Effects of Crocin on Learning and Memory in Rats Under Chronic Restraint Stress with Special Focus on the Hippocampal and Frontal Cortex Corticosterone Levels

Dastgerdi, Azadehalsadat Hosseini; Radahmadi, Maryam; Pourshanazari, Ali Asghar; Dastgerdi, Hajaralsadat Hosseini

Effects of Crocin on Learning and Memory in Rats Under Chronic Restraint Stress with Special Focus on the Hippocampal and Frontal Cortex Corticosterone Levels

Document Type : Original Article

Authors

Department of Physiology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran

Abstract

Background: Chronic stress adversely influences brain functions while crocin, as an effective component of saffron, exhibits positive effects on memory processes. This study investigated the effects of different doses of crocin on the improvement of learning and memory as well as corticosterone (CORT) levels in the hippocampus and frontal cortex of rats subjected to chronic stress. Materials and Methods: Forty male rats were randomly allocated to five different groups (n = 8): Control, sham; stress (6 h/day for 21 days) groups, and two groups receiving daily intraperitoneal injections of one of two doses (30 and 60 mg/kg) of crocin accompanied by 21 days of restraint stress. Latency was evaluated as a brain function using the passive avoidance test before and one-day after a foot shock. CORT levels were measured in the homogenized hippocampus and frontal cortex. Results: Results revealed that chronic stress had a significantly (P < 0.01) negative effect on memory. Crocin (30 and 60 mg/kg), however, gave increase to significantly (P < 0.01 and P < 0.05; respectively) improved memory functions in the stressed rats. Furthermore, the CORT levels in the hippocampus and frontal cortex declined significantly (P < 0.05) in the stress group compared to the control. Only a crocin dose of 30 mg/kg was observed modulate significantly (P < 0.05) the CORT levels in the hippocampus and frontal cortex in the stressed group. Conclusions: It was found that the lower crocin dose (30 mg/kg) had more beneficial effects than its higher (60 mg/kg) dose on learning and memory under chronic stress conditions. Moreover, it was speculated that different doses of crocin act on different neurotransmitters and biochemical factors in the brain.

Keywords

References

1.	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 Suppl 2:493-9.
2.	Radahmadi M, Alaei H, Sharifi MR, Hosseini N. Effects of different timing of stress on corticosterone, BDNF and memory in male rats. Physiol Behav 2015;139:459-67. [PUBMED]
3.	Sahin E, Gümüslü S. Immobilization stress in rat tissues: Alterations in protein oxidation, lipid peroxidation and antioxidant defense system. Comp Biochem Physiol C Toxicol Pharmacol 2007;144:342-7.
4.	Moberg GP. The Biology of Animal Stress: Basic Principles and Implications for Animal Welfare. CABI; 2000. p. 1-21.
5.	Conrad CD. A critical review of chronic stress effects on spatial learning and memory. Prog Neuropsychopharmacol Biol Psychiatry 2010;34:742-55. [PUBMED]
6.	Azadbakht AA, Eidelkhani N, Kazemi M, Radahmadi M, Reisi P. Doxepin improves stress-impaired long-term potentiation and gene expression of BDNF in the rat hippocampus. Physiol Pharmacol 2016;20:231-8.
7.	Radahmadi M, Hosseini N, Nasimi A. Effect of chronic stress on short and long-term plasticity in dentate gyrus; study of recovery and adaptation. Neuroscience 2014;280:121-9. [PUBMED]
8.	Li N, Liu RJ, Dwyer JM, Banasr M, Lee B, Son H, et al. Glutamate N-methyl-D-aspartate receptor antagonists rapidly reverse behavioral and synaptic deficits caused by chronic stress exposure. Biol Psychiatry 2011;69:754-61. [PUBMED]
9.	Holtzer R, Schoen C, Demetriou E, Mahoney JR, Izzetoglu M, Wang C, et al. Stress and gender effects on prefrontal cortex oxygenation levels assessed during single and dual-task walking conditions. Eur J Neurosci 2017;45:660-70.
10.	Cerqueira JJ, Pêgo JM, Taipa R, Bessa JM, Almeida OF, Sousa N. Morphological correlates of corticosteroid-induced changes in prefrontal cortex-dependent behaviors. J Neurosci 2005;25:7792-800.
11.	Sugimoto T, Yoshida M, Ono R, Murata S, Saji N, Niida S, et al. Frontal lobe function correlates with one-year incidence of urinary incontinence in elderly with Alzheimer disease. J Alzheimers Dis 2017;56:567-74.
12.	Kim TK, Han PL. Functional connectivity of basolateral amygdala neurons carrying orexin receptors and melanin-concentrating hormone receptors in regulating sociability and mood-related behaviors. Exp Neurobiol 2016;25:307-17. [PUBMED]
13.	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;183:141-6. [PUBMED]
14.	Mobarakeh JI, Fakhraei N, Sadr ZA, Hamidipour A, Mostafavi E, Hosseini RH, et al. Effect of aqueous, ethanolic and acetonitrile Crocus sativus L. extracts on stress biomarkers in male rats. J Med Plants Res 2013;7:3269-79.
15.	Naghizadeh B, Mansouri MT, Ghorbanzadeh B, Farbood Y, Sarkaki A. Protective effects of oral crocin against intracerebroventricular streptozotocin-induced spatial memory deficit and oxidative stress in rats. Phytomedicine 2013;20:537-42. [PUBMED]
16.	Asdaq SM, Inamdar MN. Potential of Crocus sativus (saffron) and its constituent, crocin, as hypolipidemic and antioxidant in rats. Appl Biochem Biotechnol 2010;162:358-72. [PUBMED]
17.	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 alpha-tocopherol. Neurosci Lett 2004;362:61-4. [PUBMED]
18.	Papandreou MA, Kanakis CD, Polissiou MG, Efthimiopoulos S, Cordopatis P, Margarity M, et al. 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. [PUBMED]
19.	Naghizadeh B, Boroushaki MT, Vahdati Mashhadian N, Mansouri MT. Protective effects of crocin against cisplatin-induced acute renal failure and oxidative stress in rats. Iran Biomed J 2008;12:93-100. [PUBMED]
20.	Abe K, Saito H. Effects of saffron extract and its constituent crocin on learning behaviour and long-term potentiation. Phytother Res 2000;14:149-52. [PUBMED]
21.	Radahmadi M, Alaei H, Sharifi MR, Hosseini N. Preventive and therapeutic effect of treadmill running on chronic stress-induced memory deficit in rats. J Bodyw Mov Ther 2015;19:238-45. [PUBMED]
22.	Avishai-Eliner S, Eghbal-Ahmadi M, Tabachnik E, Brunson KL, Baram TZ. Down-regulation of hypothalamic corticotropin-releasing hormone messenger ribonucleic acid (mRNA) precedes early-life experience-induced changes in hippocampal glucocorticoid receptor mRNA. Endocrinology 2001;142:89-97. [PUBMED]
23.	Radahmadi M, Hosseini N, Alaei H, Sharifi MR. The effect of preventive, therapeutic and protective exercises on hippocampal memory mediators in stressed rats. Malays J Med Sci 2016;23:29-37. [PUBMED]
24.	Yang M, Kim JS, Song MS, Kim SH, Kang SS, Bae CS, et al. Cyclophosphamide impairs hippocampus-dependent learning and memory in adult mice: Possible involvement of hippocampal neurogenesis in chemotherapy-induced memory deficits. Neurobiol Learn Mem 2010;93:487-94. [PUBMED]
25.	Reiriz AB, Reolon GK, Preissler T, Rosado JO, Henriques JA, Roesler R, et al. Cancer chemotherapy and cognitive function in rodent models: Memory impairment induced by cyclophosphamide in mice. Clin Cancer Res 2006;12:5000. [PUBMED]
26.	Huang AC, Shyu BC, Hsiao S, Chen TC, He AB. Neural substrates of fear conditioning, extinction, and spontaneous recovery in passive avoidance learning: A c-fos study in rats. Behav Brain Res 2013;237:23-31. [PUBMED]
27.	Radahmadi M, Alaei H, Sharifi MR, Hosseini N. The effect of synchronized running activity with chronic stress on passive avoidance learning and body weight in rats. Int J Prev Med 2013;4:430-7. [PUBMED]
28.	Radahmadi M, Alaei H, Sharifi MR, Hosseini N. Effect of forced exercise and exercise withdrawal on memory, serum and hippocampal corticosterone levels in rats. Exp Brain Res 2015;233:2789-99. [PUBMED]
29.	Wolf SA, Steiner B, Wengner A, Lipp M, Kammertoens T, Kempermann G. Adaptive peripheral immune response increases proliferation of neural precursor cells in the adult hippocampus. FASEB J 2009;23:3121-8. [PUBMED]
30.	Raju T. Chronic restraint stress impairs acquisition and retention of spatial memory task in rats. Curr Sci 2000;79:1581-5.
31.	Ranjbar H, Radahmadi M, Alaei H, Reisi P, Karimi S. The effect of basolateral amygdala nucleus lesion on memory under acute, mid and chronic stress in male rats. Turk J Med Sci 2016;46:1915-25. [PUBMED]
32.	Ranjbar H, Radahmadi M, Reisi P, Alaei H. Effects of electrical lesion of basolateral amygdala nucleus on rat anxiety-like behaviour under acute, sub-chronic, and chronic stresses. Clin Exp Pharmacol Physiol 2017;44:470-9. [PUBMED]
33.	Ranjbar H, Radahmadi M, Alaei H, Reisi P. Effect of different durations of stress on spatial and cognitive memory in male rats. J Isfahan Med Sch 2015;32:1933-43.
34.	Kim JJ, Diamond DM. The stressed hippocampus, synaptic plasticity and lost memories. Nat Rev Neurosci 2002;3:453-62. [PUBMED]
35.	Mizoguchi K, Yuzurihara M, Ishige A, Sasaki H, Chui DH, Tabira T. Chronic stress induces impairment of spatial working memory because of prefrontal dopaminergic dysfunction. J Neurosci 2000;20:1568-74. [PUBMED]
36.	McEwen BS. Plasticity of the hippocampus: Adaptation to chronic stress and allostatic load. Ann N Y Acad Sci 2001;933:265-77. [PUBMED]
37.	Radahmadi M, Alaei H, Sharifi MR, Hosseini N. Stress biomarker responses to different protocols of forced exercise in chronically stressed rats. J Bodyw Mov Ther 2017;21:63-8. [PUBMED]
38.	Gümüslü S, Sarikçioglu SB, Sahin E, Yargiçoglu P, Agar A. Influences of different stress models on the antioxidant status and lipid peroxidation in rat erythrocytes. Free Radic Res 2002;36:1277-82.
39.	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;667:222-9. [PUBMED]
40.	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;26:381-6. [PUBMED]
41.	Pitsikas N, Tarantilis PA. Crocins, the active constituents of Crocus sativus L. counteracted apomorphine-induced performance deficits in the novel object recognition task, but not novel object location task, in rats. Neurosci Lett 2017;644:37-42. [PUBMED]
42.	Li S, Wang C, Wang W, Dong H, Hou P, Tang Y. Chronic mild stress impairs cognition in mice: From brain homeostasis to behavior. Life Sci 2008;82:934-42. [PUBMED]
43.	Arnsten AF. Stress impairs prefrontal cortical function in rats and monkeys: Role of dopamine D1 and norepinephrine alpha-1 receptor mechanisms. Prog Brain Res 2000;126:183-92. [PUBMED]
44.	Ettehadi H, Mojabi SN, Ranjbaran M, Shams J, Sahraei H, Hedayati M, et al. Aqueous extract of saffron (Crocus sativus) increases brain dopamine and glutamate concentrations in rats. J Behav Brain Sci2013; 3, 315-19.
45.	Aleisa AM, Alzoubi KH, Gerges NZ, Alkadhi KA. Chronic psychosocial stress-induced impairment of hippocampal LTP: Possible role of BDNF. Neurobiol Dis 2006;22:453-62. [PUBMED]
46.	Chen JX, Li W, Zhao X, Yang JX. Effects of the Chinese traditional prescription Xiaoyaosan decoction on chronic immobilization stress-induced changes in behavior and brain BDNF, TrkB, and NT-3 in rats. Cell Mol Neurobiol 2008;28:745-55. [PUBMED]
47.	Harris RB, Mitchell TD, Simpson J, Redmann SM Jr., Youngblood BD, Ryan DH. Weight loss in rats exposed to repeated acute restraint stress is independent of energy or leptin status. Am J Physiol Regul Integr Comp Physiol 2002;282:R77-88.
48.	Hosseinzadeh H, Abootorabi A, Sadeghnia HR. Protective effect of Crocus sativus stigma extract and crocin (trans-crocin 4) on methyl methanesulfonate-induced DNA damage in mice organs. DNA Cell Biol 2008;27:657-64. [PUBMED]
49.	Sullivan RM, Gratton A. Prefrontal cortical regulation of hypothalamic-pituitary-adrenal function in the rat and implications for psychopathology: Side matters. Psychoneuroendocrinology 2002;27:99-114. [PUBMED]
50.	Patel PD, Lopez JF, Lyons DM, Burke S, Wallace M, Schatzberg AF. Glucocorticoid and mineralocorticoid receptor mRNA expression in squirrel monkey brain. J Psychiatr Res 2000;34:383-92. [PUBMED]
51.	Kitchener P, Di Blasi F, Borrelli E, Piazza PV. Differences between brain structures in nuclear translocation and DNA binding of the glucocorticoid receptor during stress and the circadian cycle. Eur J Neurosci 2004;19:1837-46. [PUBMED]

Advanced Biomedical Research