Crocin as Neuroprotective Agonist in Oxidative Damage and Cognitive Dysfunction Induced by Aluminium Chloride and Colchicine in Rodents
Abstract
The main constituent of saffron, Crocus sativus L., is called Crocin (CR). Water-soluble carotenoids in CR possesses anti-inflammatory, analgesic, anti-edematous, as well as anti-oxidant properties, as well as to increase the number of microtubules in sheep brain microtubules and to have neuroprotective effects. For example, Alzheimer's disease (AD), where the harm of hippocampal as well as cortical neurons results in memory as well as cognitive impairment, as well as amyotrophic lateral sclerosis (ALS), where weakness in muscle is brought on by the degeneration of spinal, bulbar, as well as cortical motor neurons, are disorders which are characterized by the progressive and irreversible loss of neurons. In the current investigation, we evaluated CR's ability to protect neurons from the oxidative harm that Colchicine (Col) and Aluminum chloride (ALCL) induce. GSH level, SOD, besides catalase reduced in the Col model's Col-treated group but was practically returned to normal in the group that received CR. When given CR instead of Col, the levels of MDA, acetylcholine esterase, and nitric oxide returned to nearly normal levels. However, in the Morris water maze test, CR significantly reduces the time it takes to reach the platform (escape latency time), indicating learning and cognitive improvement. Corresponding to this, in the passive avoidance test, the transfer delay time did not significantly increase in the CR-treated group but it did in the Col-treated group. Similar outcomes in the aluminium chloride model were attained. Thus, the present study comes to the conclusion that CR can be utilized to treat oxidative stress and illnesses linked to cognitive dysfunction, such as AD as well as Parkinson’s diseases shown against rodents resultantly.
Keywords:
Crocin, Aluminium Chloride, Alzheimer’s disease, oxidative stress, Neurodegeneration
References
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2. Mohsen K, Faezeh H. Effects of Active Constituents of Crocus sativus L, CR on Sporocin-Induced Model of Sporadic Alzheimer's Disease in Male Rats. Irani Biomedical Journal. 2010; 14:59-65.
3. Nair SC, Kurumboor SK, Hasegawa JH, Saffron chemoprevention in biology and medicine a review. Cancer Biother 1995; 10: 257-264.
4. Shen LH, Li HY, Shang HX. Synthesis and cytotoxic evaluation of new Col derivatives bearing 1,3,4-thiadiazole moieties. Chinese chemical letters. 2013; 24: 299-302.
5. Sherki YG, Melamed E, Offen D. "Oxidative stress induced neurodegenerative diseases: the need for anti-oxidant that penetrate the blood brain barrier Neuropharmacology 2001: 40(8):959-975.
6. Shimi S, Takashi O, Paopong L. CR suppresses tumor necrosis factor-a-induced cell death of neuronally differentiated PC-12 cells. Life Sciences. 2001; 69(24): 2887-2898.
7. Soedan S, Ochiaia T, Paopongb L. CR suppresses tumor necrosis factor-a induced cell death of neuronally differentiated PC-12 cells. Life Sciences. 2001; 69: 2887-2898.
8. Squire LR, Zola SM. Structure and function of declarative and non-declarative memory systems. PNAS. 1996; 93: 13515-13522.
9. Coulibaly AY, Sombie PA, Tibiri A, Kiendrebeogo M, Compaore MM, Nacoulma OG. Protective effect of Scoparia dulcis on brain and erythrocytes. Current Research Journal of Biological Sciences. 2011 May 5;3(3):254-61.
10. Husein AAM, Farath KM, Mohamed MG. Effects of chronic aluminum administration on brain and liver enzyme activities and essential elements concentration in rats: protective role of vitamin A and riboflavin. 2012: 1-21.
11. Atienzar F, Desor D, Burnel D, Keller JM, Lehr P, Vasseur P. Effect of aluminum on superoxide dismutase activity in the adult rat brain. Biological trace element research. 1998 Oct; 65:19-30.
12. Jin, CH, Wu SW, Zhou P, Liu QF, Lu XB, Shi LD and Cai Y. Effect of aluminum on Ca²+ concentration and expression of phospholipase C and NMDA receptor α genes in hippocampus of weaning rats as well as their neural behavior through subchronic exposure. Zhonghua lao Dong wei Sheng zhi ye Bing za zhi= Zhonghua Laodong Weisheng Zhiyebing Zazhi= Chinese Journal of Industrial Hygiene and Occupational Diseases. 2010; 28(9): 648-651.
13. Ingole SR, Rajput SK, Sharma S. Cognition Enhancers: Current strategies and future perspectives. Current research and information on Pharmaceutical sciences. 2008; 9:42-48.
14. Yuan CY, Lee YJ, Hsu GS. Aluminum alters NMDA receptor IA and 2A/B expression on neonatal hippocampal neurons in rats. Journal of Biomedical Science 2011; (18): 81.
15. Abdullaev FI. Biological effects of saffron. BioFactors (Oxford, England). 1993 May 1;4(2):83-6.
16. Caballero-Ortega H, Riverón-Negrete L, Pereda-Miranda R, Rivera-Luna R, Hernández M, Pérez-López I, Espinosa-Aguirre JJ. In vitro evaluation of the chemopreventive potential of saffron. Revista de investigacion clinica; organo del Hospital de Enfermedades de la Nutricion. 2002 Sep 1;54(5):430-6.
17. Hoseinzadeh H, Karimi Gh, Niapoor M. Antidepressant effects of Crocus sativus stigma extracts and its constituents, CR and safranal, in mice. Acta Hort (ISHS) 2004; 650: 435-445 .
18. Chryssanthi DG, Lamari FN, Iatrou G, Pylara A, Karamanos NK, Cordopatis P. Inhibition of breast cancer cell proliferation by style constituents of different Crocus species. Anticancer research. 2007 Jan 1;27(1A):357-62.
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21. Premkumar K. Abraham SK, Santhiya S, Tet al. Inhibition of genotoxicity by saffron (Crocus sativus L.) in mice. Drug Chem Toxicol 2001; 24:421-428.
22. Premkumar K, Abraham SK, Santhiya ST. Protective effects of saffron (Crocus sativus L.) on genotoxin-induced oxidative stress in Swiss albino mice. Phytother Res 2003; 17:614-617.
23. Nam KN, Park YM, Jung HJ. Anti-inflammatory effects of CR and crocetin in rat brain microglial cells. Eur J Pharmacol 2010; 648: 1-3.
24. Ochini T, Shimeno H, Mishima K. Protective effects of carotenoids from saffron on neuronal injury in vitro and in vivo. Biochim Biophys Acta. 2007;1770: 578-584.
25. Ochini T, Shimeno H, Mishima K. Protective effects of carotenoids from saffron on neuronal injury in vitro and in vivo. Biochim Biophys Acta. 2007; 1770(4):578-84
26. Abdullaev JF, Caballero-Ortega H, Riverón-Negrete L. "In vitro evaluation of thedemopreventive potential of saffron. Rev. Invest. Clin, 2002; 54.
27. Hosseinzadeh H, Ziace T, Sadeghi A. The effect of saffron, Crocus sativus stigma, extract and its constituents, safranal and CR on sexual behaviors in normal male rats. Phytomedicine 2008;15: 491-5.
28. El-Beshbishy HA, Hassan MH, Aly HA, Doghish AS, Alghaithy AA. CR “saffron” protects against beryllium chloride toxicity in rats through diminution of oxidative stress and enhancing gene expression of antioxidant enzymes. Ecotoxicology and environmental safety. 2012 Sep 1; 83:47-54.
29. Hoshyar R, Bathaie SZ, Sadeghizadeh M. CR triggers the apoptosis through increasing the Bax/Bcl-2 ratio and caspase activation in human gastric adenocarcinoma, AGS, cells. DNA and cell biology. 2013 Feb 1;32(2):50-7.
30. Zhang YX, Sugiura M, Saito H. Acute effects of Crocus sativus L. on passive avoidance performance in mice. Biol Pharmacol Bull 1994; 17:217-221.
31. Abe K, Sugiura M, Yamaguchi S, Shoyama Y, Saito H. Saffron extract prevents acetaldehyde-induced inhibition of long-term potentiation in the rat dentate gyrus in vivo. Brain Research. 1999 Dec 18;851(1-2):287-9.
32. Abdullaev FI. Cancer chemopreventive and tumoricidal properties of saffron (Crocus sativus L.). Experimental biology and medicine. 2002 Jan;227(1):20-5.
33. Hosseinzadeh H, Younesi HM. Antinociceptive and anti-inflammatory effects of Crocus sativus L. stigma and petal extracts in mice. BMC Pharmacol 2002; 2:1-8.
34. Jain KK. The Handbook of Neuroprotection. Springer Science 2011:25-28
35. Qi Y, Chen L, Zhang L. CR prevents retinal ischaemia/reperfusion injury-induced apoptosis in retinal ganglion cells through the PI3K/AKT signalling pathway. Exp Eye Res. 2013; 107: 44-51.
36. Rahani Foroutagheh M, Hamidoghli Y, Mohajeri SA. Effect of split foliar fertilisation on the quality and quantity of active constituents in saffron (Crocus sativus L.). J Sci Food Agric 2013.
37. Kulkami SK. Hand book of experimental pharmacology. Vallabh Prakashan 1999;117-119:135-136.
38. Tamaddonfard E, Farshid AA, Ahmadian E, Hamidhoseyni A. CR enhanced functional recovery after sciatic nerve crush injury in rats. Iranian Journal of Basic Medical Sciences. 2013 Jan 1;16(1):83-90.
39. Tamaddonfard E, Farshid AA, Asri-Rezaee S, Javadi S, Khosravi V, Rahman B, Mirfakhraee Z. CR improved learning and memory impairments in streptozotocin-induced diabetic rats. Iranian journal of basic medical sciences. 2013 Jan;16(1):91.
40. Patil S, Srinivas S, Jadhav J. Evaluation of CR and curcumin affinity on mushroom tynsinuse using Surface Plasmon Resonance. International Journal of Biological Macromolecules 2014; 65:163-166.
41. Ochiai T, Ohno S, Sooda S. CR prevents the death of rat pheochromyctoma (PC-12) cells by its antioxidant effects stronger than those of a-tocopherol. Neuroscience Letters. 2004;362(1): 61-64.
42. Vogel GH Drug discovery and Evaluation" Pharmacological assays. 2 edition, Springer science 2002:632.
43. Thiperwamy BS, Nagakannan P. Protective Effect of Emblin against Transient Global Ischemia induced brain damaged Neurofar Res. 2011: 379-386.
44. Ellman GL, Courtney KD, Andres Jr V, Featherstone RM. A new and rapid colorimetric determination of acetylcholinesterase activity. Biochemical pharmacology. 1961 Jul 1;7(2):88-95.
45. Totora GJ, Derrickson BH. "Principles of anatomy and physiology", 12" edition, vol 1; 2009:495-540.
46. Verstraeten SV Aimo L, Oteiza et al. Aluminium and lead: molecular mechanisms of brain toxicity Arch Taxicol 2008; 82(11):789-802.
47. Waugh A, Grant A. "Anatomy and Physiology in Health and Illness", Churchill Livingstone. 11 ed 2012: 148-154.
48. Zheng YQ, Liu JX, Wang JN. Effects of CR on reperfusion-induced oxidative nitrative injury to cerebral micro vessels after global cerebral ischemia. Brain Research. 2007; 1138:86-94.
49. Naghizadeh B, Mansouri MT, Ghorbanzadeh B, Farbood Y, Sarkaki A. Protective effects of oral CR against intracerebroventricular streptozotocin-induced spatial memory deficit and oxidative stress in rats. Phytomedicine. 2013 Apr 15;20(6):537-42.
50. Razavi BM, Hosseinzadeh H, Movassaghi AR, Imenshahidi M, Abnous K. Protective effect of CR on diazinon induced cardiotoxicity in rats in subchronic exposure. Chemico-biological interactions. 2013 May 25;203(3):547-55.
51. Lowry OH, Rosebrough NJ, A.Lewis Farr. Protein measurement with folin phenol reagent. J Biolchem 1991; 193: 265-275.
52. Jahanbakhsh Z, Rasoulian B, Jafari M. Protective effect of CR against reperfusion-induced cardiac arrhythmias in anaesthetized rats. EXCLI Journal 2012; 11: 20-29.
53. Zarei Jaliani H, Riazi GH, Ghaffari SM. The effect of the crocus sativus L. Carotenoid, CR, on the polymerization of microtubules, in vitro. Iran J Basic Med Sci. 2013; 16(1): 101-7.
54. Zumkley H. Bertram HP, Lison A. Al, Zn and Cu concentrations in plasma in chronic renal insufficiency. Clin Nephrol 1979; 12: 18-21.
55. Hariri AT, Moallem SA, Mahmoudi M, Hosseinzadeh H. The effect of CR and safranal, constituents of saffron, against subacute effect of diazinon on hematological and genotoxicity indices in rats. Phytomedicine. 2011 Apr 15;18(6):499-504.
56. Akhtari K, Hassanzadeh K, Fakhraci B. A density functional theory study of the reactivity descriptors and antioxidant behavior of CR Elsevier. 2013; 1013: 123-129.
57. Sugiura M, Shoyama Y, Saito Y. CR (crocetin di-gentiobiose ester) prevents the inhibitory effect of ethanol on long-term potentiation in the dentate gyrus in vivo. JPET 1994; 271: 703-707.
58. Habig WH, Pabst MJ, Jakoby WB. Glutathione S-transferases: the first enzymatic step in mercapturic acid formation. Journal of biological Chemistry. 1974 Nov 25;249(22):7130-9.
59. Kumar A. Dogra S. Neuroprotective effect of carvedilol, an adrenergic antagonist against Cols induced cognitive impairment and oxidative damage in rat. Pharmacology, Biochemistry and Behavior 2009;92:25-31.
60. Riyaz A. Dar, Pradeep K. Brahman, N. Khurana. Evaluation of antioxidant activity of CR, podophyllotoxin and kaempferol by chemical, biochemical and electrochemical assays. Arabian Journal Chemistry 2013.
61. Saladin KS. "Human anatomy". Tata Mc Graw Hill, 3 editions. 2011: 398-414.
62. Schipita AHV, Olanow CW. "Neuroprotection in Parkinson's disease: Mysteries, myths and misconceptions". JAMA. 2004; 291: 358-364.
63. Melo A, Monteiro L, Lima RM, de Oliveira DM, de Cerqueira MD, El-Bachá RS. Oxidative stress in neurodegenerative diseases: mechanisms and therapeutic perspectives. Oxidative medicine and cellular longevity. 2011 Oct;2011.
64. Kono Y. Generation of superoxide radical during autooxidation of hydroxylamine and an assay for superoxide dismutase. Arch Biochem Biophys 1978: 189–195.
65. Lari P. Abnous K. Imenshahidi M. Evaluation of diazinon-induced hepatotoxicity and protective effects of CR. Toxicol Ind Health. 2013; 13.
66. Lan P, Rashedinia M, Abnous K. CR Improves Lipid Dysregulation in Subacute Diazinon Exposure through ERK1/2 Pathway in Rat Liver. Drug Res. 2013.
67. Jnaneshwari S, Hemshekhar M, Santhosh MS, Sunitha K, Thushara R, Thirunavukkarasu C, Kemparaju K, Girish KS. CR, a dietary colorant mitigates cyclophosphamide-induced organ toxicity by modulating antioxidant status and inflammatory cytokines. Journal of Pharmacy and Pharmacology. 2013 Apr;65(4):604-14.
68. Luck H. Catalase, in Methods of enzymatic analysis edited by Bermeyer, H.W (Academic press, New York) See 3;1963:885.
69. Kyong Nyon Nam, Young-Min Park, Hoon-Ji Jung. Anti-inflammatory effects of CR and crocetin in rat brain microglial cells. European Journal of Pharmacology 2010;648(1-3): 110-116
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72. Rabani-Foroutaghich M, Hamidoghli Y, Mohajeri SA. Effect of split foliar fertilisation on the quality god quantity of active constituents in saffron (Crocus sativus L.) Journal of Stroke and Cerebrovascular Der 2014; 23(1) :106-113.
73. Razavi M, Hosseinzadeh H. Abnous K. CR restores hypotensive effect of subchronic administration of diazinon in rats. Iran J Basic Med Sci 2013; 16(1): 64-72.
2. Mohsen K, Faezeh H. Effects of Active Constituents of Crocus sativus L, CR on Sporocin-Induced Model of Sporadic Alzheimer's Disease in Male Rats. Irani Biomedical Journal. 2010; 14:59-65.
3. Nair SC, Kurumboor SK, Hasegawa JH, Saffron chemoprevention in biology and medicine a review. Cancer Biother 1995; 10: 257-264.
4. Shen LH, Li HY, Shang HX. Synthesis and cytotoxic evaluation of new Col derivatives bearing 1,3,4-thiadiazole moieties. Chinese chemical letters. 2013; 24: 299-302.
5. Sherki YG, Melamed E, Offen D. "Oxidative stress induced neurodegenerative diseases: the need for anti-oxidant that penetrate the blood brain barrier Neuropharmacology 2001: 40(8):959-975.
6. Shimi S, Takashi O, Paopong L. CR suppresses tumor necrosis factor-a-induced cell death of neuronally differentiated PC-12 cells. Life Sciences. 2001; 69(24): 2887-2898.
7. Soedan S, Ochiaia T, Paopongb L. CR suppresses tumor necrosis factor-a induced cell death of neuronally differentiated PC-12 cells. Life Sciences. 2001; 69: 2887-2898.
8. Squire LR, Zola SM. Structure and function of declarative and non-declarative memory systems. PNAS. 1996; 93: 13515-13522.
9. Coulibaly AY, Sombie PA, Tibiri A, Kiendrebeogo M, Compaore MM, Nacoulma OG. Protective effect of Scoparia dulcis on brain and erythrocytes. Current Research Journal of Biological Sciences. 2011 May 5;3(3):254-61.
10. Husein AAM, Farath KM, Mohamed MG. Effects of chronic aluminum administration on brain and liver enzyme activities and essential elements concentration in rats: protective role of vitamin A and riboflavin. 2012: 1-21.
11. Atienzar F, Desor D, Burnel D, Keller JM, Lehr P, Vasseur P. Effect of aluminum on superoxide dismutase activity in the adult rat brain. Biological trace element research. 1998 Oct; 65:19-30.
12. Jin, CH, Wu SW, Zhou P, Liu QF, Lu XB, Shi LD and Cai Y. Effect of aluminum on Ca²+ concentration and expression of phospholipase C and NMDA receptor α genes in hippocampus of weaning rats as well as their neural behavior through subchronic exposure. Zhonghua lao Dong wei Sheng zhi ye Bing za zhi= Zhonghua Laodong Weisheng Zhiyebing Zazhi= Chinese Journal of Industrial Hygiene and Occupational Diseases. 2010; 28(9): 648-651.
13. Ingole SR, Rajput SK, Sharma S. Cognition Enhancers: Current strategies and future perspectives. Current research and information on Pharmaceutical sciences. 2008; 9:42-48.
14. Yuan CY, Lee YJ, Hsu GS. Aluminum alters NMDA receptor IA and 2A/B expression on neonatal hippocampal neurons in rats. Journal of Biomedical Science 2011; (18): 81.
15. Abdullaev FI. Biological effects of saffron. BioFactors (Oxford, England). 1993 May 1;4(2):83-6.
16. Caballero-Ortega H, Riverón-Negrete L, Pereda-Miranda R, Rivera-Luna R, Hernández M, Pérez-López I, Espinosa-Aguirre JJ. In vitro evaluation of the chemopreventive potential of saffron. Revista de investigacion clinica; organo del Hospital de Enfermedades de la Nutricion. 2002 Sep 1;54(5):430-6.
17. Hoseinzadeh H, Karimi Gh, Niapoor M. Antidepressant effects of Crocus sativus stigma extracts and its constituents, CR and safranal, in mice. Acta Hort (ISHS) 2004; 650: 435-445 .
18. Chryssanthi DG, Lamari FN, Iatrou G, Pylara A, Karamanos NK, Cordopatis P. Inhibition of breast cancer cell proliferation by style constituents of different Crocus species. Anticancer research. 2007 Jan 1;27(1A):357-62.
19. Escribano J, Alonso GL, Coca-Prados M, Fernández JA. CR, safranal and picroCR from saffron (Crocus sativus L.) inhibit the growth of human cancer cells in vitro. Cancer letters. 1996 Feb 27;100(1-2):23-30.
20. Papandreou MA, Kanakis CD, Polissiou MG. Inhibitory activity on amyloid-beta aggregation and antioxidant properties of Crocus sativus stigmas extract and its CR constituents. J Agric Food Chem 2006; 54: 8762-80.
21. Premkumar K. Abraham SK, Santhiya S, Tet al. Inhibition of genotoxicity by saffron (Crocus sativus L.) in mice. Drug Chem Toxicol 2001; 24:421-428.
22. Premkumar K, Abraham SK, Santhiya ST. Protective effects of saffron (Crocus sativus L.) on genotoxin-induced oxidative stress in Swiss albino mice. Phytother Res 2003; 17:614-617.
23. Nam KN, Park YM, Jung HJ. Anti-inflammatory effects of CR and crocetin in rat brain microglial cells. Eur J Pharmacol 2010; 648: 1-3.
24. Ochini T, Shimeno H, Mishima K. Protective effects of carotenoids from saffron on neuronal injury in vitro and in vivo. Biochim Biophys Acta. 2007;1770: 578-584.
25. Ochini T, Shimeno H, Mishima K. Protective effects of carotenoids from saffron on neuronal injury in vitro and in vivo. Biochim Biophys Acta. 2007; 1770(4):578-84
26. Abdullaev JF, Caballero-Ortega H, Riverón-Negrete L. "In vitro evaluation of thedemopreventive potential of saffron. Rev. Invest. Clin, 2002; 54.
27. Hosseinzadeh H, Ziace T, Sadeghi A. The effect of saffron, Crocus sativus stigma, extract and its constituents, safranal and CR on sexual behaviors in normal male rats. Phytomedicine 2008;15: 491-5.
28. El-Beshbishy HA, Hassan MH, Aly HA, Doghish AS, Alghaithy AA. CR “saffron” protects against beryllium chloride toxicity in rats through diminution of oxidative stress and enhancing gene expression of antioxidant enzymes. Ecotoxicology and environmental safety. 2012 Sep 1; 83:47-54.
29. Hoshyar R, Bathaie SZ, Sadeghizadeh M. CR triggers the apoptosis through increasing the Bax/Bcl-2 ratio and caspase activation in human gastric adenocarcinoma, AGS, cells. DNA and cell biology. 2013 Feb 1;32(2):50-7.
30. Zhang YX, Sugiura M, Saito H. Acute effects of Crocus sativus L. on passive avoidance performance in mice. Biol Pharmacol Bull 1994; 17:217-221.
31. Abe K, Sugiura M, Yamaguchi S, Shoyama Y, Saito H. Saffron extract prevents acetaldehyde-induced inhibition of long-term potentiation in the rat dentate gyrus in vivo. Brain Research. 1999 Dec 18;851(1-2):287-9.
32. Abdullaev FI. Cancer chemopreventive and tumoricidal properties of saffron (Crocus sativus L.). Experimental biology and medicine. 2002 Jan;227(1):20-5.
33. Hosseinzadeh H, Younesi HM. Antinociceptive and anti-inflammatory effects of Crocus sativus L. stigma and petal extracts in mice. BMC Pharmacol 2002; 2:1-8.
34. Jain KK. The Handbook of Neuroprotection. Springer Science 2011:25-28
35. Qi Y, Chen L, Zhang L. CR prevents retinal ischaemia/reperfusion injury-induced apoptosis in retinal ganglion cells through the PI3K/AKT signalling pathway. Exp Eye Res. 2013; 107: 44-51.
36. Rahani Foroutagheh M, Hamidoghli Y, Mohajeri SA. Effect of split foliar fertilisation on the quality and quantity of active constituents in saffron (Crocus sativus L.). J Sci Food Agric 2013.
37. Kulkami SK. Hand book of experimental pharmacology. Vallabh Prakashan 1999;117-119:135-136.
38. Tamaddonfard E, Farshid AA, Ahmadian E, Hamidhoseyni A. CR enhanced functional recovery after sciatic nerve crush injury in rats. Iranian Journal of Basic Medical Sciences. 2013 Jan 1;16(1):83-90.
39. Tamaddonfard E, Farshid AA, Asri-Rezaee S, Javadi S, Khosravi V, Rahman B, Mirfakhraee Z. CR improved learning and memory impairments in streptozotocin-induced diabetic rats. Iranian journal of basic medical sciences. 2013 Jan;16(1):91.
40. Patil S, Srinivas S, Jadhav J. Evaluation of CR and curcumin affinity on mushroom tynsinuse using Surface Plasmon Resonance. International Journal of Biological Macromolecules 2014; 65:163-166.
41. Ochiai T, Ohno S, Sooda S. CR prevents the death of rat pheochromyctoma (PC-12) cells by its antioxidant effects stronger than those of a-tocopherol. Neuroscience Letters. 2004;362(1): 61-64.
42. Vogel GH Drug discovery and Evaluation" Pharmacological assays. 2 edition, Springer science 2002:632.
43. Thiperwamy BS, Nagakannan P. Protective Effect of Emblin against Transient Global Ischemia induced brain damaged Neurofar Res. 2011: 379-386.
44. Ellman GL, Courtney KD, Andres Jr V, Featherstone RM. A new and rapid colorimetric determination of acetylcholinesterase activity. Biochemical pharmacology. 1961 Jul 1;7(2):88-95.
45. Totora GJ, Derrickson BH. "Principles of anatomy and physiology", 12" edition, vol 1; 2009:495-540.
46. Verstraeten SV Aimo L, Oteiza et al. Aluminium and lead: molecular mechanisms of brain toxicity Arch Taxicol 2008; 82(11):789-802.
47. Waugh A, Grant A. "Anatomy and Physiology in Health and Illness", Churchill Livingstone. 11 ed 2012: 148-154.
48. Zheng YQ, Liu JX, Wang JN. Effects of CR on reperfusion-induced oxidative nitrative injury to cerebral micro vessels after global cerebral ischemia. Brain Research. 2007; 1138:86-94.
49. Naghizadeh B, Mansouri MT, Ghorbanzadeh B, Farbood Y, Sarkaki A. Protective effects of oral CR against intracerebroventricular streptozotocin-induced spatial memory deficit and oxidative stress in rats. Phytomedicine. 2013 Apr 15;20(6):537-42.
50. Razavi BM, Hosseinzadeh H, Movassaghi AR, Imenshahidi M, Abnous K. Protective effect of CR on diazinon induced cardiotoxicity in rats in subchronic exposure. Chemico-biological interactions. 2013 May 25;203(3):547-55.
51. Lowry OH, Rosebrough NJ, A.Lewis Farr. Protein measurement with folin phenol reagent. J Biolchem 1991; 193: 265-275.
52. Jahanbakhsh Z, Rasoulian B, Jafari M. Protective effect of CR against reperfusion-induced cardiac arrhythmias in anaesthetized rats. EXCLI Journal 2012; 11: 20-29.
53. Zarei Jaliani H, Riazi GH, Ghaffari SM. The effect of the crocus sativus L. Carotenoid, CR, on the polymerization of microtubules, in vitro. Iran J Basic Med Sci. 2013; 16(1): 101-7.
54. Zumkley H. Bertram HP, Lison A. Al, Zn and Cu concentrations in plasma in chronic renal insufficiency. Clin Nephrol 1979; 12: 18-21.
55. Hariri AT, Moallem SA, Mahmoudi M, Hosseinzadeh H. The effect of CR and safranal, constituents of saffron, against subacute effect of diazinon on hematological and genotoxicity indices in rats. Phytomedicine. 2011 Apr 15;18(6):499-504.
56. Akhtari K, Hassanzadeh K, Fakhraci B. A density functional theory study of the reactivity descriptors and antioxidant behavior of CR Elsevier. 2013; 1013: 123-129.
57. Sugiura M, Shoyama Y, Saito Y. CR (crocetin di-gentiobiose ester) prevents the inhibitory effect of ethanol on long-term potentiation in the dentate gyrus in vivo. JPET 1994; 271: 703-707.
58. Habig WH, Pabst MJ, Jakoby WB. Glutathione S-transferases: the first enzymatic step in mercapturic acid formation. Journal of biological Chemistry. 1974 Nov 25;249(22):7130-9.
59. Kumar A. Dogra S. Neuroprotective effect of carvedilol, an adrenergic antagonist against Cols induced cognitive impairment and oxidative damage in rat. Pharmacology, Biochemistry and Behavior 2009;92:25-31.
60. Riyaz A. Dar, Pradeep K. Brahman, N. Khurana. Evaluation of antioxidant activity of CR, podophyllotoxin and kaempferol by chemical, biochemical and electrochemical assays. Arabian Journal Chemistry 2013.
61. Saladin KS. "Human anatomy". Tata Mc Graw Hill, 3 editions. 2011: 398-414.
62. Schipita AHV, Olanow CW. "Neuroprotection in Parkinson's disease: Mysteries, myths and misconceptions". JAMA. 2004; 291: 358-364.
63. Melo A, Monteiro L, Lima RM, de Oliveira DM, de Cerqueira MD, El-Bachá RS. Oxidative stress in neurodegenerative diseases: mechanisms and therapeutic perspectives. Oxidative medicine and cellular longevity. 2011 Oct;2011.
64. Kono Y. Generation of superoxide radical during autooxidation of hydroxylamine and an assay for superoxide dismutase. Arch Biochem Biophys 1978: 189–195.
65. Lari P. Abnous K. Imenshahidi M. Evaluation of diazinon-induced hepatotoxicity and protective effects of CR. Toxicol Ind Health. 2013; 13.
66. Lan P, Rashedinia M, Abnous K. CR Improves Lipid Dysregulation in Subacute Diazinon Exposure through ERK1/2 Pathway in Rat Liver. Drug Res. 2013.
67. Jnaneshwari S, Hemshekhar M, Santhosh MS, Sunitha K, Thushara R, Thirunavukkarasu C, Kemparaju K, Girish KS. CR, a dietary colorant mitigates cyclophosphamide-induced organ toxicity by modulating antioxidant status and inflammatory cytokines. Journal of Pharmacy and Pharmacology. 2013 Apr;65(4):604-14.
68. Luck H. Catalase, in Methods of enzymatic analysis edited by Bermeyer, H.W (Academic press, New York) See 3;1963:885.
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Deepak Tomar, Mainuddin, Dhananjay Taumar, Anshika, Mayank, Prachi Jain, Khushi Goel, and Amulya Jindal. “Crocin As Neuroprotective Agonist in Oxidative Damage and Cognitive Dysfunction Induced by Aluminium Chloride and Colchicine in Rodents”. Current Research in Pharmaceutical Sciences, Apr. 2023, pp. 52-69, doi:10.24092/CRPS.2023.130105.
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