Volume 27, Issue 1 (March 2023)                   Physiol Pharmacol 2023, 27(1): 53-63 | Back to browse issues page

XML Print

Download citation:
BibTeX | RIS | EndNote | Medlars | ProCite | Reference Manager | RefWorks
Send citation to:

Hawiset T, Sriraksa N, Kongsui R, Kamsrijai U, Wanchai K, Inkaew P. Azadirachta indica A. Juss flower extract attenuates memory deficit induced by restraint stress in malerats. Physiol Pharmacol 2023; 27 (1) :53-63
URL: http://ppj.phypha.ir/article-1-1870-en.html
Abstract:   (476 Views)
Introduction: Chronic stress is related to cognitive impairment. Azadirachta indica A. Juss. (A. indica) leaf extract possesses antioxidant and cognitive enhancement effects. Therefore, this study was set up to evaluate the cognitive-enhancing effects of A. indica flower extract in stressed rats.
Methods: Male Wistar rats were randomly divided into control and stress groups. Restraint stress was induced to stress groups 3 h daily. The stressed rats were given vehicles, donepezil (a positive control meditation used to improve cognition), and A. indica at 250, 500, and 1000 mg/kg BW for 30 days. The novel object recognition test (NORT) was used to assess cognitive function, and the open field test (OFT) was utilized to assess spontaneous locomotor activity. Their brains and blood were taken to measure levels of brain-derived neurotrophic factor (BDNF), blood cortisol levels, and the density of survival neurons.
Results: The discrimination index ratio of the stressed rats treated with either donepezil or A. indica flower extract at all doses was significantly improved as measured by NORT. Moreover, there was no significant difference between the control and stress groups in the locomotor behaviors of rearing and number of crossing. The stressed rats treated with donepezil and A. indica flower extract had significantly higher BDNF levels and also survival neuron density in the brain. However, their blood cortisol levels were lower than the stressed rats given the vehicle.
Conclusion: A. indica flower extract helps improve cognitive function in stressed rats by boosting BDNF and protecting against neuronal loss in the brain.
Full-Text [PDF 2713 kb]   (34 Downloads)    

1. Alzohairy MA. Therapeutics role of Azadirachta indica (Neem) and their active constituents in diseases prevention and treatment. Evid Based Complement Alternat Med 2016; 2016: 7382506. [DOI:10.1155/2016/7382506]
2. Ávila-Villanueva M, Gómez-Ramírez J, Maestú F, Venero C, Ávila J, Fernández-Blázquez MA. The role of chronic stress as a trigger for the Alzheimer disease continuum. Front Aging Neurosci 2020; 12: 561504. [DOI:10.3389/fnagi.2020.561504]
3. Behl C, Lezoualc’h F, Trapp T, Widmann M, Skutella T, Holsboer F. Glucocorticoids enhance oxidative stress-induced cell death in hippocampal neurons in vitro. Endocrinology 1997; 138: 101-6. [DOI:10.1210/endo.138.1.4835]
4. Borwicka C, Lala R, Limb LW, Stagg CJ, Aquilia L. Dopamine depletion effects on cognitive flexibility as modulated by tDCS of the dlPFC. Brain Stimulation 2020; 13(1): 105-8. [DOI:10.1016/j.brs.2019.08.016]
5. Chaisawangwong W, Gritsanapan W. Extraction method for high free radical scavenging activity of Siamese neem tree flowers. Songklanakarin J Sci Technol 2009; 31: 419-23.
6. Chen H, Lombès M, Le Menuet D. Glucocorticoid receptor represses brain-derived neurotrophic factor expression in neuron-like cells. Mol Brain 2017; 12; 1-16.
7. Dayi A, Cetin F, Sisman AR, Aksu I, Tas A, Gönenc S, Uysal N. The effects of oxytocin on cognitive defect caused by chronic restraint stress applied to adolescent rats and on hippocampal VEGF and BDNF levels. Med Sci Monit 2015; 21: 69-75. [DOI:10.12659/MSM.893159]
8. de Boer VCJ, Dihal AA, van der Woude H, Arts ICW, Wolffram S, Alink GM, et al. Tissue distribution of quercetin in rats and pigs. J Nutr 2005; 135: 1718-25. [DOI:10.1093/jn/135.7.1718]
9. de Kloet ER, Oitzl MS, Joëls M. Stress and cognition: are corticosteroids good or bad guys? Trends Neurosci 1999; 22, 422-6.
10. Djavadian RL. Serotonin and neurogenesis in the hippocampal dentate gyrus of adult mammals. Acta Neurobiol Exp 2004; 64: 189-200.
11. Duangjai A, Nuengchanong N, Lee LH, Goh BH, Sakaew S, Suphrom N. Characterisation of an extract and fractions of Azadirachta indica flower on cholesterol lowering property and intestinal motility. Nat Prod Res 2019; 33: 1491-4 [DOI:10.1080/14786419.2017.1416386]
12. Eid A, Jaradat N, Elmarzugi N. A review of chemical constituents and traditional usage of Neem plant (Azadirachta indica). Pal Med Pharm J 2017; 2: 75-81.
13. Hall CS. Emotional behavior in the rat. I. Defecation and urination as measures of individual differences in emotionality. J Comp Psychol 1934; 18: 385-403.
14. Hawiset T, Sriraksa N, Kamsrijai U, Wanchai K, Inkaew P. Anxiolytic and antidepressant-like activities of aqueous extract of Azadirachta indica A. Juss. flower in the stressed rats. Heliyon 2022; 8: e08881.
15. Huang EJ, Reichardt LF. Neurotrophins: roles in neuronal development and function. Ann Rev Neurosci 2001; 24: 677-736. [DOI:10.1146/annurev.neuro.24.1.677]
16. Husain M, Mehta MA. Cognitive enhancement by drugs in health and disease. Trends Cogn Sci 2011; 15: 28-36. [DOI:10.1016/j.tics.2010.11.002]
17. Jaiswal AK, Bhattacharya SK, Acharya SB. Anxiolytic activity of Azadirachta indica leaf extract in rats. Indian J Exp Biol 1994; 32: 489-91.
18. Jenkins TA, Nguyen JCD, Polglaze KE, Bertrand PP. Influence of tryptophan and serotonin on mood and cognition with a possible role of the gut-brain axis. Nutrients 2016; 8: 56. [DOI:10.3390/nu8010056]
19. Khan S, Khan RA. Chronic stress leads to anxiety and depression. Ann Psychiatry Mental Health 2017; 5: 1091.
20. Kim JJ, Diamond DM. The stressed hippocampus, synaptic plasticity and lost memories. Nat Rev Neurosci 2002; 3: 453-62. [DOI:10.1038/nrn849]
21. Kumar A, Rinwa P, Kaur G, Machawal L. Stress: Neurobiology, consequences and management. J Pharm Bioallied Sci 2013; 5: 91-7. [DOI:10.4103/0975-7406.111818]
22. Li Y, Zhou S, Li J, Sun Y, Hasimu H, Liu R, Zhang T. Quercetin protects human brain microvascular endothelial cells from fibrillar β-amyloid1-40-induced toxicity. Acta Pharm Sin B 2015; 5: 47-54. [DOI:10.1016/j.apsb.2014.12.003]
23. Lin J, Huang L, Yu J, Xiang S, Wang J, Zhang J, et al. Fucoxanthin, a marine carotenoid, reverses scopolamine-induced cognitive impairments in mice and inhibits acetylcholinesterase in vitro. Mar drugs 2016; 14: 67. [DOI:10.3390/md14040067]
24. Lupien SJ, McEwen BS. The acute effects of corticosteroids on cognition: Integration of animal and human model studies. Brain Res Rev 1997; 24: 1-27. [DOI:10.1016/S0165-0173(97)00004-0]
25. Martinowich K, Lu B. Interaction between BDNF and serotonin: role in mood disorders. Neuropsychopharmacology 2008; 33: 73-83. [DOI:10.1038/sj.npp.1301571]
26. McEwen BS, Nasca C, Gray JD. Stress effects on neuronal structure: hippocampus, amygdala, and prefrontal cortex. Neuropsychopharmacology 2016; 41: 3-23. [DOI:10.1038/npp.2015.171]
27. McLaughlin KJ, Gomez JL, Baran E, Conrad CD. The effects of chronic stress on hippocampal morphology and function: an evaluation of chronic restraint paradigms. Brain Res 2007; 1161: 56-64. [DOI:10.1016/j.brainres.2007.05.042]
28. Miranda M, Morici JF, Zanoni MB, Bekinschtein P. Brain-derived neurotrophic factor: a key molecule for memory in the healthy and the pathological brain. Front Cell Neurosci 2019; 13: 363. [DOI:10.3389/fncel.2019.00363]
29. Mohammadi HS, Goudarzi I, Lashkarbolouki T, Abrari K, Salmani ME. Chronic administration of quercetin prevent spatial learning and memory deficits provoked by chronic stress in rats. Behav Brain Res 2014; 270: 196-205. [DOI:10.1016/j.bbr.2014.05.015]
30. Nakagawa T, Ohta K. Quercetin regulates the integrated stress response to improve memory. Int J Mol Sci 2019; 20: 2761. [DOI:10.3390/ijms20112761]
31. Numakawa T, Odaka H, Adachi N. Actions of brain-derived neurotrophin factor in the neurogenesis and neuronal function, and its involvement in the pathophysiology of brain diseases. Int J Mol Sci 2018; 19: 3650. [DOI:10.3390/ijms19113650.]
32. Ohira K. Dopamine as a growth differentiation factor in the mammalian brain. Int J Mol Sci 2017; 18: 2312.
33. Ortiz JB, Mathewson CM, Hoffman AN, Hanavan PD, Terwilliger EF, Conrad CD. Hippocampal brain-derived neurotrophic factor mediates recovery from chronic stress-induced spatial reference memory deficits. Eur J Neurosci 2014; 40: 3351-3362. [DOI:10.1111/ejn.12703]
34. Paxinos G, Watson C, editors. The rat brain in stereotaxic coordinates. United States of America: Academic Press, Inc., 1997, p. 55.
35. Raghavendra M, Maiti R, Kumar S, Acharya SB. Role of aqueous extract of Azadirachta indica leaves in an experimental model of Alzheimer’s disease in rats. Int J Appl Basic Med Res 2013; 3: 37-47. [DOI:10.4103/2229-516X.112239]
36. Ren S, Suo Q, Du W, Pan H, Yang M, Wang R, et al. Quercetin permeability across blood-brain barrier and its effect on the viability of U251 cells. J Sichuan Univ 2010; 41: 751-9.
37. 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. [DOI:10.1016/j.cbpc.2006.10.009]
38. Salleh MR. Life Event, Stress and Illness. Malays J Med Sci 2008; 15: 9-18.
39. Samad N, Saleem A, Yasmin F, Shehzad MA. Quercetin protects against stress-induced anxiety- and depression-like behavior and improves memory in male mice. Physiol Res 2018; 67: 795-808. [DOI:10.33549/physiolres.933776]
40. Sandi C, Pinelo-Nava MT. Stress and Memory: Behavioral effects and neurobiological mechanisms. Neural Plast 2007; 2007: 78970. [DOI:10.1155/2007/78970]
41. Sen P, Mediratta PK, Ray A. Effects of Azadirachta indica A Juss on some biochemical, immunological and visceral parameters in normal and stressed rats. Indian J Exp Biol 1992; 30: 1170-5.
42. Shirai M, Kawai Y, Yamanishi R, Kinoshita T, Chuman H, Terao J. Effect of a conjugated quercetin metabolite, quercetin 3-glucuronide, on lipid hydroperoxide-dependent formation of reactive oxygen species in differentiated PC-12 cells. Free Radic Res 2006; 40: 1047-53. [DOI:10.1080/10715760600794287]
43. Smith MA, Makino S, Kvetnansky R, Post RM. Stress and glucocorticoids affect the expression of brain-derived neurotrophic factor and neurotrophin-3 mRNAs in the hippocampus. J Neurosci 1995; 15: 1768-77. [DOI:10.1523/JNEUROSCI.15-03-01768.1995]
44. Sriraksa N, Kongsui R, Thongrong S, Duangjai A, Hawiset T. Effect of Azadirachta indica flower extract on functional recovery of sciatic nerve crush injury in rat models of DM. Exp Ther Med 2019; 17: 541-50.
45. Stier A, Schull Q, Bize P, Lefol E, Haussmann M, Roussel D, et al. Oxidative stress and mitochondrial responses to stress exposure suggest that king penguins are naturally equipped to resist stress. Sci Reports 2019; 8545: 1-12. [DOI:10.1038/s41598-019-44990-x]
46. Sun D, Zhong G, Cao HX, Hu Y, Hong XY, Li T, et al. Repeated restraint stress led to cognitive dysfunction by NMDA receptor-mediated hippocampal CA3 dendritic spine impairments in juvenile sprague-dawley rats. Front Mol Neurosci 2020; 13: 552787. [DOI:10.3389/fnmol.2020.552787]
47. Thippeswamy BS, Mishra B, Veerapur VP, Gupta G. Anxiolytic activity of Nymphaea alba Linn. in mice as experimental models of anxiety. Indian J Pharmacol 2011; 43: 50-5. [DOI:10.4103/0253-7613.75670]
48. Vellucci SV, Parrott RF, Mimmack ML. Down-regulation of BDNF mRNA, with no effect on trkB or glucocorticoid receptor m RNAs, in the porcine hippocampus after acute dexamethasone treatment. Res Vet Sci 2001; 70: 157-62. [DOI:10.1053/rvsc.2001.0456]
49. Wang DM, Li SQ, Wu WL, Zhu XY, Wang Y, Yuan HY. Effects of long-term treatment with quercetin on cognition and mitochondrial function in a mouse model of Alzheimer’s disease. Neurochem Res 2014; 39:1533-43. [DOI:10.1007/s11064-014-1343-x]
50. Wang Y, Kan H, Yin Y, Wu W, Hu W, Wang M, et al. Protective effects of ginsenoside Rg1 on chronic restraint stress induced learning and memory impairments in male mice. Pharmacol Biochem Behav 2014; 120: 73-81. [DOI:10.1016/j.pbb.2014.02.012]
51. Wanchai K, Hawiset T, Khumsrijai U, Sriraksa N. Azadirachta indica flower extract attenuates kidney oxidative stress in rat exposed to restraint stress. Thai Pharm. Health Sci J 2021; 16: 380-5.
52. Woo H, Hong CJ, Jung S, Choe S, Yu SW. Chronic restraint stress induces hippocampal memory deficits by impairing insulin signaling. Mol Brain 2018; 37: 1-13. [DOI:10.1186/s13041-018-0381-8]
53. Yeh SL, Yeh CL, Chan ST, Chuang CH. Plasma rich in quercetin metabolites induces G2/M arrest by upregulating PPAR-γ expression in human A549 lung cancer cells. Planta Med 2011; 77: 992-8. [DOI:10.1055/s-0030-1250735]

Rights and permissions
Creative Commons License This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.