Review on Pharmacological Active Saffron and Crocin
Main Article Content
Abstract
Saffron has been used for medicinal, coloring, aroma and flavoring purposes for thousands of years. In recent years, research on the pharmacological activity of saffron has become increasingly active, with particular attention being paid to saffron's anti-cognitive activity. Saffron is known to contain a number of components, among which crocetin glycosides, i.e. crocin has been found to be the active substance. Anti-crocin monoclonal antibody having wide cross-reactivity was prepared and carried out immunostaining using PC-12 cells to confirm the uptake of crocin into the cells. Saffron extract and/or crocin ameliorated learning and memory performance inhibited by ethanol in mice. Long term potentiation blocked by ethanol shows recovery by the addition of saffron extract and/or crocin to mouse hippocampus tissues. Mice injected with crocin expressed non-rem sleeping even during an activating period. The clinical trial of saffron extract ameliorated symptoms in Alzheimer’s patients. A Chinese formula prescribed with saffron reversed brain vascular dementia. PC-12 cells were used to study the mechanism of cell death by apoptosis. Crocin showed strong anti-oxidant and anti-inflammatory activities. Crocin decreased the level of ceramide by inhibition of sphingomyelinase activity and increased glutathione concentration resulting in inhibition of apoptosis. From these findings saffron and crocin can potentially be applied for treatment and prevention of dementia in patients.
Keywords:
Crocus sativus, crocin, quality control, anti-cognitive activity, non-LEM sleeping
Article Details
How to Cite
SUGIURA, Minoru et al.
Review on Pharmacological Active Saffron and Crocin.
Medical Research Archives, [S.l.], v. 11, n. 8, sep. 2023.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/4396>. Date accessed: 04 dec. 2024.
doi: https://doi.org/10.18103/mra.v11i8.4396.
Section
Review Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
1. Samarghandian S. Borji A. Anticarcinogenic effect of saffron (Crocus sativus L.) and its ingredients. Pharmacognosy Research. 2014(6);99–107.
2. Battle DE. Diagnostic and Statistical Manual of Mental Disorders (DSM). Codas 2013(25);191–192. doi:10.1590/s2317-17822013000200017
3. National Institute of Public Health (2015). MHLW grants system [in Japanese].
4. OECD homepage, Prevalence of dementia among the population aged 60 years and over, 2009.
5. Orgogozo JM. Dartigues JF. Lafont S. Letenneur L. Commenges D. Salamon R. Wine Consump¬tion and Dementia in the Elderly: a Prospective Community Study in the Bordeaux Area. Revue Neurologique (Paris) 1997(153);185–192.
6. Kalmijn S. Launer LJ. Ott A. Witteman JC. Hof-man A. Breteler MM. Dietary Fat Intake and the Risk of Incident Dementia in the Rotterdam Study. Annals of Neurology. 1997(42);776–782. doi:10.1002/ana.410420514
7. Natarajan S. Shunmugiah KP. Kasi PD. Plants Traditionally Used in Age-Related Brain Disor-ders (Dementia): an Ethanopharmacological Survey. Pharmaceutical Biology. 2013(51);492–523. doi:10.3109/13880209.2012.738423
8. Ho YS. So KF. Chang RC. Drug Discovery from Chinese Medicine against Neurodegeneration in Alzheimer’s and Vascular Dementia. Chinese Medicine. 2011(6); 15. doi:10.1186/1749-8546-6-15
9. Heinrich M. Teoh HL. Galanthamine from snow¬drop-the development of a modern drug against Alzheimer's disease from local Cauca-sian knowledge. Journal of Ethnopharmacol-ogy. 2004(92):147–62.
10. Samarghandian S. Borji A. Anticarcinogenic ef¬fect of saffron (Crocus sativus L.) and its ingre¬dients. Pharmacognosy Research. 2014(6);99–107.
11. Ríos JL. Recio MC. Giner RM. An update review of saffron and its active constituents. Phytother¬apy Research. 1996(10);189-193.
12. Zarghami NS. Heinz DE. Monoterpene alde-hydes and isophorone-related compounds of saffron. Phytochemistry. 1971(10);2755-2761.
13. Liakopoulou-Kyriakides M. Kyriakidis D. Crocus sativus-biological active constituents. Studies in Natural Products Chemistry. 2002(16);293-312.
14. Mykhailenko O. Kovalyov V. Goryacha O. Bio¬logically active compounds and pharmacologi¬cal activities of species of the genus Crocus: A review. Phytochemistry. 2019(162);56-89.
15. Tung NH. Shoyama Y. New minor glycoside components from saffron. Journal of Natural Medicine. 2013(67);672-676.
16. Ríos JL. Recio MC. Giner RM. An update review of saffron and its active constituents. Phytother¬apy Research. 1996(10)189-193.
17. Morimoto S. Umezaki Y. Shoyama Y. Saito H. Nishi K. Irino N. Post-harvest degradation of ca¬rotenoid glucose esters in saffron. Planta Medica. 1994(60);438-440.
18. Sugiura M. Shoyama Y. Saito H. Crocin im-proves the ethanol-inducd impairment of lean-ing behaviors and mice in in passive avoidance tasks. Proceedings of the Japan Academy Se¬ries B: Physical and Biological Sciences. 1995(71);319-324.
19. Masaki M. Aritake K. Tanaka H. Shoyama Y. Huang ZL. Urade Y. Crocin promotes non-rapid eye movement sleep in mice. Molecular Nutrition and Food Research. 2012(56);304-308.
20. Bolandi M. Flavour and colour changes during processing and storage of saffron (Crocus sa-tivus L.), Developments in Food Science. 2006(43);323-326.
21. Caballero-Ortega H. Pereda R. HPLC quantifi-cation of major active components from 11 dif¬ferent saffron (Crocus sativus L.) sources. Food Chemistry. 2007(100);1126-1131. doi.10.1016/j.foodchem.2005.11.020
22. Ordoudi SA. Cagliani LR. Lalou S. Naziri E. Tsimidou MZ. Consonni R. 1H NMR-based metabolomics of saffron reveals markers for its quality deterioration. Food Research Interna-tional. 2015(70); 1-6.
23. Alehosseini A. Gómez-ascaraque LG. Ghorani B. López-Rubio A. Stabilization of a saffron ex¬tract through its encapsulation within electro¬spun/electrosprayed zein structures. LWT. 2019(113);October 2019, 108280. doi.org/10.1016/j.lwt.2019.108280).
24. Sugiura M. Shoyama Y. Saito H. Crocin (crocetin di-gentiobiose ester) prevents the inhibitory ef¬fect of ethanol on long-term potentiation in the dentate gyrus in vivo. Journal of Pharmacology and Experimental Therapeutics. 1994(271);703-707
25. Shimada K. Ishii N. Ohishi K. Structure-activity relationship of cardiac steroids having a double linked sugar and related compounds for the in¬hibition of Na+,K +-adenosine triphosphatase. Journal of Pharmacobio-Dynamics. 1986;755-759.
26. Takemoto T. Ueyama T. Saito H. Potentiation of nerve growth factor-mediated nerve fiber pro¬duction in organ cultures of chicken embryonic ganglia by ginseng saponins: structure-activity relationship. Chemical and Pharmaceutical Bul¬letin. 1984(32);3128-3133.
27. Abe H. Sakaguchi M. Konishi H. The effects of saikosaponins on biological membranes. 1. The relationship between the structures of sai-kosaponins and haemolytic activity. Planta Medica. 1978(34);160-166.
28. Voutquenne L. Lavaud C. Massiot G. Structure-activity relationships of haemolytic saponins. Pharmaceutical Biology. 2002(40);253-262.
29. Shoyama Y. Studies on natural products using monoclonal antibodies: a review. Antibodies. 2021(10); 43 doi.org/10.3390/an-tib10040043
30. Shan S. Tanaka H. Shoyama Y. Enzyme-linked immunosorbent assay for glycyrrhizin using anti-glycyrrhizin monoclonal antibody and a new eastern blotting for glucronides of glycyr-rhetinic acid. Analytical Chemistry. 2001(73); 5784-5790.
31. Shoyama Y. Sakata R. Isobe R. Murakami H. Kusai A. Nojima K. Direct determination of for-skolin-bovine serum albumin conjugate by ma-trix-assisted laser desorption ionization mass spectrometry. Organic Mass Spectroscopy. 1993(28);987-988.
32. Xuan L. Tanaka H. Xu Y. Shoyama Y. Prepara-tion of monoclonal antibody against crocin and its characterization. Cytotechnology. 1999(29);65-70.
33. Ochiai T. Ohno S. Soeda S. Tanaka H. Shoyama Y. Shimeno H. Crocin prevents the death of rat pheochromyctoma (PC-12) cells by its antioxi¬dant effects stronger than those of α-tocoph¬erol. Neuroscience Letter. 2004(362);61-64. doi: 10.1016/j.neulet.2004.02.067.
34. Papandreou MA. Kanakis CD. Polissiou MG. Efthimiopoulos S. Cordopatis P. Margarity M. (2006). Inhibitory Activity on Amyloid-Beta Ag¬gregation and Antioxidant Properties of Crocus Sativus Stigmas Extract and its Crocin Constitu¬ents. Journal of Agricultural and Food Infor¬mation. 2006(54);8762–8768. doi:10.1021/jf061932a
35. Roustazade R. Radahmadi M. Yazdani Y. Ther¬apeutic Effects of Saffron Extract on Different Memory Types, Anxiety, and Hippocampal BDNF and TNF-α Gene Expressions in Sub-chronically Stressed Rats. Nutritional Neurosci¬ence. 2021(25);192–206. doi:10.1080/1028415X.2021.1943138
36. Zhang Y. Shoyama Y. Sugiura M. Saito H. Biolog¬ical and Pharmaceutical Bulletin. 1994(17);217-221.
37. Sugiura M. Shoyama Y. Saito H. Kazuo Abe. Ethanol extract of Crocus sativus L. antagonizes the inhibitory action of ethanol on hippocampal long-term potentiation in vivo. Phytotherapy Research.1995(9);100-104.
38. Sugiura M. Shoyama Y. Saito H. Kazuo Abe. The effects of ethanol and crocin on the induction of long-term potentiation in the region of rat hippocampal slices, Japanese Journal of Pharmacology. 1995(67);395-397. doi: 10.1254/jjp.67.395.)
39. Zhang Y. Shoyama Y. Sugiura M. Saito H. Effects of Crocus sativus L. on the Ethanol-Induced Impairment of Passive Avoidance Performances in Mice. Biological and Pharmaceutical Bulletin. 1994(17);217-221.
40. Takeda R. Yamamoto K., Tokuda M. Koga J. Higaki M. Kondo S. Yamashita A. Sawada A. Improvement in quality of sleep by the intake of saffron derived crocin and safranal-A randomized, double blind, placebo controlled, parallel group trial. Japanese Pharmacology and Therapeutics. 2020(48);497-504.
41. Nishida A. Fujita T. Nagaregawa Y. Shoyama Y. Ohnuki K., Shimizu K. Sleep enhancement by saffron extract affron in randomized control trial. Japanese Pharmacology and Therapeutics. (2018)46;1407-1415.
42. Matsuhashi T. The Effect of Saffron for Sleep Induction. Journal of New Remedies and Clinics (1993)42;595–597.
43. Fujii S. Morita Y. Ohta T. Uto T. Shoyama Y. Saffron (Crucus sativus L.) as a valuable spice and food product: a narrative review Longhua Chinese Medicine. 2022(5);18 | https://dx.doi.org/10.21037/lcm-2
44. Department of Health and Human Services; Subchapter B - Food For Human Consumption (Continued); Part 182.10 - Substances Generally Recognized as Safe (GRAS). Available online: https://www.accessdata.fda.gov/scripts/ cdrh/cfdocs/cfcfr/cfrsearch.cfm?fr=182
45. Saeedi M. Rashidy-Pour A. Association between chronic stress and Alzheimer's disease: Therapeutic effects of Saffron. Biomedical and Pharmacotherapy. 2021(133);110995.
46. Akhondzadeh S. Shafiee-Sabet M. Harirchian MH. A 22-week, multicenter, randomized, double-blind controlled trial of Crocus sativus in the treatment of mild to-moderate Alzheimer's disease. Psychopharmacology (Berl) 2010(207);637-643.
47. Kella G. Raob A. Beccariaa G. Claytonc P. Manuel A. Prodanove M. Affron® a novel saffron extract（Crocus sativus L.） improves mood in healthy adults over 4 weeks in a double-blind, parallel, randomized, placebo controlled clinical trial. Complementary Therapies in Medicine. 2017(23);58-64.
48. Li J. Huang Q. Chen J. Neuroprotective Potentials of Panax Ginseng Against Alzheimer's Disease: A Review of Preclinical and Clinical Evidences. Frontier Pharmacology. 2021(12);688490. 80
49. Heo JH. Lee ST. Chu K. Heat-processed ginseng enhances the cognitive function in patients with moderately severe Alzheimer's disease. Nutritional Neuroscience. 2012(15);278-282.
50. Heo JH. Lee ST. Chu K. An open-label trial of Korean red ginseng as an adjuvant treatment for cognitive impairment in patients with Alzheimer's disease. European Journal of Neurology. 2008(15);865-868.
51. Rapp M. Burkart M. Kohlmann T. Bohlken J. Similar treatment outcomes with Ginkgo biloba extract EGb 761 and donepezil in Alzheimer’s dementia in very old age: a retrospective observational study. International Journal of Clinical Pharmacology and Therapeutics. 2018(3);130–133. doi: 10.5414/CP203103.
52. Ihl R. Bachinskaya N. Korczyn AD. Vakhapova V. Tribanek M. Hoerr R. Napryeyenko O. Efficacy and safety of a once-daily formulation of Ginkgo extract E G b 761 in dementia with neuropsychiatric features: a randomized controlled trial. International Journal of Geriatric Psychiatry. 2011(11);1186-1194. doi: 10.1002/gps.2662.
53. Clostre F. Ginkgo biloba extract (EGb 761). State of knowledge in the dawn of the year. Annales Pharmaceutiques Francaises. 1999(57) ;1S8-88.
54. Jia J., Wei C. Chen S. Li F. Tang Y. Qui W. Efficacy and safety of the compound Chinese medicine SaiLuoTong in vascular dementia: A randomized clinical trial. Alzheimer’s Dementia. 2018(4);108-117. doi: 10.1016/j.trci.2018.02.004.
55. Soeda S. Ochiai T. Shimeno H. Saito H. Abe K. Tanaka H. Shoyama Y. Pharmacological activities of crocin in saffron, Journal of Natural Medicine. 2007(61);102-111. doi: 10.1107/s11418-006-0120-9.
56. Ochiai T. Ohno S. Soeda S. Tanaka H. Shoyama Y. Shimeno H. Crocin prevents the death of rat pheochromyctoma (PC-12) cells by its antioxidant effects stronger than those of α-tocopherol. Neuroscience Letter. 2004(362); 61-64.
57. Ochiai T. Soeda S. Ohno S. Tanaka H. Shoyama Y. Shimeno H. Crocin prevents the death of PC-12 cells through sphingomyelinase-ceramide signaling by increasing glutathione synthesis. Neurochemistry International. 2004(44);321-330.
58. Colombaioni L. Frago LM. Varela-Nieto I. Pesi R. Garcia-Gil M. (2002). Serum deprivation increases ceramide levels and induces apoptosis in undifferentiated HN9.10e cells. Neurochemical International. 2002(49); 327-336. doi: 10.1016/s0197-0186(01)00090-0.
59. Verheij M. Bose R. Lin XH. Yao B. Jarvis WD. Grant S. Requirement for Ceramide-Initiated SAPK/JNK Signalling in Stress-Induced Apoptosis. Nature. 1996(380);75–79. doi:10.1038/380075a0.
60. Rukenstein A. Rydel RE. Greene LA. Multiple Agents rescue PC12 Cells from Serum-free Cell Death by Translation- and Transcription independent Mechanisms. Journal of Neuroscience. 1991(11);2552–2563. doi:10. 1523/JNEUROSCI.11-08-02552.1991
61. Soeda S. Ochiai T. Paopong L. Tanaka H. Shoyama Y. Shimeno H. Crocin suppresses tumor necrosis factor-induced cell death of neuronally differentiated PC-12 cells. Life Science. 2001(69);2887-2898.
62. Lymperopoulou CD. Lamari FN. Saffron safety in humans: lessons from the animal and clinical studies. Journal of Medicinal and Aromatic Plants. 2015(4 5) doi: 10.4172/2167-0412.1000e164.
63. Abe K. Sugiura M. Shoyama Y. Saito H. Crocin Antagonizes Ethanol Inhibition of NMDA Receptor-Mediated Responses in Rat Hippocampal Neurons. Brain Research. 1998(787);132–138. doi:10.1016/s0006-8993(97) 01505-9
64. Kawabata K. Tung NH. Shoyama Y. Sugie S. Mori T. Tanaka T. Dietary Crocin Inhibits Colitis and Colitis-Associated Colorectal Carcino-genesis in Male ICR Mice. Evidence-Based Complementary and Alternative Medicine. (2012)820415. doi:10.1155/2012/820415.toda
65. Ochiai T. Shimeno H. Mishima K. Iwasaki K. Fujiwara M. Tanaka H. Shoyama Y. Toda A. Eyanagi R. Soeda S. Protective effects of carotenoids from saffron on neuronal injury in vitro and in vivo. Biochimica ET Biophysica Acta. 2007(1770);578-584.
66. Butnariu M. Quispe C. Herrera-Bravo J. Sharifi-Rad J. Singh L. Aborehab NM. Bouyahya A. Venditti A. Sen S. Acharya K. Bashiry M. Ezzat SM. The Pharmacological Activities of Crocus sativus L.: A Review Based on the Mechanisms and Therapeutic Opportunities of its phytoconstituents. Oxidative Medicine and Cellular Longevity. 2022(2022); 28214821. doi.org/10.1155/2022/82148.
2. Battle DE. Diagnostic and Statistical Manual of Mental Disorders (DSM). Codas 2013(25);191–192. doi:10.1590/s2317-17822013000200017
3. National Institute of Public Health (2015). MHLW grants system [in Japanese].
4. OECD homepage, Prevalence of dementia among the population aged 60 years and over, 2009.
5. Orgogozo JM. Dartigues JF. Lafont S. Letenneur L. Commenges D. Salamon R. Wine Consump¬tion and Dementia in the Elderly: a Prospective Community Study in the Bordeaux Area. Revue Neurologique (Paris) 1997(153);185–192.
6. Kalmijn S. Launer LJ. Ott A. Witteman JC. Hof-man A. Breteler MM. Dietary Fat Intake and the Risk of Incident Dementia in the Rotterdam Study. Annals of Neurology. 1997(42);776–782. doi:10.1002/ana.410420514
7. Natarajan S. Shunmugiah KP. Kasi PD. Plants Traditionally Used in Age-Related Brain Disor-ders (Dementia): an Ethanopharmacological Survey. Pharmaceutical Biology. 2013(51);492–523. doi:10.3109/13880209.2012.738423
8. Ho YS. So KF. Chang RC. Drug Discovery from Chinese Medicine against Neurodegeneration in Alzheimer’s and Vascular Dementia. Chinese Medicine. 2011(6); 15. doi:10.1186/1749-8546-6-15
9. Heinrich M. Teoh HL. Galanthamine from snow¬drop-the development of a modern drug against Alzheimer's disease from local Cauca-sian knowledge. Journal of Ethnopharmacol-ogy. 2004(92):147–62.
10. Samarghandian S. Borji A. Anticarcinogenic ef¬fect of saffron (Crocus sativus L.) and its ingre¬dients. Pharmacognosy Research. 2014(6);99–107.
11. Ríos JL. Recio MC. Giner RM. An update review of saffron and its active constituents. Phytother¬apy Research. 1996(10);189-193.
12. Zarghami NS. Heinz DE. Monoterpene alde-hydes and isophorone-related compounds of saffron. Phytochemistry. 1971(10);2755-2761.
13. Liakopoulou-Kyriakides M. Kyriakidis D. Crocus sativus-biological active constituents. Studies in Natural Products Chemistry. 2002(16);293-312.
14. Mykhailenko O. Kovalyov V. Goryacha O. Bio¬logically active compounds and pharmacologi¬cal activities of species of the genus Crocus: A review. Phytochemistry. 2019(162);56-89.
15. Tung NH. Shoyama Y. New minor glycoside components from saffron. Journal of Natural Medicine. 2013(67);672-676.
16. Ríos JL. Recio MC. Giner RM. An update review of saffron and its active constituents. Phytother¬apy Research. 1996(10)189-193.
17. Morimoto S. Umezaki Y. Shoyama Y. Saito H. Nishi K. Irino N. Post-harvest degradation of ca¬rotenoid glucose esters in saffron. Planta Medica. 1994(60);438-440.
18. Sugiura M. Shoyama Y. Saito H. Crocin im-proves the ethanol-inducd impairment of lean-ing behaviors and mice in in passive avoidance tasks. Proceedings of the Japan Academy Se¬ries B: Physical and Biological Sciences. 1995(71);319-324.
19. Masaki M. Aritake K. Tanaka H. Shoyama Y. Huang ZL. Urade Y. Crocin promotes non-rapid eye movement sleep in mice. Molecular Nutrition and Food Research. 2012(56);304-308.
20. Bolandi M. Flavour and colour changes during processing and storage of saffron (Crocus sa-tivus L.), Developments in Food Science. 2006(43);323-326.
21. Caballero-Ortega H. Pereda R. HPLC quantifi-cation of major active components from 11 dif¬ferent saffron (Crocus sativus L.) sources. Food Chemistry. 2007(100);1126-1131. doi.10.1016/j.foodchem.2005.11.020
22. Ordoudi SA. Cagliani LR. Lalou S. Naziri E. Tsimidou MZ. Consonni R. 1H NMR-based metabolomics of saffron reveals markers for its quality deterioration. Food Research Interna-tional. 2015(70); 1-6.
23. Alehosseini A. Gómez-ascaraque LG. Ghorani B. López-Rubio A. Stabilization of a saffron ex¬tract through its encapsulation within electro¬spun/electrosprayed zein structures. LWT. 2019(113);October 2019, 108280. doi.org/10.1016/j.lwt.2019.108280).
24. Sugiura M. Shoyama Y. Saito H. Crocin (crocetin di-gentiobiose ester) prevents the inhibitory ef¬fect of ethanol on long-term potentiation in the dentate gyrus in vivo. Journal of Pharmacology and Experimental Therapeutics. 1994(271);703-707
25. Shimada K. Ishii N. Ohishi K. Structure-activity relationship of cardiac steroids having a double linked sugar and related compounds for the in¬hibition of Na+,K +-adenosine triphosphatase. Journal of Pharmacobio-Dynamics. 1986;755-759.
26. Takemoto T. Ueyama T. Saito H. Potentiation of nerve growth factor-mediated nerve fiber pro¬duction in organ cultures of chicken embryonic ganglia by ginseng saponins: structure-activity relationship. Chemical and Pharmaceutical Bul¬letin. 1984(32);3128-3133.
27. Abe H. Sakaguchi M. Konishi H. The effects of saikosaponins on biological membranes. 1. The relationship between the structures of sai-kosaponins and haemolytic activity. Planta Medica. 1978(34);160-166.
28. Voutquenne L. Lavaud C. Massiot G. Structure-activity relationships of haemolytic saponins. Pharmaceutical Biology. 2002(40);253-262.
29. Shoyama Y. Studies on natural products using monoclonal antibodies: a review. Antibodies. 2021(10); 43 doi.org/10.3390/an-tib10040043
30. Shan S. Tanaka H. Shoyama Y. Enzyme-linked immunosorbent assay for glycyrrhizin using anti-glycyrrhizin monoclonal antibody and a new eastern blotting for glucronides of glycyr-rhetinic acid. Analytical Chemistry. 2001(73); 5784-5790.
31. Shoyama Y. Sakata R. Isobe R. Murakami H. Kusai A. Nojima K. Direct determination of for-skolin-bovine serum albumin conjugate by ma-trix-assisted laser desorption ionization mass spectrometry. Organic Mass Spectroscopy. 1993(28);987-988.
32. Xuan L. Tanaka H. Xu Y. Shoyama Y. Prepara-tion of monoclonal antibody against crocin and its characterization. Cytotechnology. 1999(29);65-70.
33. Ochiai T. Ohno S. Soeda S. Tanaka H. Shoyama Y. Shimeno H. Crocin prevents the death of rat pheochromyctoma (PC-12) cells by its antioxi¬dant effects stronger than those of α-tocoph¬erol. Neuroscience Letter. 2004(362);61-64. doi: 10.1016/j.neulet.2004.02.067.
34. Papandreou MA. Kanakis CD. Polissiou MG. Efthimiopoulos S. Cordopatis P. Margarity M. (2006). Inhibitory Activity on Amyloid-Beta Ag¬gregation and Antioxidant Properties of Crocus Sativus Stigmas Extract and its Crocin Constitu¬ents. Journal of Agricultural and Food Infor¬mation. 2006(54);8762–8768. doi:10.1021/jf061932a
35. Roustazade R. Radahmadi M. Yazdani Y. Ther¬apeutic Effects of Saffron Extract on Different Memory Types, Anxiety, and Hippocampal BDNF and TNF-α Gene Expressions in Sub-chronically Stressed Rats. Nutritional Neurosci¬ence. 2021(25);192–206. doi:10.1080/1028415X.2021.1943138
36. Zhang Y. Shoyama Y. Sugiura M. Saito H. Biolog¬ical and Pharmaceutical Bulletin. 1994(17);217-221.
37. Sugiura M. Shoyama Y. Saito H. Kazuo Abe. Ethanol extract of Crocus sativus L. antagonizes the inhibitory action of ethanol on hippocampal long-term potentiation in vivo. Phytotherapy Research.1995(9);100-104.
38. Sugiura M. Shoyama Y. Saito H. Kazuo Abe. The effects of ethanol and crocin on the induction of long-term potentiation in the region of rat hippocampal slices, Japanese Journal of Pharmacology. 1995(67);395-397. doi: 10.1254/jjp.67.395.)
39. Zhang Y. Shoyama Y. Sugiura M. Saito H. Effects of Crocus sativus L. on the Ethanol-Induced Impairment of Passive Avoidance Performances in Mice. Biological and Pharmaceutical Bulletin. 1994(17);217-221.
40. Takeda R. Yamamoto K., Tokuda M. Koga J. Higaki M. Kondo S. Yamashita A. Sawada A. Improvement in quality of sleep by the intake of saffron derived crocin and safranal-A randomized, double blind, placebo controlled, parallel group trial. Japanese Pharmacology and Therapeutics. 2020(48);497-504.
41. Nishida A. Fujita T. Nagaregawa Y. Shoyama Y. Ohnuki K., Shimizu K. Sleep enhancement by saffron extract affron in randomized control trial. Japanese Pharmacology and Therapeutics. (2018)46;1407-1415.
42. Matsuhashi T. The Effect of Saffron for Sleep Induction. Journal of New Remedies and Clinics (1993)42;595–597.
43. Fujii S. Morita Y. Ohta T. Uto T. Shoyama Y. Saffron (Crucus sativus L.) as a valuable spice and food product: a narrative review Longhua Chinese Medicine. 2022(5);18 | https://dx.doi.org/10.21037/lcm-2
44. Department of Health and Human Services; Subchapter B - Food For Human Consumption (Continued); Part 182.10 - Substances Generally Recognized as Safe (GRAS). Available online: https://www.accessdata.fda.gov/scripts/ cdrh/cfdocs/cfcfr/cfrsearch.cfm?fr=182
45. Saeedi M. Rashidy-Pour A. Association between chronic stress and Alzheimer's disease: Therapeutic effects of Saffron. Biomedical and Pharmacotherapy. 2021(133);110995.
46. Akhondzadeh S. Shafiee-Sabet M. Harirchian MH. A 22-week, multicenter, randomized, double-blind controlled trial of Crocus sativus in the treatment of mild to-moderate Alzheimer's disease. Psychopharmacology (Berl) 2010(207);637-643.
47. Kella G. Raob A. Beccariaa G. Claytonc P. Manuel A. Prodanove M. Affron® a novel saffron extract（Crocus sativus L.） improves mood in healthy adults over 4 weeks in a double-blind, parallel, randomized, placebo controlled clinical trial. Complementary Therapies in Medicine. 2017(23);58-64.
48. Li J. Huang Q. Chen J. Neuroprotective Potentials of Panax Ginseng Against Alzheimer's Disease: A Review of Preclinical and Clinical Evidences. Frontier Pharmacology. 2021(12);688490. 80
49. Heo JH. Lee ST. Chu K. Heat-processed ginseng enhances the cognitive function in patients with moderately severe Alzheimer's disease. Nutritional Neuroscience. 2012(15);278-282.
50. Heo JH. Lee ST. Chu K. An open-label trial of Korean red ginseng as an adjuvant treatment for cognitive impairment in patients with Alzheimer's disease. European Journal of Neurology. 2008(15);865-868.
51. Rapp M. Burkart M. Kohlmann T. Bohlken J. Similar treatment outcomes with Ginkgo biloba extract EGb 761 and donepezil in Alzheimer’s dementia in very old age: a retrospective observational study. International Journal of Clinical Pharmacology and Therapeutics. 2018(3);130–133. doi: 10.5414/CP203103.
52. Ihl R. Bachinskaya N. Korczyn AD. Vakhapova V. Tribanek M. Hoerr R. Napryeyenko O. Efficacy and safety of a once-daily formulation of Ginkgo extract E G b 761 in dementia with neuropsychiatric features: a randomized controlled trial. International Journal of Geriatric Psychiatry. 2011(11);1186-1194. doi: 10.1002/gps.2662.
53. Clostre F. Ginkgo biloba extract (EGb 761). State of knowledge in the dawn of the year. Annales Pharmaceutiques Francaises. 1999(57) ;1S8-88.
54. Jia J., Wei C. Chen S. Li F. Tang Y. Qui W. Efficacy and safety of the compound Chinese medicine SaiLuoTong in vascular dementia: A randomized clinical trial. Alzheimer’s Dementia. 2018(4);108-117. doi: 10.1016/j.trci.2018.02.004.
55. Soeda S. Ochiai T. Shimeno H. Saito H. Abe K. Tanaka H. Shoyama Y. Pharmacological activities of crocin in saffron, Journal of Natural Medicine. 2007(61);102-111. doi: 10.1107/s11418-006-0120-9.
56. Ochiai T. Ohno S. Soeda S. Tanaka H. Shoyama Y. Shimeno H. Crocin prevents the death of rat pheochromyctoma (PC-12) cells by its antioxidant effects stronger than those of α-tocopherol. Neuroscience Letter. 2004(362); 61-64.
57. Ochiai T. Soeda S. Ohno S. Tanaka H. Shoyama Y. Shimeno H. Crocin prevents the death of PC-12 cells through sphingomyelinase-ceramide signaling by increasing glutathione synthesis. Neurochemistry International. 2004(44);321-330.
58. Colombaioni L. Frago LM. Varela-Nieto I. Pesi R. Garcia-Gil M. (2002). Serum deprivation increases ceramide levels and induces apoptosis in undifferentiated HN9.10e cells. Neurochemical International. 2002(49); 327-336. doi: 10.1016/s0197-0186(01)00090-0.
59. Verheij M. Bose R. Lin XH. Yao B. Jarvis WD. Grant S. Requirement for Ceramide-Initiated SAPK/JNK Signalling in Stress-Induced Apoptosis. Nature. 1996(380);75–79. doi:10.1038/380075a0.
60. Rukenstein A. Rydel RE. Greene LA. Multiple Agents rescue PC12 Cells from Serum-free Cell Death by Translation- and Transcription independent Mechanisms. Journal of Neuroscience. 1991(11);2552–2563. doi:10. 1523/JNEUROSCI.11-08-02552.1991
61. Soeda S. Ochiai T. Paopong L. Tanaka H. Shoyama Y. Shimeno H. Crocin suppresses tumor necrosis factor-induced cell death of neuronally differentiated PC-12 cells. Life Science. 2001(69);2887-2898.
62. Lymperopoulou CD. Lamari FN. Saffron safety in humans: lessons from the animal and clinical studies. Journal of Medicinal and Aromatic Plants. 2015(4 5) doi: 10.4172/2167-0412.1000e164.
63. Abe K. Sugiura M. Shoyama Y. Saito H. Crocin Antagonizes Ethanol Inhibition of NMDA Receptor-Mediated Responses in Rat Hippocampal Neurons. Brain Research. 1998(787);132–138. doi:10.1016/s0006-8993(97) 01505-9
64. Kawabata K. Tung NH. Shoyama Y. Sugie S. Mori T. Tanaka T. Dietary Crocin Inhibits Colitis and Colitis-Associated Colorectal Carcino-genesis in Male ICR Mice. Evidence-Based Complementary and Alternative Medicine. (2012)820415. doi:10.1155/2012/820415.toda
65. Ochiai T. Shimeno H. Mishima K. Iwasaki K. Fujiwara M. Tanaka H. Shoyama Y. Toda A. Eyanagi R. Soeda S. Protective effects of carotenoids from saffron on neuronal injury in vitro and in vivo. Biochimica ET Biophysica Acta. 2007(1770);578-584.
66. Butnariu M. Quispe C. Herrera-Bravo J. Sharifi-Rad J. Singh L. Aborehab NM. Bouyahya A. Venditti A. Sen S. Acharya K. Bashiry M. Ezzat SM. The Pharmacological Activities of Crocus sativus L.: A Review Based on the Mechanisms and Therapeutic Opportunities of its phytoconstituents. Oxidative Medicine and Cellular Longevity. 2022(2022); 28214821. doi.org/10.1155/2022/82148.