Effect of Chrysin on Methotrexate Chemotherapy Induced Reductions of Memory and Hippocampal Neurogenesis in Adult Rats
Keywords:
Chrysin; Methotrexate; Memory impairmentAbstract
Background and objective: Methotrexate (MTX)is a chemotherapy drug that is the most widely used to protect against many malignancies. Several reports have shown that MTX can induce cognitive impairment. Chrysin is a natural flavonoid that is found in natural products. Previous studies have found that chrysin has neuroprotective and cognitive improving properties. Therefore, this study was designed to determine the protective effect of chrysin against MTX-induced memory impairments.
Methods: Seventy-two male Sprague Dawley rats were divided into 6 groups; control, MTX, chrysin 10, chrysin 30, chrysin 10+MTX and chrysin 30+MTX groups. The control group received saline and propylene glycol. Chrysin (10 and 30 mg/kg) was administered by oral gavage for 15 days. A single dose of MTX (75 mg/kg) was administered by intravenous injection on days 8 and 15. Three days after the end of drug administration, the body weight and locomotor activity were determined. The memories were evaluated using novel object location (NOL) and novel object recognition (NOR) tests.
Results: The data of all groups showed no significant differences in term of total exploration times. In both the NOL and NOR tests, the control, chrysin 10, chrysin 30, chrysin 10+MTX and chrysin 30+MTX groups could significantly discriminate between the familiar and novel location or object except the MTX group.
Conclusion: This study demonstrates that MTX induces memory impairment. In contrast, chrysin could improve memory impairment in rats received MTX.
References
2. Kremer JM. Toward a better understanding of methotrexate. Arthritis Rheum 2004; 50(5): 1370-1382.
3. Foley JJ, Raffa RB, Walker EA. Effects of chemotherapeutic agents 5-fluorouracil and methotrexate alone and combined in a mouse model of learning and memory. Psychopharmacology 2008; 199(4): 527-38.
4. 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(7): e0180650.
5. Mustafa S, Walker A, Bennett G, Wigmore P. 5-Fluorouracil chemotherapy affects spatial working memory and newborn neurons in the adult rat hippocampus. Eur J Neurosci 2008; 28: 323-330.
6. Naewla S, Sirichoat A, Pannangrong W, Chaisawang P, Wigmore P, Welbat J. Hesperidin alleviates methotrexate-induced memory deficits via hippocampal neurogenesis in adult rats. Nutrients 2019; 11: 936.
7. 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: 8413-8423.
8. Yao Y, Chen L, Xiao J, Wang C, Jiang W, Zhang R, et al. Chrysin protects against focal cerebral ischemia/reperfusion injury in mice through attenuation of oxidative stress and inflammation. Int J Mol Sci 2014; 15: 20913-20926.
9. He X-L, Wang Y-H, Bi M-G, Du G-H. Chrysin improves cognitive deficits and brain damage induced by chronic cerebral hypoperfusion in rats. Eur J Pharmacol 2012; 680(1): 41-48.
10. Souza L, Antunes M, Filho C, Fabbro L, Gomes M, Goes A, et al. Flavonoid Chrysin prevents age-related cognitive decline via attenuation of oxidative stress and modulation of BDNF levels in aged mouse brain. Pharmacol Biochem Behav 2015; 134: 22-30.
11. 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(5): 632-637.
12. Yüncü M, Eralp A, Koruk M, Sari I, Bagci C, Inalöz S. Effect of vitamin a against methotrexate-induced damage to the small intestine in rats. Med Princ Pract 2004; 13: 346-452.
13. Bøttger P, Doğanlı C, Lykke-Hartmann K. Migraine- and dystonia-related disease-mutations of Na+/K+-ATPases: Relevance of behavioral studies in mice to disease symptoms and neurological manifestations in humans. Neurosci Biobehav Rev 2012; 36(2): 855-871.
14. Lyons L, Elbeltagy M, Welbat 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 (Berl) 2011; 215(1): 105-115.
15. Seigers R, Schagen S, Coppens C, Van der Most P, Dam F, Koolhaas J, et al. Methotrexate decreases hippocampal cell proliferation and induces memory deficits in rats. Brainresbull 2009; 201: 279-284.
16. Lledo P-M, Alonso M, Grubb M. Adult neurogenesis and functional plasticity in neuronal circuits. Nat Rev Neurosci 2006; 7(3): 179-193.
17. Milner B, Johnsrude I, Crane J. Right medial temporal-lobe contribution to object-location memory. Philos Trans R Soc Lond B Biol Sci 1997; 352(1360): 1469-1474.
18. Best PJ, Thompson L. Persistence, reticence, and opportunism of place-field activity in hippocampal neurons. Psychobiology 1989; 17: 230-235.
19. Seigers R, Pourtau L, Schagen S, Dam F, Koolhaas J, Konsman JP, et al. Inhibition of hippocampal cell proliferation by methotrexate in rats is not potentiated by the presence of a tumor. Brainresbull 2009; 81: 472-476.
20. Yang M, Joong Sun K, Kim J, Kim S-H, Kim J, Wang H, et al. Neurotoxicity of methotrexate to hippocampal cells in vivo and in vitro. Biochem Pharmacol 2011; 82: 72-80.
21. Uzar E, Sahin O, Koyuncuoglu H, 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: 125-133.
22. Prajit R, Sritawan N, Suwannakot K, Naewla S, Aranarochana A, Sirichoat A, et al. Chrysin protects against memory and hippocampal neurogenesis depletion in d-galactose-induced aging in rats. Nutrients 2020; 12: 1100.
23. Zeinali M, Rezaee SAR, Hosseinzadeh H. An overview on immunoregulatory and anti-inflammatory properties of chrysin and flavonoids substances. Biomed Pharmacother 2017; 92: 998-1009.