Effects of Hesperidin on Memory Impairments Induced by Methotrexate in Adult Rats

Authors

  • Salinee Naewla Department of Anatomy, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand.
  • Kornrawee Suwannakot Department of Anatomy, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand.
  • Wanassanun Pannangrong Department of Anatomy, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand.
  • Jariya Umka Welbat Department of Anatomy, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand.

Keywords:

Hesperidin; Methotrexate; Memory impairment

Abstract

Background and objectives: Methotrexate is a chemotherapy drug used to treat many different cancers. Several studies have reported that methotrexate has neurotoxic effects, leading to memory impairments. Hesperidin is a natural compound which exhibits anti-inflammatory and antioxidant properties. Furthermore, hesperidin enhances learning and memory. Therefore, the aim of this study was to investigate the effect of hesperidin on memory impairment caused by methotrexate.

Methods: Twenty-four male Sprague Dawley rats (age: 4-5 weeks) were divided into 4 groups (6 animals/group). Vehicle group received saline and propylene glycol. Hesperidin group received hesperidin only. Finally, methotrexate group received only methotrexate and methotrexate+hesperidin group received both methotrexate and hesperidin. A single dose of methotrexate (75 mg/kg) was administered by intravenous injection on day 8 and 15. Hesperidin (100 mg/kg) was administered per oral for 21 days. Three days after the end of drug administration, memory was tested using the novel object location and novel object recognition.

Results: The results showed that total exploration time was not significantly different among groups in both novel object location and novel object recognition tests (p>0.05). In novel object location test, rats in vehicle, hesperidin and methotrexate+hesperidin groups could significantly discriminate between the objects placed in the novel and familiar locations (p< 0.05). Similar, in the novel object recognition test, rats in vehicle, hesperidin and methotrexate+hesperidin groups could significantly discriminate between the novel and familiar objects, whereas rats in methotrexate group did not discriminate between the novel and familiar objects (p<0.05).

Conclusion: The results of this experiment indicated that hesperidin is able to prevent and improve the memory impairments induced by methotrexate in adult rats.

References

1. Wigmore P. The effect of systemic chemotherapy on neurogenesis, plasticity and memory. Curr Top Behav Neurosci. 2013; 15: 211-40.
2. Monje M, Dietrich J. Cognitive side effects of cancer therapy demonstrate a functional role for adult neurogenesis. Behav Brain Res. 2012; 227: 376-9.
3. Dietrich J. Chemotherapy associated central nervous system damage. Adv Exp Med Biol. 2010; 678: 77-85.
4. Kunin-Batson A, Kadan-Lottick N, Neglia JP. The contribution of neurocognitive functioning to quality of life after childhood acute lymphoblastic leukemia. Psychooncology. 2014; 23: 692-9.
5. Pincus T, Ferraccioli G, Sokka T, Larsen A, Rau R, Kushner I, et al. Evidence from clinical trials and long-term observational studies that disease-modifying anti-rheumatic drugs slow radiographic progression in rheumatoid arthritis: updating a 1983 review. Rheumatology (Oxford). 2002; 41: 1346-56.
6. Vezmar S, Becker A, Bode U, Jaehde U. Biochemical and clinical aspects of methotrexate neurotoxicity. Chemotherapy. 2003; 49: 92-104.
7. Krull KR, Brinkman TM, Li C, Armstrong GT, Ness KK, Srivastava DK, et al. Neurocognitive outcomes decades after treatment for childhood acute lymphoblastic leukemia: a report from the St Jude lifetime cohort study. J Clin Oncol. 2013; 31: 4407-15.
8. Seigers R, Schagen SB, Beerling W, Boogerd W, van Tellingen O, van Dam FS, et al. Long-lasting suppression of hippocampal cell proliferation and impaired cognitive performance by methotrexate in the rat. Behav Brain Res. 2008; 186: 168-75.
9. Phillips DC, Woollard KJ, Griffiths HR. The anti-inflammatory actions of methotrexate are critically dependent upon the production of reactive oxygen species. Br J Pharmacol. 2003; 138: 501-11.
10. Herman S, Zurgil N, Deutsch M. Low dose methotrexate induces apoptosis with reactive oxygen species involvement in T lymphocytic cell lines to a greater extent than in monocytic lines. Inflamm Res. 2005; 54: 273-80.
11. Huang C, Hsu P, Hung Y, Liao Y, Liu C, Hour C, et al. Ornithine decarboxylase prevents methotrexate-induced apoptosis by reducing intracellular reactive oxygen species production. Apoptosis. 2005; 10: 895-907.
12. Hsu PC, Hour TC, Liao YF, Hung YC, Liu CC, Chang WH, et al. Increasing ornithine decarboxylase activity is another way of prolactin preventing methotrexate-induced apoptosis: crosstalk between ODC and BCL-2. Apoptosis. 2006; 11: 389-99.
13. Garg A, Garg S, Zaneveld LJ, Singla AK. Chemistry and pharmacology of the Citrus bioflavonoid hesperidin. Phytother Res. 2001; 15: 655-69.
14. Tamilselvam K, Braidy N, Manivasagam T, Essa MM, Prasad NR, Karthikeyan S, et al. Neuroprotective effects of hesperidin, a plant flavanone, on rotenone-induced oxidative stress and apoptosis in a cellular model for Parkinson's disease. Oxid Med Cell Longev. 2013; 2013: 102741.
15. Mandel S, Youdim MB. Catechin polyphenols: neurodegeneration and neuroprotection in neurodegenerative diseases. Free Radic Biol Med. 2004; 37: 304-17.
16. Spencer JP. The interactions of flavonoids within neuronal signalling pathways. Genes Nutr. 2007; 2: 257-73.
17. Wang D, Liu L, Zhu X, Wu W, Wang Y. Hesperidin alleviates cognitive impairment, mitochondrial dysfunction and oxidative stress in a mouse model of Alzheimer's disease. Cell Mol Neurobiol. 2014; 34: 1209-21.
18. Boarman DM, Baram J, Allegra CJ. Mechanism of leucovorin reversal of methotrexate cytotoxicity in human MCF-7 breast cancer cells. Biochem Pharmacol.. 1990; 40: 2651-60.
19. Dix SL, Aggleton JP. Extending the spontaneous preference test of recognition: evidence of object-location and object-context recognition. Behav Brain Res. 1999; 99: 191-200.
20. Lyons L, ElBeltagy M, Umka J, Markwick R, Startin C, Bennett G, et al. Fluoxetine reverses the memory impairment and reduction in proliferation and survival of hippocampal cells caused by methotrexate chemotherapy. Psychopharmacology. 2011; 215: 105-15.
21. Antunes M, Biala G. The novel object recognition memory: neurobiology, test procedure, and its modifications. Cogn Process. 2012;13(2):93-110.
22. Umka J, Mustafa S, ElBeltagy M, Thorpe A, Latif L, Bennett G, et al. Valproic acid reduces spatial working memory and cell proliferation in the hippocampus. Neuroscience. 2010; 166: 15-22.
23. Sirichoat A, Chaijaroonkhanarak W, Prachaney P, Pannangrong W, Leksomboon R, Chaichun A, et al. Effects of Asiatic Acid on Spatial Working Memory and Cell Proliferation in the Adult Rat Hippocampus. Nutrients. 2015; 7: 8413-23.
24. Chaisawang P, Sirichoat A, Chaijaroonkhanarak W, Pannangrong W, Sripanidkulchai B, Wigmore P, et al. Asiatic acid protects against cognitive deficits and reductions in cell proliferation and survival in the rat hippocampus caused by 5-fluorouracil chemotherapy. PLoS One . 2017; 12: e0180650.
25. Keefe DM, Brealey J, Goland GJ, Cummins AG. Chemotherapy for cancer causes apoptosis that precedes hypoplasia in crypts of the small intestine in humans. Gut. 2000; 47: 632-7.
26. Yano S, Umeda D, Yamashita T, Ninomiya Y, Sumida M, Fujimura Y, et al. Dietary flavones suppresses IgE and Th2 cytokines in OVA-immunized BALB/c mice. Eur J Nutr. 2007; 46: 257-63.
27. Jenkins LW, Povlishock JT, Lewelt W, Miller JD, Becker DP. The role of postischemic recirculation in the development of ischemic neuronal injury following complete cerebral ischemia. Acta Neuropathol. 1981; 55: 205-20.
28. Winocur G, Vardy J, Binns MA, Kerr L, Tannock I. The effects of the anti-cancer drugs, methotrexate and 5-fluorouracil, on cognitive function in mice. Pharmacol Biochem Behav. 2006; 85: 66-75.
29. Yang M, Kim JS, Kim J, Kim SH, Kim JC, Kim J, et al. Neurotoxicity of methotrexate to hippocampal cells in vivo and in vitro. Biochem Pharmacol. 2011; 82: 72-80.
30. Seigers R, Pourtau L, Schagen SB, van Dam FS, Koolhaas JM, Konsman JP, et al. Inhibition of hippocampal cell proliferation by methotrexate in rats is not potentiated by the presence of a tumor. Brain Res Bull. 2010; 81: 472-6.
31. Youdim KA, Dobbie MS, Kuhnle G, Proteggente AR, Abbott NJ, Rice-Evans C. Interaction between flavonoids and the blood-brain barrier: in vitro studies. J Neurochem. 2003; 85: 180-92.
32. Uzar E, Sahin O, Koyuncuoglu HR, Uz E, Bas O, Kilbas S, et al. The activity of adenosine deaminase and the level of nitric oxide in spinal cord of methotrexate administered rats: protective effect of caffeic acid phenethyl ester. Toxicology. 2006; 218: 125-33.
33. Uz E, Oktem F, Yilmaz HR, Uzar E, Ozguner F. The activities of purine-catabolizing enzymes and the level of nitric oxide in rat kidneys subjected to methotrexate: protective effect of caffeic acid phenethyl ester. Mol Cell Biochem. 2005; 277: 165-70.
34. Celik H, Kosar M. Inhibitory effects of dietary flavonoids on purified hepatic NADH-cytochrome b5 reductase: structure-activity relationships. Chem Biol Interact. 2012; 197: 103-9.
35. Hong Y, An Z. Hesperidin attenuates learning and memory deficits in APP/PS1 mice through activation of Akt/Nrf2 signaling and inhibition of RAGE/NF-kappaB signaling. Arch Pharm Res. 2018; 41: 655-663.

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Published

2019-02-20

How to Cite

1.
Naewla S, Suwannakot K, Pannangrong W, Welbat JU. Effects of Hesperidin on Memory Impairments Induced by Methotrexate in Adult Rats. SRIMEDJ [Internet]. 2019 Feb. 20 [cited 2024 Apr. 25];34(1):26-35. Available from: https://li01.tci-thaijo.org/index.php/SRIMEDJ/article/view/173283

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