Neuroprotective Activities of Saffron and Crocin

  • Shinji Soeda
  • Kosuke Aritake
  • Yoshihiro Urade
  • Hiroshi Sato
  • Yukihiro ShoyamaEmail author
Part of the Advances in Neurobiology book series (NEUROBIOL, volume 12)


We first considered that saffron is really safety food because it has a long-use history. The neuroprotective activities of saffron and its major constituent, crocin, are separately discussed in vitro and in vivo. We reviewed the inhibitory activities of crocin against PC-12 cell apoptosis. The oxidative stress decreased the cellular levels of glutathione (GSH) which is an inhibitor of neutral sphingomyelinase (N-SMase). Therefore, the level of GSH was assayed by the addition of crocin resulted in the activation of glutathione reductase (GR). It became evident that crocin treatment prevents the N-SMase activation resulting in the decrease of ceramide release. From these evidences we summarized the role of crocin for neuronal cell death. We used the ethanol-blocking assay system for learning and memory activities. The effect of saffron and crocin on improving ethanol-induced impairment of learning behaviors of mice in passive avoidance tasks has been clear. Further, we did make clear that saffron and crocin prevent the inhibitory effect of ethanol on long-term potentiation (LTP) in the dentate gyrus. Finally we found that 100 mg/kg of crocin gave non-rapid eye movement sleep (non-REM sleep) although mice were started to be active during night time.


Saffron Crocus sativus Crocin Neuroprotective activity Learning and memory Non-REM sleep 



Dulbecco’s modified Eagle’s medium


Enzyme-linked immunosorbent assay


Fumonisin B1


c-Glutamylcysteinyl synthase


Glutathione peroxidase


Glutathione reductase






c-Jun kinase


Long-term potentiation


Monoclonal antibody


Nerve growth factor



Non-REM sleeping

Non-rapid eye movement sleep


Neutral sphingomyelinase




Stress-activated protein kinase






Superoxide dismutase


Step through


Tumor necrosis factor


Traditional Chinese medicine


Compliance with Ethics Requirements

The authors declare that they have no conflicts of interest.


  1. Abdullaev FI. Cancer chemopreventive and tumoricidal properties of saffron (Crocus sativus L.). Exp Biol Med. 2002;227:20–5.Google Scholar
  2. Abe K, Xie F, Saito H. Epidermal growth factor enhances short-time potentiation and facilitates induction of long-term potentiation of evoked potential in rat hippocampal slices. Brain Res. 1991;547:171–4.CrossRefPubMedGoogle Scholar
  3. Abe K, Sugiura M, Shoyama Y, Saito H. Crocin antagonizes ethanol inhibition of NMDA receptor-mediated responses in rat hippocampal neurons. Brain Res. 1998;787:132–8.CrossRefPubMedGoogle Scholar
  4. Aung HH, Wang CZ, Ni M, Fishbein A, Mehendale SR, Xie JT, et al. Crocin from Crocus sativus possesses significant antiproliferation effects on human colorectal cancer cells. Exp Oncol. 2007;29:175–80.PubMedPubMedCentralGoogle Scholar
  5. Batistatou A, Green LA. Aurintricarboxylic acid rescues PC-12 cells and sympathetic neurons from cell death caused by nerve growth factor deprivation: correlation with suppression of endonuclease activity. J Cell Biol. 1991;115:461–71.CrossRefPubMedGoogle Scholar
  6. Chryssanthi DG, Lamari FN, Iatrou G, Pylara A, Karamanos NK. Inhibition of breast cancer cell proliferation by style constituents of different Crocus species. Anticancer Res. 2007;27:357–62.PubMedGoogle Scholar
  7. Colombaioni L, Frago LM, Varela-Nieto I, Pesi R, Garcia-Gil M. Serum deprivation increases ceramide levels and induces apoptosis in undifferentiated HN9.10e cells. Neurochem Int. 2002;40:327–36.CrossRefPubMedGoogle Scholar
  8. Crowe MJ, Bresnahan JC, Shumann SL, Masters JN, Beattie MS. Apoptosis and delayed degeneration after spinal cord injury in rats and monkeys. Nat Med. 1997;3:73–6.CrossRefPubMedGoogle Scholar
  9. Cui Y, Wang YJ, Zhao DY, Shoyama Y, Li G, Liu C. Effects of crocin on Bcl-2, Bax and caspase-3 expression of PC-12 cells injured by H2O2. Nat Prod Res Dev. 2015;27:411–5.Google Scholar
  10. Gunnarsson R, Berne C, Hellerstrom C. Cytotoxic effects of streptozotocin and N-nitrosomethylurea on the pancreatic b-cell with special regards to the role of nicotinamide-adenine dinucleotide. Biochem J. 1974;140:487–94.CrossRefPubMedPubMedCentralGoogle Scholar
  11. Hill IE, MacManus JP, Rasquinha I, Tuor UI. DNA fragmentation indicative of apoptosis following unilateral cerebral hypoxia-ischemia in the neonatal rat. Brain Res. 1995;676:398–403.CrossRefPubMedGoogle Scholar
  12. Ishiyama J, Saito H, Abe K. Epidermal growth factor and basic fibroblast growth factor promote the generation of long-term potentiation in the dentate gyrus of anaesthetized rats. Neurosci Lett. 1991;12:403–11.Google Scholar
  13. Kawabata K, Tung NH, Shoyama Y, Sugie S, Mori T, Tanaka T. Dietary crocin inhibits colitis and colitis-associated colorectal carcinogenesis in male ICR mice. Evid Based Complement Alternat Med. 2012;2012:820415.CrossRefPubMedPubMedCentralGoogle Scholar
  14. Konoshima T, Takasaki M, Tokuda H, Morimoto S, Tanaka H, Kawata E, et al. Crocin and crocetin derivatives inhibit skin tumour promotion in mice. Phytother Res. 1998;12:400–4.CrossRefGoogle Scholar
  15. Lechtenberg M, Schepmann D, Niehues M, Hellenbrand N, Wunsch B. Quality and functionality of saffron: quality control, species assortment and affinity of extract and isolated saffron compounds to NMDA and sigma1 (sigma-1) receptors. Planta Med. 2008;74:764–72.CrossRefPubMedGoogle Scholar
  16. Lee IA, Lee JH, Baek NI, Kim DH. Anti-hyperlipidemic effect of crocin isolated from the fructus of Gardenia jasminoides and its metabolite Crocetin. Biol Pharm Bull. 2005;28:2106–10.CrossRefPubMedGoogle Scholar
  17. Lim JH, Wen TC, Matsuda S, Tanaka J, Maeda N, Peng H, et al. Protection of ischemic hippocampal neurons by ginsenoside Rb1, a main ingredient of ginseng root. Neurosci Res. 1997;28:191–200.CrossRefPubMedGoogle Scholar
  18. Liu B, Hannun YA. Inhibition of the neutral magnesium-dependent sphingomyelinase by glutathione. J Biol Chem. 1997;272:16381–7.Google Scholar
  19. Masaki M, Aritake K, Tanaka H, Shoyama Y, Huang ZL, Urade Y. Crocin promotes non-rapid eye movement sleep in mice. Mol Nutr Food Res. 2012;56:304–8.CrossRefPubMedGoogle Scholar
  20. Merrill Jr AH, van Echten G, Wang E, Sandhoff K. Fumonisin B1 inhibits sphingosine (sphinganine) N-acyltransferase and de novo sphingolipid biosynthesis in cultured neurons in situ. J Biol Chem. 1993;268:27299–306.PubMedGoogle Scholar
  21. Mesner PW, Winters TR, Green SH. Nerve growth factor withdrawal-induced cell death in neuronal PC-12 cells resembles that in sympathetic neurons. J Cell Biol. 1992;119:1669–80.CrossRefPubMedGoogle Scholar
  22. Morimoto S, Umezaki Y, Shoyama Y, Saito H, Nishi K, Irino N. Post-harvest degradation of carotenoid glucose esters in saffron. Planta Med. 1994;60:438–40.CrossRefPubMedGoogle Scholar
  23. Mukhopadhyay P, Rajesh M, Hasko G, Hawkins BJ, Madesh M, Pacher P. Simultaneous detection of apoptosis and mitochondrial superoxide production in live cells by flow cytometry and confocal microscopy. Nat Protoc. 2007;2:2295–301.CrossRefPubMedPubMedCentralGoogle Scholar
  24. Naghibi SM, Hosseini M, Khani F, Rahimi M, Vafaee F, Rakhshandeh H, et al. Effect of aqueous extract of Crocus sativus L. on morphine-induced memory impairment. Adv Pharmacol Sci. 2012;2012:494367. doi: 10.1155/2012/494367.PubMedPubMedCentralGoogle Scholar
  25. Nakajima A, Yamada K, Zou LB, Yan Y, Mizuno M, Nabeshima T. Interleukin-6 protects PC12 cells from 4-hydroxynonenal- induced cytotoxicity by increasing intracellular glutathione levels. Free Radic Biol Med. 2002;32:1324–32.CrossRefPubMedGoogle Scholar
  26. Ochiai T, Shimeno H, Mishima K, Iwasaki K, Fujiwara M, Tanaka H, et al. Protective effects of carotenoids from saffron on neuronal injury in vitro and in vivo. Biochim Biophys Acta. 2007;1770:578–84.CrossRefPubMedGoogle Scholar
  27. Ochiai T, Ohno S, Soeda S, Tanaka H, Shoyama Y, Shimeno H. Crocin prevents the death of rat pheochromocytoma (PC-12) cells by its antioxidant effects stronger than those of alpha-tocopherol. Neurosci Lett. 2004;362:61–4.CrossRefPubMedGoogle Scholar
  28. Oppenheim RW. Cell death during development of the nervous system. Annu Rev Neurosci. 1991;14:453–501.CrossRefPubMedGoogle Scholar
  29. Papandreou MA, Kanakis CD, Polissiou MG, Efthimiopoulos S, Cordopatis P. Inhibitory activity on amyloid-beta aggregation and antioxidant properties of Crocus sativus stigmas extract and its crocin constituents. J Agric Food Chem. 2006;54:8762–8.CrossRefPubMedGoogle Scholar
  30. Pettmann B, Henderson CE. Neuronal cell death. Neuron. 1998;20:633–47.CrossRefPubMedGoogle Scholar
  31. Pittman RN, Wang S, DiBenedetto AJ, Mills JC. A system for characterizing cellular and molecular events in programmed neuronal cell death. J Neurosci. 1993;13:3669–80.PubMedGoogle Scholar
  32. Rigobello MP, Scutari G, Boscolo R, Bindoli A. Inhibition of lipid peroxidation by S-nitrosoglutathione and copper. Free Radic Res. 2002;36:1071–7.CrossRefPubMedGoogle Scholar
  33. Rukenstein A, Rydel RE, Green LA. Multiple agents rescue PC-12 cells from serum-free cell death by translational transcription-independent mechanisms. J Neurosci. 1991;11:2552–63.PubMedGoogle Scholar
  34. Sheng L, Qian Z, Zheng S, Xi L. Mechanism of hypolipidemic effect of crocin in rats: crocin inhibits pancreatic lipase. Eur J Pharmacol. 2006;543:116–22.CrossRefPubMedGoogle Scholar
  35. Shimada K, Ishii N, Ohishi K, Ro JS, Nambara T. Structure-activity relationship of cardiac steroids having a double linked sugar and related compounds for the inhibition of Na+, K + -adenosine triphosphatase. J Pharmacobiodyn. 1986;9:755–9.CrossRefPubMedGoogle Scholar
  36. Soeda S, Ochiai T, Paopong L, Tanaka H, Shoyma Y, Shimeno H. Crocin suppresses tumor necrosis factor-α induced cell death of neuronally differentiated PC-12 cells. Life Sci. 2001;69:2887–98.CrossRefPubMedGoogle Scholar
  37. Sugiura M, Shoyama Y, Saito H, Abe K. The effects of ethanol and crocin on the induction of long-term potentiation in the CA1 region of rat hippocampal slices. Jpn J Pharmacol. 1995a;67:395–7.CrossRefPubMedGoogle Scholar
  38. Sugiura M, Shoyama Y, Saito H, Abe K. Crocin (crocetin di-gentiobiose ester) prevents the inhibitory effect of ethanol on long-term potentiation in the dentate gyrus in vivo. J Pharmacol Exp Ther. 1995b;271:703–7.Google Scholar
  39. Sugiura M, Shoyama Y, Saito H, Abe K. Ethanol extract of Crocus sativus L. antagonizes the inhibitory action of ethanol on hippocampal long-term potentiation in vivo. Phytother Res. 1995c;9:100–4.CrossRefGoogle Scholar
  40. Sugiura M, Shoyama Y, Saito H, Nishiyama N. Crocin improves the ethanol-induced impairment of learning behaviors of mice in passive avoidance tasks. Proc Jpn Acad. 1995d;71:319–24.CrossRefGoogle Scholar
  41. Sugiura M, Shoyama Y, Zhang YX, Saito H, Abe K. Effects of ethanol extract of Crocus sativus L. and its purified chemicals on learning behavior and long-term potentiation. Int Acad Biomed Drug Res. 1996;11:270–6.Google Scholar
  42. Takemoto Y, Ueyama T, Saito H, Horio S, Shoji J, Yahara S, et al. Potentiation of nerve growth factor-mediated nerve fiber production in organ cultures of chicken embryonic ganglia by ginseng saponins: structure-activity relationship. Chem Pharmacol Bull. 1984;32:3128–33.CrossRefGoogle Scholar
  43. Trease GE, Evans WC. Pharmacognosy edt. Baltimore: Williams and Wilkins Company; 2002. p. 626.Google Scholar
  44. Tung NH, Shoyama Y. New minor glycoside component from saffron. J Nat Med. 2013;67:672–6.CrossRefPubMedGoogle Scholar
  45. Urata Y, Yamamoto H, Goto S, Tsushima H, Akazawa S, Yamashita S, et al. Long exposure to high glucose concentration impairs the responsive expression of c-glutamylcysteine synthase by interleukin-1b and tumor necrosis factor-a in mouse endothelial cells. J Biol Chem. 1996;271:15146–52.CrossRefPubMedGoogle Scholar
  46. Vakili A, Einali MR, Bandegi AR. Protective effect of crocin against cerebral ischemia in a dose-dependent manner in a rat model of ischemic stroke. J Stroke Cerebrovasc Dis. 2014;23:106–13.CrossRefPubMedGoogle Scholar
  47. Verheij M, Bose R, Lin XH, Yao B, Jarvis WD, Grant S, et al. Requirement for ceramide-initiated SAPF/JNK signaling in stress-induced apoptosis. Nature. 1996;380:75–9.CrossRefPubMedGoogle Scholar
  48. Wang E, Norred WP, Bacon CW, Riley RT, Merrill AH. Inhibition of sphingolipid biosynthesis by fumonisins: implications for diseases associated with Fusarium moniliforme. J Biol Chem. 1991;266:14486–90.PubMedGoogle Scholar
  49. Xu GL, Yu SQ, Gong ZN, Zhang SQ. Study of the effect of crocin on rat experimental hyperlipidemia and the underlying mechanisms. Zhongguo Zhong Yao Za Zhi. 2005;30:369–72.PubMedGoogle Scholar
  50. Xu GL, Qian ZY, Yu SQ, Gong ZN, Shen XC. Evidence of crocin against endothelial injury induced by hydrogen peroxide in vitro. J Asian Nat Prod Res. 2006;8:79–85.CrossRefPubMedGoogle Scholar
  51. Xu GL, Li G, Ma HP, Zhong H, Liu F. Preventive effect of crocin in inflamed animals and in LPS-challenged RAW 264.7 cells. J Agric Food Chem. 2009;57:8325–30.CrossRefPubMedGoogle Scholar
  52. Xuan L, Tanaka H, Xu Y, Shoyama Y. Preparation of monoclonal antibody against crocin and its characterization. Cytotechnology. 1999;29:65–70.CrossRefPubMedPubMedCentralGoogle Scholar
  53. Yoshimura S, Banno Y, Nakashima S, Takenaka K, Sakai H, Nishimura Y, et al. Ceramide formation leads to caspase-3 activation during hypoxic PC-12 cell death. J Biol Chem. 1998;273:6921–7.CrossRefPubMedGoogle Scholar
  54. Yoshimura S, Banno Y, Nakashima S, Hayashi K, Yamakawa H, Sawada M, et al. Inhibition of neutral sphingomyelinase activation and ceramide formation by glutathione in hypoxic PC-12 cell death. J Neurochem. 1999;73:675–83.CrossRefPubMedGoogle Scholar
  55. Zhang XY, Shoyama Y, Sugiura M, Saito H. Acute effects of Crocus sativus L. on passive avoidance performance in mice. Biol Pharm Bull. 1994a;17:217–21.CrossRefPubMedGoogle Scholar
  56. Zhang Y, Shoyama Y, Sugiura M, Saito H. Effects of Crocus sativus L. on the ethanol-induced impairment of passive avoidance performances in mice. Biol Pharm Bull. 1994b;17:217–21.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  • Shinji Soeda
    • 1
  • Kosuke Aritake
    • 2
  • Yoshihiro Urade
    • 2
  • Hiroshi Sato
    • 3
  • Yukihiro Shoyama
    • 3
    Email author
  1. 1.Faculty of Pharmaceutical ScienceFukuoka UniversityFukuokaJapan
  2. 2.International Institute for Integrative Sleep MedicineTsukuba UniversityTsukubaJapan
  3. 3.Faculty of Pharmaceutical ScienceNagasaki International UniversityNagasakiJapan

Personalised recommendations