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Curcumin and hesperetin attenuate D-galactose-induced brain senescence in vitro and in vivo

  • Lee, Jihye (Department of Nutritional Science and Food Management, Ewha Womans University) ;
  • Kim, Yoo Sun (Department of Nutritional Science and Food Management, Ewha Womans University) ;
  • Kim, Eunju (Department of Nutritional Science and Food Management, Ewha Womans University) ;
  • Kim, Yerin (Department of Nutritional Science and Food Management, Ewha Womans University) ;
  • Kim, Yuri (Department of Nutritional Science and Food Management, Ewha Womans University)
  • Received : 2020.04.14
  • Accepted : 2020.07.16
  • Published : 2020.10.01

Abstract

BACKGROUND/OBJECTIVES: Brain senescence causes cognitive impairment and neurodegeneration. It has also been demonstrated that curcumin (Cur) and hesperetin (Hes), both antioxidant polyphenolic compounds, mediate anti-aging and neuroprotective effects. Therefore, the objective of this study was to investigate whether Cur, Hes, and/or their combination exert anti-aging effects in D-galactose (Dg)-induced aged neuronal cells and rats. MATERIALS/METHODS: SH-SY5Y cells differentiated in response to retinoic acid were treated with Cur (1 μM), Hes (1 μM), or a combination of both, followed by 300 mM Dg. Neuronal loss was subsequently evaluated by measuring average neurite length and analyzing expression of β-tubulin III, phosphorylated extracellular signal-regulated kinases, and neurofilament heavy polypeptide. Cellular senescence and related proteins, p16 and p21, were also investigated, including their regulation of antioxidant enzymes. In vivo, brain aging was induced by injecting 250 mg/kg body weight (b.w.) Dg. The effects of supplementing this model with 50 mg/kg b.w. Cur, 50 mg/kg b.w. Hes, or a combination of both for 3 months were subsequently evaluated. Brain aging was examined with a step-through passive avoidance test and apoptosis markers were analyzed in brain cortex tissues. RESULTS: Cur, Hes, and their combination improved neuron length and cellular senescence by decreasing the number of β-gal stained cells, down-regulated expression of p16 and p21, and up-regulated expression of antioxidant enzymes, including superoxide dismutase 1, glutathione peroxidase 1, and catalase. Administration of Cur, Hes, or their combination also tended to ameliorate cognitive impairment and suppress apoptosis in the cerebral cortex by down-regulating Bax and poly (ADP-ribose) polymerase expression and increasing Bcl-2 expression. CONCLUSIONS: Cur and Hes appear to attenuate Dg-induced brain aging via regulation of antioxidant enzymes and apoptosis. These results suggest that Cur and Hes may mediate neuroprotective effects in the aging process, and further study of these antioxidant polyphenolic compounds is warranted.

Keywords

References

  1. Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell 2013;153:1194-217. https://doi.org/10.1016/j.cell.2013.05.039
  2. Peters R. Ageing and the brain. Postgrad Med J 2006;82:84-8. https://doi.org/10.1136/pgmj.2005.036665
  3. Shwe T, Pratchayasakul W, Chattipakorn N, Chattipakorn SC. Role of D-galactose-induced brain aging and its potential used for therapeutic interventions. Exp Gerontol 2018;101:13-36. https://doi.org/10.1016/j.exger.2017.10.029
  4. Stites SD, Harkins K, Rubright JD, Karlawish J. Relationships between cognitive complaints and quality of life in older adults with mild cognitive impairment, mild Alzheimer disease dementia, and normal cognition. Alzheimer Dis Assoc Disord 2018;32:276-83. https://doi.org/10.1097/wad.0000000000000262
  5. Fjell AM, McEvoy L, Holland D, Dale AM, Walhovd KB; Alzheimer's Disease Neuroimaging Initiative. What is normal in normal aging? Effects of aging, amyloid and Alzheimer's disease on the cerebral cortex and the hippocampus. Prog Neurobiol 2014;117:20-40. https://doi.org/10.1016/j.pneurobio.2014.02.004
  6. Rubin RD, Watson PD, Duff MC, Cohen NJ. The role of the hippocampus in flexible cognition and social behavior. Front Hum Neurosci 2014;8:742. https://doi.org/10.3389/fnhum.2014.00742
  7. Crews L, Masliah E. Molecular mechanisms of neurodegeneration in Alzheimer's disease. Hum Mol Genet 2010;19:R12-20. https://doi.org/10.1093/hmg/ddq160
  8. Espuny-Camacho I, Arranz AM, Fiers M, Snellinx A, Ando K, Munck S, Bonnefont J, Lambot L, Corthout N, Omodho L, Eynden EV, Radaelli E, Tesseur I, Wray S, Ebneth A, Hardy J, Leroy K, Brion JP, Vanderhaeghen P, De Strooper B. Hallmarks of Alzheimer's disease in stem-cell-derived human neurons transplanted into mouse brain. Neuron 2017;93:1066-1081.e8. https://doi.org/10.1016/j.neuron.2017.02.001
  9. Yokotsuka T. Soy sauce biochemistry. Adv Food Res 1986;30:195-329. https://doi.org/10.1016/S0065-2628(08)60350-X
  10. Chen P, Chen F, Zhou B. Antioxidative, anti-inflammatory and anti-apoptotic effects of ellagic acid in liver and brain of rats treated by D-galactose. Sci Rep 2018;8:1465. https://doi.org/10.1038/s41598-018-19732-0
  11. Shan Q, Lu J, Zheng Y, Li J, Zhou Z, Hu B, Zhang Z, Fan S, Mao Z, Wang YJ, Ma D. Purple sweet potato color ameliorates cognition deficits and attenuates oxidative damage and inflammation in aging mouse brain induced by D-galactose. J Biomed Biotechnol 2009;2009:564737. https://doi.org/10.1155/2009/564737
  12. Kim Y, Kim E, Kim Y. L-histidine and L-carnosine accelerate wound healing via regulation of corticosterone and PI3K/Akt phosphorylation in D-galactose-induced aging models in vitro and in vivo. J Funct Foods 2019;58:227-37. https://doi.org/10.1016/j.jff.2019.04.060
  13. Chen X, Li Y, Chen W, Nong Z, Huang J, Chen C. Protective effect of hyperbaric oxygen on cognitive impairment induced by D-galactose in mice. Neurochem Res 2016;41:3032-41. https://doi.org/10.1007/s11064-016-2022-x
  14. Spencer JPE. Flavonoids: modulators of brain function? Br J Nutr 2008;99:ES60-77. https://doi.org/10.1017/s0007114508965776
  15. Rehman SU, Shah SA, Ali T, Chung JI, Kim MO. Anthocyanins reversed D-galactose-induced oxidative stress and neuroinflammation mediated cognitive impairment in adult rats. Mol Neurobiol 2017;54:255-71. https://doi.org/10.1007/s12035-015-9604-5
  16. Hsieh HM, Wu WM, Hu ML. Soy isoflavones attenuate oxidative stress and improve parameters related to aging and Alzheimer's disease in C57BL/6J mice treated with D-galactose. Food Chem Toxicol 2009;47:625-32. https://doi.org/10.1016/j.fct.2008.12.026
  17. Ritchie K, Carriere I, de Mendonca A, Portet F, Dartigues JF, Rouaud O, Barberger-Gateau P, Ancelin ML. The neuroprotective effects of caffeine: a prospective population study (the three city study). Neurology 2007;69:536-45. https://doi.org/10.1212/01.wnl.0000266670.35219.0c
  18. Tsuda T. Curcumin as a functional food-derived factor: degradation products, metabolites, bioactivity, and future perspectives. Food Funct 2018;9:705-14. https://doi.org/10.1039/c7fo01242j
  19. Shen LR, Parnell LD, Ordovas JM, Lai CQ. Curcumin and aging. Biofactors 2013;39:133-40. https://doi.org/10.1002/biof.1086
  20. Liao VH, Yu CW, Chu YJ, Li WH, Hsieh YC, Wang TT. Curcumin-mediated lifespan extension in Caenorhabditis elegans. Mech Ageing Dev 2011;132:480-7. https://doi.org/10.1016/j.mad.2011.07.008
  21. Lee KS, Lee BS, Semnani S, Avanesian A, Um CY, Jeon HJ, Seong KM, Yu K, Min KJ, Jafari M. Curcumin extends life span, improves health span, and modulates the expression of age-associated aging genes in Drosophila melanogaster. Rejuvenation Res 2010;13:561-70. https://doi.org/10.1089/rej.2010.1031
  22. Kitani K, Osawa T, Yokozawa T. The effects of tetrahydrocurcumin and green tea polyphenol on the survival of male C57BL/6 mice. Biogerontology 2007;8:567-73. https://doi.org/10.1007/s10522-007-9100-z
  23. Banji D, Banji OJF, Dasaroju S, Kranthi KCH. Curcumin and piperine abrogate lipid and protein oxidation induced by D-galactose in rat brain. Brain Res 2013;1515:1-11. https://doi.org/10.1016/j.brainres.2013.03.023
  24. Liu Y, Liu D, Zhu L, Gan Q, Le X. Temperature-dependent structure stability and in vitro release of chitosan-coated curcumin liposome. Food Res Int 2015;74:97-105. https://doi.org/10.1016/j.foodres.2015.04.024
  25. Abdul Manap AS, Wei Tan AC, Leong WH, Yin Chia AY, Vijayabalan S, Arya A, Wong EH, Rizwan F, Bindal U, Koshy S, Madhavan P. Synergistic effects of curcumin and piperine as potent acetylcholine and amyloidogenic inhibitors with significant neuroprotective activity in SH-SY5Y cells via computational molecular modeling and in vitro assay. Front Aging Neurosci 2019;11:206. https://doi.org/10.3389/fnagi.2019.00206
  26. Cho J. Antioxidant and neuroprotective effects of hesperidin and its aglycone hesperetin. Arch Pharm Res 2006;29:699-706. https://doi.org/10.1007/BF02968255
  27. Spencer JP, Vauzour D, Rendeiro C. Flavonoids and cognition: the molecular mechanisms underlying their behavioural effects. Arch Biochem Biophys 2009;492:1-9. https://doi.org/10.1016/j.abb.2009.10.003
  28. Hirata A, Murakami Y, Shoji M, Kadoma Y, Fujisawa S. Kinetics of radical-scavenging activity of hesperetin and hesperidin and their inhibitory activity on COX-2 expression. Anticancer Res 2005;25:3367-74.
  29. Khalili M, Roghani M, Ekhlasi M. The effect of aqueous crocus sativus L. extract on intracerebroventricular streptozotocin-induced cognitive deficits in rat: a behavioral analysis. Iran J Pharm Res 2009;8:185-91.
  30. Quillfeldt JA. Behavioral methods to study learning and memory in rats. In: Andersen M., Tufik S, editors. Rodent Model as Tools in Ethical Biomedical Research. Cham: Springer; 2016. p.271-311.
  31. Rahnama S, Rabiei Z, Alibabaei Z, Mokhtari S, Rafieian-Kopaei M, Deris F. Anti-amnesic activity of Citrus aurantium flowers extract against scopolamine-induced memory impairments in rats. Neurol Sci 2015;36:553-60. https://doi.org/10.1007/s10072-014-1991-2
  32. Song X, Bao M, Li D, Li YM. Advanced glycation in D-galactose induced mouse aging model. Mech Ageing Dev 1999;108:239-51. https://doi.org/10.1016/S0047-6374(99)00022-6
  33. Shen Y, Gao H, Shi X, Wang N, Ai D, Li J, Ouyang L, Yang J, Tian Y, Lu J. Glutamine synthetase plays a role in D-galactose-induced astrocyte aging in vitro and in vivo. Exp Gerontol 2014;58:166-73. https://doi.org/10.1016/j.exger.2014.08.006
  34. Lin WL, Wang SM, Ho YJ, Kuo HC, Lee YJ, Tseng TH. Ethyl acetate extract of Wedelia chinensis inhibits tert-butyl hydroperoxide-induced damage in PC12 cells and D-galactose-induced neuronal cell loss in mice. BMC Complement Altern Med 2014;14:491. https://doi.org/10.1186/1472-6882-14-491
  35. Wang T, Di G, Yang L, Dun Y, Sun Z, Wan J, Peng B, Liu C, Xiong G, Zhang C, Yuan D. Saponins from Panax japonicus attenuate D-galactose-induced cognitive impairment through its anti-oxidative and anti-apoptotic effects in rats. J Pharm Pharmacol 2015;67:1284-96. https://doi.org/10.1111/jphp.12413
  36. Rahimi VB, Askari VR, Mousavi SH. Ellagic acid reveals promising anti-aging effects against D-galactose-induced aging on human neuroblastoma cell line, SH-SY5Y: a mechanistic study. Biomed Pharmacother 2018;108:1712-24. https://doi.org/10.1016/j.biopha.2018.10.024
  37. Ullah F, Ali T, Ullah N, Kim MO. Caffeine prevents D-galactose-induced cognitive deficits, oxidative stress, neuroinflammation and neurodegeneration in the adult rat brain. Neurochem Int 2015;90:114-24. https://doi.org/10.1016/j.neuint.2015.07.001
  38. Gao J, He H, Jiang W, Chang X, Zhu L, Luo F, Zhou R, Ma C, Yan T. Salidroside ameliorates cognitive impairment in a D-galactose-induced rat model of Alzheimer's disease. Behav Brain Res 2015;293:27-33. https://doi.org/10.1016/j.bbr.2015.06.045
  39. Kodali M, Parihar VK, Hattiangady B, Mishra V, Shuai B, Shetty AK. Resveratrol prevents age-related memory and mood dysfunction with increased hippocampal neurogenesis and microvasculature, and reduced glial activation. Sci Rep 2015;5:8075. https://doi.org/10.1038/srep08075
  40. Alharbi MH, Lamport DJ, Dodd GF, Saunders C, Harkness L, Butler LT, Spencer JP. Flavonoid-rich orange juice is associated with acute improvements in cognitive function in healthy middle-aged males. Eur J Nutr 2016;55:2021-9. https://doi.org/10.1007/s00394-015-1016-9
  41. Sikora E, Scapagnini G, Barbagallo M. Curcumin, inflammation, ageing and age-related diseases. Immun Ageing 2010;7:1. https://doi.org/10.1186/1742-4933-7-S1-S1
  42. Jurenka JS. Anti-inflammatory properties of curcumin, a major constituent of Curcuma longa: a review of preclinical and clinical research. Altern Med Rev 2009;14:141-53.
  43. Ringman JM, Frautschy SA, Teng E, Begum AN, Bardens J, Beigi M, Gylys KH, Badmaev V, Heath DD, Apostolova LG, Porter V, Vanek Z, Marshall GA, Hellemann G, Sugar C, Masterman DL, Montine TJ, Cummings JL, Cole GM. Oral curcumin for Alzheimer's disease: tolerability and efficacy in a 24-week randomized, double blind, placebo-controlled study. Alzheimers Res Ther 2012;4:43. https://doi.org/10.1186/alzrt146
  44. Baum L, Lam CWK, Cheung SK, Kwok T, Lui V, Tsoh J, Lam L, Leung V, Hui E, Ng C, Woo J, Chiu HF, Goggins WB, Zee BC, Cheng KF, Fong CY, Wong A, Mok H, Chow MS, Ho PC, Ip SP, Ho CS, Yu XW, Lai CY, Chan MH, Szeto S, Chan IH, Mok V. Six-month randomized, placebo-controlled, double-blind, pilot clinical trial of curcumin in patients with Alzheimer disease. J Clin Psychopharmacol 2008;28:110-3. https://doi.org/10.1097/jcp.0b013e318160862c
  45. Cui Q, Li X, Zhu H. Curcumin ameliorates dopaminergic neuronal oxidative damage via activation of the Akt/Nrf2 pathway. Mol Med Rep 2016;13:1381-8. https://doi.org/10.3892/mmr.2015.4657
  46. Banji OJ, Banji D, Ch K. Curcumin and hesperidin improve cognition by suppressing mitochondrial dysfunction and apoptosis induced by D-galactose in rat brain. Food Chem Toxicol 2014;74:51-9. https://doi.org/10.1016/j.fct.2014.08.020
  47. Banji OJ, Banji D, Soumya N, Chilipi KK, Kalpana CH, Kranthi Kumar CH, Annamalai AR. Combination of carvacrol with methotrexate suppresses Complete Freund's Adjuvant induced synovial inflammation with reduced hepatotoxicity in rats. Eur J Pharmacol 2014;723:91-8. https://doi.org/10.1016/j.ejphar.2013.12.009
  48. Rainey-Smith S, Schroetke LW, Bahia P, Fahmi A, Skilton R, Spencer JP, Rice-Evans C, Rattray M, Williams RJ. Neuroprotective effects of hesperetin in mouse primary neurones are independent of CREB activation. Neurosci Lett 2008;438:29-33. https://doi.org/10.1016/j.neulet.2008.04.056
  49. Parhiz H, Roohbakhsh A, Soltani F, Rezaee R, Iranshahi M. Antioxidant and anti-inflammatory properties of the citrus flavonoids hesperidin and hesperetin: an updated review of their molecular mechanisms and experimental models. Phytother Res 2015;29:323-31. https://doi.org/10.1002/ptr.5256
  50. Roohbakhsh A, Parhiz H, Soltani F, Rezaee R, Iranshahi M. Neuropharmacological properties and pharmacokinetics of the citrus flavonoids hesperidin and hesperetin--a mini-review. Life Sci 2014;113:1-6. https://doi.org/10.1016/j.lfs.2014.07.029
  51. Hwang SL, Yen GC. Neuroprotective effects of the citrus flavanones against H2O2-induced cytotoxicity in PC12 cells. J Agric Food Chem 2008;56:859-64. https://doi.org/10.1021/jf072826r
  52. Huang SM, Tsai SY, Lin JA, Wu CH, Yen GC. Cytoprotective effects of hesperetin and hesperidin against amyloid ${\beta}$-induced impairment of glucose transport through downregulation of neuronal autophagy. Mol Nutr Food Res 2012;56:601-9. https://doi.org/10.1002/mnfr.201100682
  53. Nasser TIN, Spencer GE. Neurite outgrowth. In: Reference Module in Biomedical Sciences. Amsterdam: Elsevier; 2017.
  54. Kashyap G, Bapat D, Das D, Gowaikar R, Amritkar RE, Rangarajan G, Ravindranath V, Ambika G. Synapse loss and progress of Alzheimer's disease -a network model. Sci Rep 2019;9:6555. https://doi.org/10.1038/s41598-019-43076-y
  55. Zhu J, Mu X, Zeng J, Xu C, Liu J, Zhang M, Li C, Chen J, Li T, Wang Y. Ginsenoside Rg1 prevents cognitive impairment and hippocampus senescence in a rat model of D-galactose-induced aging. PLoS One 2014;9:e101291. https://doi.org/10.1371/journal.pone.0101291
  56. Elzi DJ, Song M, Shiio Y. Role of galactose in cellular senescence. Exp Gerontol 2016;73:1-4. https://doi.org/10.1016/j.exger.2015.11.003
  57. Nopparat C, Chantadul V, Permpoonputtana K, Govitrapong P. The anti-inflammatory effect of melatonin in SH-SY5Y neuroblastoma cells exposed to sublethal dose of hydrogen peroxide. Mech Ageing Dev 2017;164:49-60. https://doi.org/10.1016/j.mad.2017.04.001
  58. Justin Thenmozhi A, William Raja TR, Manivasagam T, Janakiraman U, Essa MM. Hesperidin ameliorates cognitive dysfunction, oxidative stress and apoptosis against aluminium chloride induced rat model of Alzheimer's disease. Nutr Neurosci 2017;20:360-8. https://doi.org/10.1080/1028415X.2016.1144846
  59. Dimpfel W. Different anticonvulsive effects of hesperidin and its aglycone hesperetin on electrical activity in the rat hippocampus in-vitro. J Pharm Pharmacol 2006;58:375-9. https://doi.org/10.1211/jpp.58.3.0012
  60. Kumar A, Dogra S, Prakash A. Effect of carvedilol on behavioral, mitochondrial dysfunction, and oxidative damage against D-galactose induced senescence in mice. Naunyn Schmiedebergs Arch Pharmacol 2009;380:431-41. https://doi.org/10.1007/s00210-009-0442-8
  61. Metzler M, Pfeiffer E, Schulz SI, Dempe JS. Curcumin uptake and metabolism. Biofactors 2013;39:14-20. https://doi.org/10.1002/biof.1042
  62. Kanaze FI, Bounartzi MI, Georgarakis M, Niopas I. Pharmacokinetics of the citrus flavanone aglycones hesperetin and naringenin after single oral administration in human subjects. Eur J Clin Nutr 2007;61:472-7. https://doi.org/10.1038/sj.ejcn.1602543
  63. Ghosh SS, He H, Wang J, Gehr TW, Ghosh S. Curcumin-mediated regulation of intestinal barrier function: the mechanism underlying its beneficial effects. Tissue Barriers 2018;6:e1425085. https://doi.org/10.1080/21688370.2018.1425085
  64. Trivedi PP, Tripathi DN, Jena GB. Hesperetin protects testicular toxicity of doxorubicin in rat: role of $NF{\kappa}B$, p38 and caspase-3. Food Chem Toxicol 2011;49:838-47. https://doi.org/10.1016/j.fct.2010.12.005
  65. Reagan-Shaw S, Nihal M, Ahmad N. Dose translation from animal to human studies revisited. FASEB J 2008;22:659-61. https://doi.org/10.1096/fj.07-9574lsf
  66. Mishra S, Palanivelu K. The effect of curcumin (turmeric) on Alzheimer's disease: an overview. Ann Indian Acad Neurol 2008;11:13-9. https://doi.org/10.4103/0972-2327.40220
  67. Bielak-Zmijewska A, Grabowska W, Ciolko A, Bojko A, Mosieniak G, Bijoch L, Sikora E. The role of curcumin in the modulation of ageing. Int J Mol Sci 2019;20:1239. https://doi.org/10.3390/ijms20051239
  68. Mouly P, Gaydou EM, Auffray A. Simultaneous separation of flavanone glycosides and polymethoxylated flavones in citrus juices using liquid chromatography. J Chromatogr A 1998;800:171-9. https://doi.org/10.1016/S0021-9673(97)01131-X
  69. Erlund I, Silaste ML, Alfthan G, Rantala M, Kesaniemi YA, Aro A. Plasma concentrations of the flavonoids hesperetin, naringenin and quercetin in human subjects following their habitual diets, and diets high or low in fruit and vegetables. Eur J Clin Nutr 2002;56:891-8. https://doi.org/10.1038/sj.ejcn.1601409
  70. Cheng AL, Hsu CH, Lin JK, Hsu MM, Ho YF, Shen TS, Ko JY, Lin JT, Lin BR, Ming-Shiang W, Yu HS, Jee SH, Chen GS, Chen TM, Chen CA, Lai MK, Pu YS, Pan MH, Wang YJ, Tsai CC, Hsieh CY. Phase I clinical trial of curcumin, a chemopreventive agent, in patients with high-risk or pre-malignant lesions. Anticancer Res 2001;21:2895-900.
  71. Garcia-Alloza M, Borrelli LA, Rozkalne A, Hyman BT, Bacskai BJ. Curcumin labels amyloid pathology in vivo, disrupts existing plaques, and partially restores distorted neurites in an Alzheimer mouse model. J Neurochem 2007;102:1095-104. https://doi.org/10.1111/j.1471-4159.2007.04613.x

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