Yaşa bağlı oksidatif stres ve nitrik oksit azalışında 7,8-dihidroksiflavonun etkisi

Year 2022, , 712 - 719, 01.10.2022

Selma Cırrık , Gulay Hacıoğlu , Emine Gülçeri Güleç Peker , Hatıce Keser , Selcen Abıdın

https://doi.org/10.31362/patd.1071847

Abstract

Amaç: Beyin kaynaklı nörotrofik faktör (BDNF) reseptör agonisti olarak bilinen 7,8-dihidroksiflavon (7,8-DHF)’un antioksidan özelliklerinin yanı sıra, nitrik oksit (NO) üretimini de etkilediği bildirilmiştir. Yaşlı rodentlerde 7,8-DHF’nin merkezi sinir sisteminde olumlu etkileri gösterilmiş olsa da, nöral olmayan dokulardaki etkileri bilinmemektedir. Literatürde karaciğer, böbrek ve kalp dokularının yaşa bağlı oksidatif stres ve NO düzensizliği gösterdiği belirtilmiştir. Bu çalışmada 7,8-DHF'nin yaşlı farelerde karaciğer, böbrek ve kalp dokularında oksidatif stres ve NO üretimi üzerine etkileri araştırıldı.
Gereç ve yöntem: Erkek C57BL/6 fareler; genç (5 aylık, n=10), yaşlı (18 aylık, n=10) ve DHF-yaşlı (n=7) olmak üzere 3 gruba ayrıldı. DHF-yaşlı grubundaki farelere 3 hafta boyunca 7,8-DHF (5 mg.kg-1.gün-1, intraperitoneal) uygulaması yapıldı. Farelerin karaciğer, kalp ve böbrek dokularında malondialdehid (MDA), redükte glutatyon (GSH) ve nitrit-nitrat (NO_x) seviyeleri ölçüldü.
Bulgular: Yaşlı grupta gözlenen hepatik MDA artışı (p<0,001) ve GSH azalışı (p<0,01), 7,8-DHF tedavisi ile önemli ölçüde değişti. Yaşlı grupta değişmeyen hepatik NO_x seviyesi 7,8-DHF tedavisi ile yükseldi (p<0,001). 7,8-DHF tedavisi yaşa bağlı renal MDA artışını etkilemedi, ancak renal GSH (p<0,05) ve NO_x (p<0,001) azalışlarını hafifletti. 7,8-DHF tedavisi kardiyak oksidatif stresi etkilemedi, ancak yaşa bağlı NO_x azalışını hafifletti (p<0,001).
Sonuç: 7,8-DHF karaciğer ve böbrek dokusunda yaşa bağlı oksidatif stres artışını, karaciğer, kalp ve böbrek dokusunda ise yaşa bağlı NO azalışını engellemede etkili olmuştur. Yaşlılıkta sinir sistemi dışındaki dokularda gözlenen fonksiyonel kayıpların engellenmesinde 7,8-DHF ümit verici bir bileşik olabilir. Bu bileşiğin tüm etkilerini ortaya koymak için yeni araştırmalara ihtiyaç vardır.

Keywords

Yaşlanma, oksidatif stres, Nox, 7,8-dihidroksiflavon

The effect of 7,8-dihydroxyflavone on age related oxidative stress and nitric oxide depletion

Abstract

Purpose: It has been reported that 7,8-dihydroxyflavone (7,8-DHF), known as a brain-derived neurotrophic factor (BDNF) receptor agonist, affects nitric oxide (NO) production as well as its antioxidant properties. Although favorable effects of 7,8-DHF have been reported in the central nervous system in aged rodents, its effects on non-neural tissues are not fully understood yet. In the literature, it has been stated that liver, kidney and heart tissues show age-related oxidative stress and NO dysregulation. In this study, the effects of 7,8-DHF on oxidative stress and NO production in liver, kidney and heart tissues in aged mice were investigated.
Materials and methods: Male C57BL/6 mice were divided into 3 groups as young (5 months old, n=10), elderly (18 months old, n=10) and DHF-elderly (18 months old, n=7). The mice in DHF-elderly group were treated with 7,8-DHF (5 mg/kg-1.day-1, intraperitoneally) for 3 weeks. The malondialdehyde (MDA), reduced glutathione (GSH) and nitrite/nitrate (NO_x) levels were measured in the liver, heart and kidney tissues of mice.
Results: Hepatic MDA increase (p<0.001) and GSH decrease (p<0.01) observed in the elderly group were significantly reversed with 7,8-DHF treatment. Unchanged hepatic NO_x level in the elderly group, increased with 7,8-DHF treatment (p<0.001). 7,8-DHF treatment did not affect the age-related increase in renal MDA, but attenuated the renal GSH (p<0.05) and NO_x (p<0.001) decrements. 7,8-DHF treatment did not affect cardiac oxidative stress, but attenuated age-related NO_x reduction (p<0.001).
Conclusion: 7,8-DHF was effective in preventing age-related oxidative stress in hepatic and renal tissue, and age-related NO decrement in liver, heart and kidney. 7,8-DHF might be a promising compound in preventing age related functional loss in non-neural tissues. Further studies are needed to reveal all effects of this compound.

Keywords

Aging, oxidative stress, NOx, 7,8-dihydroxyflavone

References

• 1. Liguori I, Russo G, Curcio F, et al. Oxidative stress, aging, and diseases. Clin Interv Aging 2018;13:757-772.
• 2. Vaiserman A, Koliada A, Zayachkivska A, Lushchak O. Nanodelivery of natural antioxidants: an anti-aging perspective. Front Bioeng Biotechnol 2020;7:447.
• 3. Lyons D, Roy S, Patel M, Benjamin N, Swift CG. Impaired nitric oxide-mediated vasodilatation and total body nitric oxide production in healthy old age. Clin Sci (Lond) 1997;93(6):519-525.
• 4. Johnson LC, DeVan AE, Justice JN, Seals DR. Nitrate and Nitrite in Aging and Age-Related Disease. In: Bryan N., Loscalzo J. (eds) Nitrite and Nitrate in Human Health and Disease. Nutrition and Health. Cham: Humana Press; 2017. p. 169-186.
• 5. Rozanska O, Uruska A, Zozulinska-Ziolkiewicz D. Brain-derived neurotrophic factor and diabetes. Int J Mol Sci 2020;21(3): 841.
• 6. 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.
• 7. Zeng Y, Lv F, Li L, Yu H, Dong M, Fu Q. 7,8-dihydroxyflavone rescues spatial memory and synaptic plasticity in cognitively impaired aged rats. J Neurochem 2012;122(4):800-811.
• 8. Keser H, Doğramacı Ş, Şahin E, Sağlam N, Erdem M, Alver A, Aydin-Abidin S.: The TrkB agonist 7,8-dihydroxyflavone improves sensory-motor performance and reduces lipid peroxidation in old mice. Gen Physiol Biophys 2020;39(5):471-479.
• 9. Kumar D, Dwivedi DK, Lahkar M, Jangra A. Hepatoprotective potential of 7,8-Dihydroxyflavone against alcohol and high-fat diet induced liver toxicity via attenuation of oxido-nitrosative stress and NF-κB activation. Pharmacol Rep 2019;71(6):1235-1243.
• 10. Wood J, Tse MCL, Yang X, et al. BDNF mimetic alleviates body weight gain in obese mice by enhancing mitochondrial biogenesis in skeletal muscle. Metabolism 2018;87:113-122.
• 11. Huai R, Han X, Wang B, et al. Vasorelaxing and antihypertensive effects of 7,8-dihydroxyflavone. Am J Hypertens 2014;27(5):750-760.
• 12. Park HY, Park C, Hwang HJ, et al. 7,8-Dihydroxyflavone attenuates the release of pro-inflammatory mediators and cytokines in lipopolysaccharide-stimulated BV2 microglial cells through the suppression of the NF-κB and MAPK signaling pathways. Int J Mol Med 2014;33(4):1027-1034.
• 13. Wang B, Wu N, Liang F, et al. 7,8-dihydroxyflavone, a small-molecule tropomyosin-related kinase B (TrkB) agonist, attenuates cerebral ischemia and reperfusion injury in rats. J Mol Histol 2014;45(2):129-140.
• 14. Hunt NJ, Kang SWS, Lockwood GP, Le Couteur DG, Cogger VC. Hallmarks of aging in the liver. Comput Struct Biotechnol J 2019;17:1151-1161.
• 15. Mármol F, Sánchez J, López D, et al. Role of oxidative stress and adenosine nucleotides in the liver of aging rats. Physiol Res 2010;59(4):553-560.
• 16. Weinstein JR, Anderson S. The aging kidney: physiological changes. Adv Chronic Kidney Dis 2010;17(4):302-307.
• 17. Cheitlin MD. Cardiovascular physiology-changes with aging. Am J Geriatr Cardiol 2003;12(1):9-13.
• 18. Casini AF, Ferrali M, Pompella A, Maellaro E, Comporti M. Lipid peroxidation and cellular damage in extrahepatic tissues of bromobenzene-intoxicated mice. Am J Pathol 1986;123(3):520-531.
• 19. Aykaç G, Uysal M, Yalçin AS, Koçak-Toker N, Sivas A, Oz H. The effect of chronic ethanol ingestion on hepatic lipid peroxide, glutathione, glutathione peroxidase and glutathione transferase in rats. Toxicology 1985;36(1):71-6.
• 20. Miranda KM, Espey MG, Wink DA. A rapid, simple spectrophotometric method for simultaneous detection of nitrate and nitrite. Nitric Oxide 2001;5(1):62-71.
• 21. Zhang Y, Chen X, Yang L, Zu Y, Lu Q. Effects of rosmarinic acid on liver and kidney antioxidant enzymes, lipid peroxidation and tissue ultrastructure in aging mice. Food Funct 2015;6(3):927-931.
• 22. Han L, Li M, Liu Y, Han C, Ye P. Atorvastatin may delay cardiac aging by upregulating peroxisome proliferator-activated receptors in rats. Pharmacology 2012;89(1-2):74-82.
• 23. De Lutiis MA, Felaco M, Gizzi F, et al. A scavenger role for nitric oxide in the aged rat kidney. Int J Immunopathol Pharmacol 2004;17(3):265-271.
• 24. Yang B, Larson DF, Watson RR. Modulation of iNOS activity in age-related cardiac dysfunction. Life Sci 2004;75(6):655-667.
• 25. Zieman SJ, Gerstenblith G, Lakatta EG, et al. Upregulation of the nitric oxide-cGMP pathway in aged myocardium: physiological response to l-arginine. Circ Res 2001;88(1):97-102.
• 26. Valdez LB, Zaobornyj T, Alvarez S, Bustamante J, Costa LE, Boveris A. Heart mitochondrial nitric oxide synthase. Effects of hypoxia and aging. Mol Aspects Med 2004;25(1-2):49-59.
• 27. Han X, Zhu S, Wang B, et al. Antioxidant action of 7,8-dihydroxyflavone protects PC12 cells against 6-hydroxydopamine-induced cytotoxicity. Neurochem Int 2014;64:18-23.
• 28. Emili M, Guidi S, Uguagliati B, Giacomini A, Bartesaghi R, Stagni F. Treatment with the flavonoid 7,8-Dihydroxyflavone: a promising strategy for a constellation of body and brain disorders. Crit Rev Food Sci Nutr 2022;62(1):13-50.
• 29. Wang Z, Wang SP, Shao Q, et al. Brain-derived neurotrophic factor mimetic, 7,8-dihydroxyflavone, protects against myocardial ischemia by rebalancing optic atrophy 1 processing. Free Radic Biol Med 2019;145:187-197.
• 30. Zhao J, Du J, Pan Y, et al. Activation of cardiac TrkB receptor by its small molecular agonist 7,8-dihydroxyflavone inhibits doxorubicin-induced cardiotoxicity via enhancing mitochondrial oxidative phosphorylation. Free Radic Biol Med 2019;130:557-567.
• 31. Ma R, Zhang J, Liu X, Yue S, Zhao Q, Xu Y. 7,8-DHF treatment induces Cyr61 expression to suppress hypoxia induced ER stress in HK-2 cells. Biomed Res Int 2016;2016:5029797.
• 32. Payá M, Ferrandiz ML, Sanz MJ, Alcaraz MJ. Effects of phenolic compounds on bromobenzene-mediated hepatotoxicity in mice. Xenobiotica 1993;23(3):327-333.
• 33. Zeng N, Xu J, Yao W, Li S, Ruan W, Xiao F. Brain-Derived Neurotrophic Factor Attenuates Septic Myocardial Dysfunction via eNOS/NO Pathway in Rats. Oxid Med Cell Longev 2017;2017:1721434.
• 34. Choi JW, Lee J, Park YI. 7,8-Dihydroxyflavone attenuates TNF-α-induced skin aging in Hs68 human dermal fibroblast cells via down-regulation of the MAPKs/Akt signaling pathways. Biomed Pharmacother 2017;95:1580-1587.