Home Rutin ameliorates scopolamine-induced learning and memory impairments through enhancement of antioxidant defense system and cholinergic signaling
Article
Licensed
Unlicensed Requires Authentication

Rutin ameliorates scopolamine-induced learning and memory impairments through enhancement of antioxidant defense system and cholinergic signaling

  • Ismail O. Ishola EMAIL logo , Taiwo G. Olubodun-Obadun , Mariam A. Ojulari and Olufunmilayo O. Adeyemi
Published/Copyright: September 30, 2020

Abstract

Objectives

The brain’s cholinergic system occupies a central role in normal cognition and age-related cognitive decline, including Alzheimer’s disease (AD). This study sought to investigate the role of antioxidant defense and cholinergic systems on rutin-induced antiamnesia in mice.

Methods

Rutin (1, 5, or 50 mg/kg, p.o.) or vehicle (10 ml/kg, p.o.) was administered for three consecutive days. One hour post-treatment on day 3, scopolamine (3 mg/kg, i.p) was given, 5 min post-scopolamine injection, open field, Y-maze, or Morris water maze (MWM) (five days consecutive training sessions) tasks was carried out. The mice were sacrificed on day 7 to assays for biomarkers of oxidative stress and cholinergic system.

Results

Scopolamine significantly reduced spontaneous alternation behavior in Y-maze and prolonged escape latency in MWM tasks when compared to vehicle-treated control indicative of working memory and spatial learning deficits. However, the pretreatment of mice with rutin (1, 5, or 50 mg/kg) prevented scopolamine-induced working memory and spatial learning impairments without affecting spontaneous locomotor activity. Scopolamine-induced nitrosative/oxidative stress and increased acetylcholinesterase activity in the prefrontal cortex and hippocampus were significantly attenuated by the pretreatment of mice with rutin.

Conclusions

rutin restored cognitive function in scopolamine-induced amnesia through enhancement of antioxidant defense and cholinergic systems.


Corresponding author: Ismail O. Ishola, PhD, Department of Pharmacology, Therapeutics and Toxicology, Faculty of Basic Medical Sciences, College of Medicine, University of Lagos, Lagos, Nigeria, Phone: +2348033018908, E-mail:

Acknowledgments

We are grateful to Mr. M. C. Chijioke of the Department of Pharmacology, Therapeutics and Toxicology, CMUL for his technical assistance.

  1. Research funding: None declared.

  2. Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.

  3. Competing interests: Authors state no conflict of interest.

  4. Informed consent: Informed consent was obtained from all individuals included in this study.

  5. Ethical approval: The study was approved by the Health Research Ethics Committee of the College of Medicine, University of Lagos, Nigeria (CMUL/HREC/10/17/450) and is in accordance with the United States National Institute of Health Guidelines for Care and Use of Laboratory Animals in Biochemical Research (2002).

References

1. Hampel, H, Mesulam, MM, Cuello, AC, Farlow, MR, Giacobini, E, Grossberg, GT, et al. The cholinergic system in the pathophysiology and treatment of Alzheimer’s disease. Brain 2018;141:1917–33. https://doi.org/10.1093/brain/awy132.Search in Google Scholar

2. Pepeu, G, Grazia Giovannini, M. The fate of the brain cholinergic neurons in neurodegenerative diseases. Brain Res 2017;1670:173–84. https://doi.org/10.1016/j.brainres.2017.06.023.Search in Google Scholar

3. Kidd, PM. Alzheimer’s disease, amnestic mild cognitive impairment, and age-associated memory impairment: current understanding and progress toward integrative prevention. Altern Med Rev 2008;13:85–115. 18590347.Search in Google Scholar

4. Nunomura, A, Perry, G, Pappolla, MA, Wade, R, Hirai, K, Chiba, S, et al. RNA oxidation is a prominent feature of vulnerable neurons in Alzheimer’s disease. J Neurosci 1999 Mar 15;19:1959–64. https://doi.org/10.1523/jneurosci.19-06-01959.1999.Search in Google Scholar

5. Kamat, PK, Kalani, A, Rai, S, Swarnkar, S, Tota, S, Nath, C, et al. Mechanism of oxidative stress and synapse dysfunction in the pathogenesis of Alzheimer’s disease: understanding the therapeutics strategies. Mol Neurobiol 2016;53:648–661. https://doi.org/10.1007/s12035-014-9053-6.Search in Google Scholar

6. Ishola, IO, Adamson, FM, Adeyemi, OO. Ameliorative effect of Kolaviron, a biflavonoid complex from Garcinia kola seeds against scopolamine-induced memory impairment in rats: role of antioxidant defense system. Metab Brain Dis 2017;32:235–45. https://doi.org/10.1007/s11011-016-9902-2.Search in Google Scholar

7. Di Domenico, F, Barone, E, Perluigi, M, Butterfield, DA. Strategy to reduce free radical species in Alzheimer’s disease: an update of selected antioxidants. Expert Rev Neurother 2015;15:19–40. https://doi.org/10.1586/14737175.2015.955853.Search in Google Scholar

8. Anand David, AV, Arulmoli, R, Parasuraman, S. Overviews of biological importance of quercetin: a bioactive flavonoid. Pharmacogn Rev 2016;10:84–9. https://doi.org/10.4103/0973-7847.194044.Search in Google Scholar

9. Wobst, HJ, Sharma, A, Diamond, MI, Wanker, EE, Bieschke, J. The green tea polyphenol (–)-epigallocatechin gallate prevents the aggregation of tau protein into toxic oligomers at substoichiometric ratios. FEBS Lett 2015;589:77–83. https://doi.org/10.1016/j.febslet.2014.11.026.Search in Google Scholar

10. Lopez del Amo, JM, Fink, U, Dasari, M, Grelle, G, Wanger, EE, Bieschke, J, et al. Structural properties of EGCG-induced, nontoxic Alzheimer’s disease Aβ oligomers. J Mol Biol 2012;421:517–524. https://doi.org/10.1016/j.jmb.2012.01.013.Search in Google Scholar

11. Hosseinzadeh, H, Nassiri-Asl, M. Review of the protective effects of rutin on the metabolic function as an important dietary flavonoid. J Endocrinol Invest 2014;37:783–8. https://doi.org/10.1007/s40618-014-0096-3.Search in Google Scholar

12. Al-Shabib, NA, Khan, JM, Malik, A, Sen, P, Alsenaidy, MA, Husain, FM, et al. A quercetin-based flavanoid (rutin) reverses amyloid fibrillation in β-lactoglobulin at pH 2.0 and 358 K. Spectrochim Acta A Mol Biomol Spectrosc 2019;214:40–48. https://doi.org/10.1016/j.saa.2019.02.004.Search in Google Scholar

13. Aitken, JF, Loomes, KM, Riba-Garcia, I, Unwin, RD, Prijic, G, Phillips, AS, et al. Rutin suppresses human-amylin/hIAPP misfolding and oligomer formation in-vitro, and ameliorates diabetes and its impacts in human-amylin/hIAPP transgenic mice. Biochem Biophys Res Commun 2017 Jan 22;482:625–31. https://doi.org/10.1016/j.bbrc.2016.11.083.Search in Google Scholar

14. Patil, SL, Rao, NB, Somashekarappa, HM, Rajashekhar, KP. Antigenotoxic potential of rutin and quercetin in Swiss mice exposed to gamma radiation. Biomed J 2014;37:305–13. https://doi.org/10.4103/2319-4170.132880.Search in Google Scholar

15. Moghbelinejad, S, Nassiri-Asl, M, Farivar, TN, Abbasi, E, Sheikhi, M, Taghiloo, M, et al. Hajiali F Rutin activates the MAPK pathway and BDNF gene expression on beta-amyloid induced neurotoxicity in rats. Toxicol Lett 2014;224:108–13. https://doi.org/10.1016/j.toxlet.2013.10.010.Search in Google Scholar

16. Ramalingayya, GV, Nampoothiri, M, Nayak, PG, Kishore, A, Shenoy, RR, Mallikarjuna Rao, C, et al. Naringin and rutin alleviates episodic memory deficits in two differentially challenged object recognition tasks. Pharmacogn Mag 2016;12:S63–70. https://doi.org/10.4103/0973-1296.176104.Search in Google Scholar

17. Ishola, IO, Osele, MO, Chijioke, MC, Adeyemi, OO. Isorhamnetin enhanced cortico-hippocampal learning and memory capability in mice with scopolamine-induced amnesia: role of antioxidant defense, cholinergic and BDNF signaling. Brain Res 2019;1712:188–96. https://doi.org/10.1016/j.brainres.2019.02.017.Search in Google Scholar

18. Ishola, IO, Awoyemi, AA, Afolayan, GO. Involvement of antioxidant system in the amelioration of scopolamine-induced memory impairment by grains of paradise (Aframomum melegueta K. Schum.) extract. Drug Res (Stuttg). 2016;66:455–463. https://doi.org/10.1055/s-0042-109391.Search in Google Scholar

19. Ishola, IO, Adeyemi, OO, Agbaje, EO, Tota, S, Shukla, R. Combretum mucronatum and Capparis thonningii prevent scopolamine-induced memory deficit in mice. Pharm Biol 2013;51:49–5. https://doi.org/10.3109/13880209.2012.704518.Search in Google Scholar

20. Sedlák, J, Hanus, L. Changes of glutathione and protein bound SH-groups concentration in rat adrenals under acute and repeated stress. Endocrinol Exp 1982;16:103–9, 6980783.Search in Google Scholar

21. Nauseef, WM. Detection of superoxide anion and hydrogen peroxide production by cellular NADPH oxidases. Biochim Biophys Acta 2014;1840:757–767. https://doi.org/10.1016/j.bbagen.2013.04.040.Search in Google Scholar

22. Green, A, Ellis, KA, Ellis, J, Bartholomeusz, CF, Ilic, S, Croft, RJ, Phan, KL, Nathan, PJ. Muscarinic and nicotinic receptor modulation of object and spatial n-back working memory in humans. Pharmacol Biochem Behav 2005;81:575–84. https://doi.org/10.1016/j.pbb.2005.04.010.Search in Google Scholar

23. Sinha, AK. Colorimetric assay of catalase. Anal Biochem 1972;47:389–394. https://doi.org/10.1016/0003-2697(72)90132-7.Search in Google Scholar

24. Riener, CK, Kada, G, Gruber, HJ. Quick measurement of protein sulfhydryls with Ellman’s reagent and with 4,4’-dithiodipyridine. Anal Bioanal Chem 2002;373:266–276. https://doi.org/10.1007/s00216-002-1347-2.Search in Google Scholar

25. Haider, S, Batool, Z, Ahmad, S, Siddiqui, RA, Haleem, DJ. Walnut supplementation reverses the scopolamine-induced memory impairment by restoration of cholinergic function via mitigating oxidative stress in rats: a potential therapeutic intervention for age related neurodegenerative disorders. Metab Brain Dis 2018;33:39–51. https://doi.org/10.1007/s11011-017-0120-3.Search in Google Scholar

26. Terry, AVJr. Spatial navigation (water maze) tasks. In: Buccafusco, JJ, editor. Methods of behavior analysis in neuroscience, 2nd ed. Boca Raton (FL): CRC Press/Taylor & Francis; 2009.Chapter 13.10.1201/9781420041811.ch10Search in Google Scholar

27. Tönnies, E, Trushina, E. Oxidative stress, synaptic dysfunction, and Alzheimer’s disease. J Alzheimers Dis 2017;57:1105–21. https://doi.org/10.3233/jad-161088.Search in Google Scholar

28. Chen, Z, Zhong, C. Oxidative stress in Alzheimer’s disease. Neurosci Bull 2014;30:271–81. https://doi.org/10.1007/s12264-013-1423-y.Search in Google Scholar

29. Xu, PX, Wang, SW, Yu, XL, Su, YJ, Wang, T, Zhou, WW, et al. Rutin improves spatial memory in Alzheimer’s disease transgenic mice by reducing Aβ oligomer level and attenuating oxidative stress and neuroinflammation. Behav Brain Res 2014;264:173–80. https://doi.org/10.1016/j.bbr.2014.02.002.Search in Google Scholar

30. Enogieru, AB, Haylett, W, Hiss, DC, Bardien, S, Ekpo, OE. Rutin as a potent antioxidant: implications for neurodegenerative disorders. Oxid Med Cell Longev 2018:6241017. https://doi.org/10.1155/2018/6241017.Search in Google Scholar

31. Haam, J, Yakel, JL. Cholinergic modulation of the hippocampal region and memory function. J Neurochem 2017;142:111–21. https://doi.org/10.1111/jnc.14052.Search in Google Scholar

32. Ferreira-Vieira, TH, Guimaraes, IM, Silva, FR, Ribeiro, FM. Alzheimer’s disease: targeting the cholinergic system. Curr Neuropharmacol 2016;14:101–15. https://doi.org/10.2174/1570159x13666150716165726.Search in Google Scholar

Received: 2020-05-02
Accepted: 2020-08-07
Published Online: 2020-09-30

© 2020 Walter de Gruyter GmbH, Berlin/Boston

Downloaded on 15.9.2025 from https://www.degruyterbrill.com/document/doi/10.1515/dmpt-2020-0118/html
Scroll to top button