Memory enhancement and protective effects of crocin against D-galactose aging model in the hippocampus of Wistar rats

Document Type: Original Article

Authors

1 Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

2 Pharmaceutical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

Abstract

Objective(s): The neurodegeneration and loss of memory function are common consequences of aging. Medicinal plants have potent protective effects against chronic neurodegenerative diseases. The aim of this study was to investigate the beneficial effects and molecular mechanisms of crocin on brain function in D-galactose (D-gal)-induced aging model in rats.
Materials and Methods: Male Wistar rats weighing 220 ± 20 g were randomly divided into six groups: control, D-gal (400 mg/kg, SC), D-gal (400 mg/kg) plus crocin (7.5, 15, 30 mg/kg, IP) and crocin alone at dose of 30 mg/kg for 8 weeks. The neuroprotective effects of crocin were evaluated by Morris water maze, determination of malondialdehyde (MDA) levels and Western blot analysis.
Results: Crocin significantly inhibited the neurotoxic effects of D-gal through improvement of spatial learning and memory functions as well as the reduction of MDA levels. It was also found that administration of crocin up-regulated pAkt/Akt and pErk/Erk ratio which were decreased by chronic D-gal treatment. In addition, the elevated level of carboxymethyl lysine (CML), as an advance glycation product (AGE), NF-κB p65, TNFα and IL1β significantly decreased in crocin treated rats compared to D-gal group.
Conclusion: These findings suggest that crocin is able to enhance memory function in D-gal aging model through anti-glycative and anti-oxidative properties which finally can suppress brain inflammatory mediators (IL-1, TNF and NF-κB) formations and increase PI3K/Akt and Erk/MAPK pathways activity. Therefore, crocin can be considered as healthcare product to prevent age-related brain diseases such as Alzheimer.

Keywords


1. Zhou Y, Dong Y, Xu Q, He Y, Tian S, Zhu S, et al. Mussel oligopeptides ameliorate cognition deficit and attenuate brain senescence in D-galactose-induced aging mice. Food Chem Toxicol 2013; 59:412-420.

2. Park D-S, Lee S-H, Choi Y-J, Bae D-K, Yang Y-H, Yang G-E, et al. Improving effect of silk peptides on the cognitive function of rats with aging brain facilitated by D-galactose. Biomol Ther 2011; 19:224-230.

3. Kuhla A, Ludwig SC, Kuhla B, Münch G, Vollmar B. Advanced glycation end products are mitogenic signals and trigger cell cycle reentry of neurons in Alzheimer's disease brain. Neurobiol Aging 2015; 36:753-761.

4. Nowotny K, Jung T, Hohn A, Weber D, Grune T. Advanced glycation end products and oxidative stress in type 2 diabetes mellitus. Biomolecules 2015; 5:194-222.

5. Li JH, Wang W, Huang XR, Oldfield M, Schmidt AM, Cooper ME, et al. Advanced glycation end products induce tubular epithelial-myofibroblast transition through the RAGE-ERK1/2 MAP kinase signaling pathway. Am J Pathol 2004; 164:1389-1397.

6. Tanikawa T, Okada Y, Tanikawa R, Tanaka Y. Advanced glycation end products induce calcification of vascular smooth muscle cells through RAGE/p38 MAPK. J Vasc Res 2009; 46:572-580.

7. Hirose A, Tanikawa T, Mori H, Okada Y, Tanaka Y. Advanced glycation end products increase endothelial permeability through the RAGE/Rho signaling pathway. FEBS Lett 2010; 584:61-66.

8. Lin L, Park S, Lakatta EG. RAGE signaling in inflammation and arterial aging. Front Biosci 2009; 14:1403–1413.

9. Libermann TA, Baltimore D. Activation of interleukin-6 gene expression through the NF-kappa B transcription factor. Mol Cell Biol 1990; 10:2327-2334.

10. Zhang K-L, Lou D-D, Guan Z-Z. Activation of the AGE/RAGE system in the brains of rats and in SH-SY5Y cells exposed to high level of fluoride might connect to oxidative stress. Neurotoxicol Teratol 2015; 48:49-55.

11. Tsai SJ, Yin MC. Anti-glycative and anti-inflammatory effects of protocatechuic acid in brain of mice treated by D-galactose. Food Chem Toxicol 2012; 50:3198-3205.

12. Wu H, Zhao J, Chen M, Wang H, Yao Q, Fan J, et al. The anti-aging effect of erythropoietin via the ERK/Nrf2-ARE pathway in aging rats. J Mol Neurosci 2017; 61: 449-458

13. Wang X, Wang Z, Yao Y, Li J, Zhang X, Li C, et al. Essential role of ERK activation in neurite outgrowth induced by alpha-lipoic acid. Biochim Biophys Acta 2011; 1813:827-838.

14. Bandegi AR, Rashidy-Pour A, Vafaei AA, Ghadrdoost B. 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 2014; 4:493-499.

15. Cao P-C, Xiao W-X, Yan Y-B, Zhao X, Liu S, Feng J, et al. Preventive effect of crocin on osteoporosis in an ovariectomized rat model. Evid Based Complement Alternat Med 2014; 2014: 825181

16.  Moshiri M, Vahabzadeh M, Hosseinzadeh H. Clinical applications of saffron (Crocus sativus) and its constituents: a review. Drug Res 2015; 65:287-295.

17. Soeda S, Ochiai T, Shimeno H, Saito H, Abe K, Tanaka H, et al. Pharmacological activities of crocin in saffron. J Nat Med 2007; 61:102-111.

18. Abdullaev FI. Cancer chemopreventive and tumoricidal properties of saffron (Crocus sativus L.). Exp Biol Med 2002; 227:20-25.

19. Vahdati Hassani F, Naseri V, Razavi BM, Mehri S, Abnous K, Hosseinzadeh H. Antidepressant effects of crocin and its effects on transcript and protein levels of CREB, BDNF, and VGF in rat hippocampus. Daru 2014; 22:16-25.

20. Wang Y, Han T, Zhu Y, Zheng C-J, Ming Q-L, Rahman K, et al. Antidepressant properties of bioactive fractions from the extract of Crocus sativus L. J Nat Med 2010; 64:24-30.

21. Hosseinzadeh H, Noraei NB. Anxiolytic and hypnotic effect of Crocus sativus aqueous extract and its constituents, crocin and safranal, in mice. Phytother Res 2009; 23:768-774.

22. Ding Q, Zhong H, Qi Y, Cheng Y, Li W, Yan S, et al. Anti-arthritic effects of crocin in interleukin-1beta-treated articular chondrocytes and cartilage in a rabbit osteoarthritic model. Inflamm Res 2013; 62:17-25.

23. Essa MM, Vijayan RK, Castellano-Gonzalez G, Memon MA, Braidy N, Guillemin GJ. Neuroprotective effect of natural products against Alzheimer’s disease. Neurochem Res 2012; 37:1829-1842.

24. Hosseinzadeh H, Ziaei T. Effects of Crocus sativus L. stigma extract and its constituents, crocin and safranal, on intact memory and scopolamine-induced learning deficits in rats performing the Morris water maze task. J Med Plants 2006; 3:40-50.

25. Pitsikas N, Zisopoulou S, Tarantilis PA, Kanakis CD, Polissiou MG, Sakellaridis N. Effects of the active constituents of Crocus sativus L., crocins on recognition and spatial rats’ memory. Behav Brain Res 2007; 183:141-146.

26. Rao SV, Muralidhara, Yenisetti SC, Rajini PS. Evidence of neuroprotective effects of saffron and crocin in a Drosophila model of parkinsonism. Neurotoxicology 2016; 52:230-242.

27. Hazman O, Aksoy L, Buyukben A. Effects of crocin on experimental obesity and type-2 diabetes. Turk J Med Sci 2016; 46:1593-1602.

28. Yousefsani BS, Pourahmad J, Hosseinzadeh H. The Mechanism of protective effect of crocin against liver mitochondrial toxicity caused by Arsenic III. Toxicol Mech Methods 2017; Aug 31:1-10. doi: 10.1080/15376516.2017.1368054. [Epub ahead of print].

29. Vahdati Hassani F, Mehri S, Abnous K, Birner-Gruenberger R, Hosseinzadeh H. Protective effect of crocin on BPA-induced liver toxicity in rats through inhibition of oxidative stress and downregulation of MAPK and MAPKAP signaling pathway and miRNA-122 expression. Food Chem Toxicol 2017; 107:395-405.

30. Alavizadeh SH, Hosseinzadeh H. Bioactivity assessment and toxicity of crocin: a comprehensive review. Food Chem Toxicol 2014; 64:65-80.

31. Rashedinia M, Lari P, Abnous K, Hosseinzadeh H. Protective effect of crocin on acrolein-induced tau phosphorylation in the rat brain. Acta Neurobiol Exp 2015; 75:208-219.

32. Hosseinzadeh H, Sadeghnia HR, Ghaeni FA, Motamedshariaty VS, Mohajeri SA. Effects of saffron (Crocus sativus L.) and its active constituent, crocin, on recognition and spatial memory after chronic cerebral hypoperfusion in rats. Phytother Res 2012; 26:381-386.

33.Tamaddonfard E, Farshid AA, Asri-Rezaee S, Javadi S, Khosravi V, Rahman B, et al. Crocin improved learning and memory impairments in streptozotocin-induced diabetic rats. Iran J Basic Med Sci 2013; 16:91-100.

34. Ahmadi M, Rajaei Z, Hadjzadeh MA, Nemati H, Hosseini M. Crocin improves spatial learning and memory deficits in the Morris water maze via attenuating cortical oxidative damage in diabetic rats. Neurosci Lett 2017; 642:1-6.

35. Asadi F, Jamshidi AH, Khodagholi F, Yans A, Azimi L, Faizi M, et al. Reversal effects of crocin on amyloid beta-induced memory deficit: Modification of autophagy or apoptosis markers. Pharmacol Biochem Behav 2015; 139:47-58.

36. Hadizadeh F, Mohajeri SA, Seifi M. Extraction and purification of crocin from saffron stigmas employing a simple and efficient crystallization method. Pak J Biol Sci 2010; 13:691-698.

37. Haider S, Liaquat L, Shahzad S, Sadir S, Madiha S, Batool Z, et al. A high dose of short term exogenous D-galactose administration in young male rats produces symptoms simulating the natural aging process. Life Sci 2015; 124:110-119.

38. Wang T, Di G, Yang L, Dun Y, Sun Z, Wan J, et al. Saponins from Panax japonicus attenuate D-galactose-induced cognitive impairment through its anti-oxidative and anti-apoptotic effects in rats. J Pharm Pharmacol 2015; 67:1284-1296.

39. Vorhees CV, Williams MT. Morris water maze: procedures for assessing spatial and related forms of learning and memory. Nat Protoc 2006; 1:848-858.

40. Mehri S, Abnous K, Khooei A, Mousavi SH, Shariaty VM, Hosseinzadeh H. Crocin reduced acrylamide-induced neurotoxicity in Wistar rat through inhibition of oxidative stress. Iran J  Basic Med Sci 2015; 18:902-908.

41. Ghasemi T, Abnous K, Vahdati F, Mehri S, Razavi BM, Hosseinzadeh H. Antidepressant effect of Crocus sativus aqueous extract and its effect on CREB, BDNF, and VGF transcript and protein levels in rat hippocampus. Drug Res 2015; 65:337-343.

42. Dammann P, Sell DR, Begall S, Strauch C, Monnier VM. Advanced glycation end-products as markers of aging and longevity in the long-lived Ansell’s mole-rat (Fukomys anselli). J Gerontol A Biol Sci Med Sci. 2011; 67:573-583.

43. Rolewska P, Al-Robaiy S, Santos AN, Simm A, Silber R-E, Bartling B. Age‐related expression, enzymatic solubility and modification with advanced glycation end‐products of fibrillar collagens in mouse lung. Exp Gerontol. 2013; 48:29-37.

44. Masoro EJ. Use of rodents as models for the study of “normal aging”: conceptual and practical issues. Neurobiol Aging. 1991; 12:639-643.

45. Kumar A, Prakash A, Dogra S. Centella asiatica attenuates D-Galactose-induced cognitive impairment, oxidative and mitochondrial dysfunction in mice. Int J Alzheimers Dis 2011; 2011:347569.

46. Haider S, Liaquat L, Shahzad S, Sadir S, Madiha S, Batool Z, et al. A high dose of short term exogenous D-galactose administration in young male rats produces symptoms simulating the natural aging process. Life Sci 2015; 124:110-119.

47. Ghadrdoost B, Vafaei AA, Rashidy-Pour A, Hajisoltani R, Bandegi AR, Motamedi F, et al. Protective effects of saffron extract and its active constituent crocin against oxidative stress and spatial learning and memory deficits induced by chronic stress in rats. Eur J Pharmacol 2011; 667:222-229.

48. Ansari MA, Scheff SW. Oxidative stress in the progression of Alzheimer disease in the frontal cortex. J Neuropathol Exp Neurol 2010; 69:155-167.

49. Gilca M, Stoian I, Atanasiu V, Virgolici B. The oxidative hypothesis of senescence. J Postgrad Med 2007; 53:207-213.

50. Banji D, Banji OJ, Dasaroju S, Kranthi KC. Curcumin and piperine abrogate lipid and protein oxidation induced by D-galactose in rat brain. Brain Res 2013; 1515:1-11.

51. Mao Z, Zheng Y-l, Zhang Y-q, Han B-p, Zhu X-w, Chang Q, et al. The anti-apoptosis effects of daidzein in the brain of D-galactose treated mice. Molecules 2007; 12:1455-1470.

52. Gaweł S, Wardas M, Niedworok E, Wardas P. Malondialdehyde (MDA) as a lipid peroxidation marker. Wiad lek 2003; 57:453-455.

53. Hosseinzadeh H, Shamsaie F, Mehri S. Antioxidant activity of aqueous and ethanolic extracts of Crocus sativus L. stigma and its bioactive constituents, crocin and safranal. Pharmacogn Mag 2009; 5:419-424.

54. Liu YY, Nagpure BV, Wong PT, Bian JS. Hydrogen sulfide protects SH-SY5Y neuronal cells against d-galactose induced cell injury by suppression of advanced glycation end products formation and oxidative stress. Neurochem Int 2013; 62:603-609.

55. Luevano-Contreras C, Chapman-Novakofski K. Dietary advanced glycation end products and aging. Nutrients 2010; 2:1247-1265.

56. Rajaei Z, Hadjzadeh M-A-R, Nemati H, Hosseini M, Ahmadi M, Shafiee S. Antihyperglycemic and antioxidant activity of crocin in streptozotocin-induced diabetic rats. J Med Food 2013; 16:206-210.

57. Mo L, Ren Q, Duchemin A-M, Neff NH, Hadjiconstantinou M. GM1 and ERK signaling in the aged brain. Brain Res 2005; 1054:125-134.

58. Yufune S, Satoh Y, Akai R, Yoshinaga Y, Kobayashi Y, Endo S, et al. Suppression of ERK phosphorylation through oxidative stress is involved in the mechanism underlying sevoflurane-induced toxicity in the developing brain. Sci Rep 2016; 6:21859.

59. Lesné S, Gabriel C, Nelson DA, White E, MacKenzie ET, Vivien D, et al. Akt-dependent expression of NAIP-1 protects neurons against amyloid-β toxicity. J Biol Chem 2005; 280:24941-24947.

60. Liu J, He J, Huang L, Dou L, Wu S, Yuan Q. Neuroprotective effects of ginsenoside Rb1 on hippocampal neuronal injury and neurite outgrowth. Neural Regen Res 2014; 9:943-950.

61. Zhao R, Zhang Z, Song Y, Wang D, Qi J, Wen S. RETRACTED: Implication of phosphatidylinositol-3 kinase/Akt/glycogen synthase kinase-3β pathway in ginsenoside Rb1's attenuation of beta-amyloid-induced neurotoxicity and tau phosphorylation. J Ethnopharmacol 2011; 133:1109-1116.

62. Granic I, Dolga AM, Nijholt IM, van Dijk G, Eisel UL. Inflammation and NF-κB in Alzheimer's disease and diabetes. J Alzheimer's Dis 2009; 16:809-821.

63. Shih R-H, Wang C-Y, Yang C-M. NF-kappaB signaling pathways in neurological inflammation: a mini review. Front Mol Neurosci 2015; 8:77.