Article  CAS  ADS  Google Scholar 

  16. 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

    Article  CAS  PubMed  Google Scholar 

  17. 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

    Article  CAS  PubMed  Google Scholar 

  18. 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

    Article  CAS  Google Scholar 

  19. 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

    Article  PubMed  Google Scholar 

  20. 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

    Article  CAS  PubMed  Google Scholar 

  21. 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

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 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

    Article  CAS  PubMed  Google Scholar 

  23. 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

    Article  CAS  PubMed  Google Scholar 

  24. 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

    PubMed  PubMed Central  Google Scholar 

  25. Oz M, Atalik KEN, Yerlikaya FH, Demir EA (2015) Curcumin alleviates cisplatin-induced learning and memory impairments. Neurobiol Learn Mem 123:43–49

    Article  CAS  PubMed  Google Scholar 

  26. 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

    Article  CAS  PubMed  Google Scholar 

  27. 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

    CAS  Google Scholar 

  28. 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

    Google Scholar 

  29. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. 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

    Article  CAS  PubMed  Google Scholar 

  31. 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

    Article  CAS  PubMed  Google Scholar 

  32. Buege JA, Aust SD (1978) Microsomal lipid peroxidation. Methods in enzymology. Elsevier, Amsterdam, pp 302–310

    Google Scholar 

  33. 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

    Article  PubMed  Google Scholar 

  34. 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

    Article  CAS  PubMed  Google Scholar 

  35. 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

    Article  PubMed  Google Scholar 

  36. Correa DD, Ahles TA (2008) Neurocognitive changes in cancer survivors. Cancer J 14:396–400

    Article  PubMed  Google Scholar 

  37. 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

    Article  CAS  PubMed  Google Scholar 

  38. 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

    Article  CAS  PubMed  Google Scholar 

  39. 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

    Article  PubMed  Google Scholar 

  40. 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

    Article  PubMed  Google Scholar 

  41. 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

    Article  CAS  PubMed  Google Scholar 

  42. 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

    Article  CAS  PubMed  Google Scholar 

  43. 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

    Article  CAS  PubMed  Google Scholar 

  44. 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

    Article  CAS  PubMed  Google Scholar 

  45. 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

    Article  CAS  PubMed  Google Scholar 

  46. 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

    Article  CAS  PubMed  Google Scholar 

  47. 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

    Article  CAS  PubMed  Google Scholar 

  48. 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

    Article  PubMed  Google Scholar 

  49. 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

    Article  CAS  Google Scholar 

  50. 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

    Article  CAS  PubMed  Google Scholar 

  51. 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

    Article  CAS  Google Scholar 

  52. 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

    Article  CAS  PubMed  Google Scholar 

  53. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. 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

    Article  PubMed  Google Scholar 

  55. 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

    Article  PubMed  PubMed Central  Google Scholar 

  56. 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

    Article  PubMed  Google Scholar 

Download references

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.

Funding

We are grateful to the Research Council of Shahid Chamran University of Ahvaz for financial support.

Author information

Authors and Affiliations

Authors

Contributions

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.

Corresponding author

Correspondence to Zohreh Ghotbeddin.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical Approval

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).

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 22.1 kb)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-023-04059-8

Keywords

Navigation