Login Register Cart 0
Generic placeholder image

Current Pharmaceutical Biotechnology

Editor-in-Chief

ISSN (Print): 1389-2010
ISSN (Online): 1873-4316

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Saponins of Panax japonicus Confer Neuroprotection against Brain Aging through Mitochondrial Related Oxidative Stress and Autophagy in Rats

Author(s): Jing-zhi Wan, Rui Wang, Zhi-yong Zhou, Li-li Deng, Chang-cheng Zhang, Chao-qi Liu, Hai-xia Zhao, Cheng-fu Yuan, Yu-min He, Yao-yan Dun, Ding Yuan* and Ting Wang*

Volume 21, Issue 8, 2020

Page: [667 - 680] Pages: 14

DOI: 10.2174/1389201021666191216114815

Price: $65

Abstract

Background: Oxidative stress and mitochondrial dysfunction play a vital role in the pathogenesis of brain aging. Saponins from Panax japonicus (SPJ) have attracted much attention for their potential to attenuate age-related oxidative stress as the main ingredient in rhizomes of Panax japonicus.

Objective: This study aimed to investigate the neuroprotective effects of SPJ on natural aging rats as well as the underlying mechanisms regarding oxidative stress and mitochondrial pathway.

Methods: Sprague-Dawley rats were divided into control groups (3-, 9-, 15- and 24-month old groups) and SPJ-treated groups. For SPJ-treated groups, SPJ were orally administrated to 18-month old rats at doses of 10 mg/kg, 30 mg/kg and 60 mg/kg once daily. Control groups were given the same volume of saline. After the treatment with SPJ or saline for six months, the cortex and hippocampus were rapidly harvested and deposited at -80°C after the rats were decapitated under anesthesia. The neuroprotective effects of SPJ were estimated by histopathological observation, TUNEL detection, biochemical determination and western blotting.

Results: SPJ improved pathomorphological changes in neuronal cells and decreased apoptosis in the cortex and hippocampus of aging rats, increased the activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), Na+/K+-ATPase, Ca2+-ATPase and Ca2+/Mg2+-ATPase whereas, decreased malondialdehyde (MDA) contents in the cortex of aging rats. Furthermore, the SPJ increased silent mating type information regulation 2 homolog-1 (SIRT1) protein expression, decreased acetylated level of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) in the cortex and hippocampus of aging rats, and reversed the aging-induced decline of Forkhead box O3 (Foxo3a), Superoxide Dismutase 2 (SOD2), microtubule-associated protein light chain 3 (LC3II) and Beclin1 levels in the cortex and hippocampus.

Conclusion: Our data showed that SPJ conferred neuroprotection partly through the regulation of oxidative stress and mitochondria-related pathways in aging rats.

Keywords: Saponins, Panax japonicus, aging, oxidative stress, mitochondria, autophagy.

« Previous Next »
Graphical Abstract

[1]
Floyd, R.A.; Hensley, K. Oxidative stress in brain aging. Implications for therapeutics of neurodegenerative diseases. Neurobiol. Aging, 2002, 23(5), 795-807.
[http://dx.doi.org/10.1016/S0197-4580(02)00019-2] [PMID: 12392783]
[2]
Cenini, G.; Lloret, A.; Cascella, R. Oxidative stress in neurodegenerative disease: From a mitochondrial point of view. Oxid. Med. Cell. Longev., 2019, 2019,2105607.
[http://dx.doi.org/10.1155/2019/2105607] [PMID: 31210837]
[3]
Gilmer, L.K.; Ansari, M.A.; Roberts, K.N.; Scheff, S.W. Age-related changes in mitochondrial respiration and oxidative damage in the cerebral cortex of the Fischer 344 rat. Mech. Ageing Dev., 2010, 131(2), 133-143.
[http://dx.doi.org/10.1016/j.mad.2009.12.011] [PMID: 20080122]
[4]
Cenini, G.; Voos, W. Role of mitochondrial protein quality control in oxidative stress-induced neurodegenerative diseases. Curr. Alzheimer Res., 2016, 13(2), 164-173.
[http://dx.doi.org/10.2174/1567205012666150921103213] [PMID: 26391041]
[5]
Lejri, I.; Agapouda, A.; Grimm, A.; Eckert, A. Mitochondria- and oxidative stress-targeting substances in cognitive decline-related disorders: From molecular mechanisms to clinical evidence. Oxid. Med. Cell. Longev., 2019, 2019,9695412.
[http://dx.doi.org/10.1155/2019/9695412] [PMID: 31214285]
[6]
Dei, R.; Takeda, A.; Niwa, H.; Li, M.; Nakagomi, Y.; Watanabe, M.; Inagaki, T.; Washimi, Y.; Yasuda, Y.; Horie, K.; Miyata, T.; Sobue, G. Lipid peroxidation and advanced glycation end products in the brain in normal aging and in Alzheimer’s disease. Acta Neuropathol., 2002, 104(2), 113-122.
[http://dx.doi.org/10.1007/s00401-002-0523-y] [PMID: 12111353]
[7]
Gemma, C.; Mesches, M.H.; Sepesi, B.; Choo, K.; Holmes, D.B.; Bickford, P.C. Diets enriched in foods with high antioxidant activity reverse age-induced decreases in cerebellar beta-adrenergic function and increases in proinflammatory cytokines. J. Neurosci., 2002, 22(14), 6114-6120.
[http://dx.doi.org/10.1523/JNEUROSCI.22-14-06114.2002] [PMID: 12122072]
[8]
Li, Y.N.; Guo, Y.; Xi, M.M.; Yang, P.; Zhou, X.Y.; Yin, S.; Hai, C.X.; Li, J.G.; Qin, X.J. Saponins from Aralia taibaiensis attenuate D-galactose-induced aging in rats by activating FOXO3a and Nrf2 pathways. Oxid. Med. Cell. Longev., 2014, 2014,320513.
[http://dx.doi.org/10.1155/2014/320513] [PMID: 24669284]
[9]
Grimm, A.; Eckert, A. Brain aging and neurodegeneration: from a mitochondrial point of view. J. Neurochem., 2017, 143(4), 418-431.
[http://dx.doi.org/10.1111/jnc.14037] [PMID: 28397282]
[10]
Mattson, M.P.; Gleichmann, M.; Cheng, A. Mitochondria in neuroplasticity and neurological disorders. Neuron, 2008, 60(5), 748-766.
[http://dx.doi.org/10.1016/j.neuron.2008.10.010] [PMID: 19081372]
[11]
Mizushima, N.; Komatsu, M. Autophagy: renovation of cells and tissues. Cell, 2011, 147(4), 728-741.
[http://dx.doi.org/10.1016/j.cell.2011.10.026] [PMID: 22078875]
[12]
Cuervo, A.M.; Bergamini, E.; Brunk, U.T.; Dröge, W.; Ffrench, M.; Terman, A. Autophagy and aging: the importance of maintaining “clean” cells. Autophagy, 2005, 1(3), 131-140.
[http://dx.doi.org/10.4161/auto.1.3.2017] [PMID: 16874025]
[13]
Tang, P.; Hou, H.; Zhang, L.; Lan, X.; Mao, Z.; Liu, D.; He, C.; Du, H.; Zhang, L. Autophagy reduces neuronal damage and promotes locomotor recovery via inhibition of apoptosis after spinal cord injury in rats. Mol. Neurobiol., 2014, 49(1), 276-287.
[http://dx.doi.org/10.1007/s12035-013-8518-3] [PMID: 23954967]
[14]
He, H.; Xu, J.; Xu, Y.; Zhang, C.; Wang, H.; He, Y.; Wang, T.; Yuan, D. Cardioprotective effects of saponins from Panax japonicus on acute myocardial ischemia against oxidative stress-triggered damage and cardiac cell death in rats. J. Ethnopharmacol., 2012, 140(1), 73-82.
[http://dx.doi.org/10.1016/j.jep.2011.12.024] [PMID: 22226974]
[15]
Li, Y.G.; Ji, D.F.; Zhong, S.; Shi, L.G.; Hu, G.Y.; Chen, S. Saponins from Panax japonicus protect against alcohol-induced hepatic injury in mice by up-regulating the expression of GPX3, SOD1 and SOD3. Alcohol Alcohol., 2010, 45(4), 320-331.
[http://dx.doi.org/10.1093/alcalc/agq034] [PMID: 20554696]
[16]
Deng, L.L.; Yuan, D.; Zhou, Z.Y.; Wan, J.Z.; Zhang, C.C.; Liu, C.Q.; Dun, Y.Y.; Zhao, H.X.; Zhao, B.; Yang, Y.J.; Wang, T. Saponins from Panax japonicus attenuate age-related neuroinflammation via regulation of the mitogen-activated protein kinase and nuclear factor kappa B signaling pathways. Neural Regen. Res., 2017, 12(11), 1877-1884.
[http://dx.doi.org/10.4103/1673-5374.219047] [PMID: 29239335]
[17]
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(9), 1284-1296.
[http://dx.doi.org/10.1111/jphp.12413] [PMID: 25892055]
[18]
He, C.; Yu, Z.; He, Y.; Xu, C.; Zhang, C.; Yuan, D. Purification of macroporous adsorption resin and decolorization of ion exchange resin of total saponins of Panax japonicus. Chin. Tradit. Herbal Drugs, 2017, 48(6), 1146-1152.
[19]
Furukawa-Hibi, Y.; Kobayashi, Y.; Chen, C.; Motoyama, N. FOXO transcription factors in cell-cycle regulation and the response to oxidative stress. Antioxid. Redox Signal., 2005, 7(5-6), 752-760.
[http://dx.doi.org/10.1089/ars.2005.7.752] [PMID: 15890021]
[20]
Scarpulla, R.C. Metabolic control of mitochondrial biogenesis through the PGC-1 family regulatory network. Biochim. Biophys. Acta, 2011, 1813(7), 1269-1278.
[http://dx.doi.org/10.1016/j.bbamcr.2010.09.019] [PMID: 20933024]
[21]
Niccoli, T.; Partridge, L. Ageing as a risk factor for disease. Curr. Biol., 2012, 22(17), R741-R752.
[http://dx.doi.org/10.1016/j.cub.2012.07.024] [PMID: 22975005]
[22]
López-Otín, C.; Blasco, M.A.; Partridge, L.; Serrano, M.; Kroemer, G. The hallmarks of aging. Cell, 2013, 153(6), 1194-1217.
[http://dx.doi.org/10.1016/j.cell.2013.05.039] [PMID: 23746838]
[23]
Gemma, C.; Vila, J.; Bachstetter, A.; Bickford, P.C. Oxidative stress and the aging brain: from theory to prevention.Brain Aging: Models, Methods, and Mechanisms; Riddle, D.R., Ed.; CRC Press/Taylor & Francis: Boca Raton, FL, 2007.
[http://dx.doi.org/10.1201/9781420005523-15]
[24]
Indo, H.P.; Yen, H.C.; Nakanishi, I.; Matsumoto, K.; Tamura, M.; Nagano, Y.; Matsui, H.; Gusev, O.; Cornette, R.; Okuda, T.; Minamiyama, Y.; Ichikawa, H.; Suenaga, S.; Oki, M.; Sato, T.; Ozawa, T.; Clair, D.K.; Majima, H.J. A mitochondrial superoxide theory for oxidative stress diseases and aging. J. Clin. Biochem. Nutr., 2015, 56(1), 1-7.
[http://dx.doi.org/10.3164/jcbn.14-42] [PMID: 25834301]
[25]
Shigenaga, M.K.; Hagen, T.M.; Ames, B.N. Oxidative damage and mitochondrial decay in aging. Proc. Natl. Acad. Sci. USA, 1994, 91(23), 10771-10778.
[http://dx.doi.org/10.1073/pnas.91.23.10771] [PMID: 7971961]
[26]
Zeng, L.; Yang, Y.; Hu, Y.; Sun, Y.; Du, Z.; Xie, Z.; Zhou, T.; Kong, W. Age-related decrease in the mitochondrial sirtuin deacetylase Sirt3 expression associated with ROS accumulation in the auditory cortex of the mimetic aging rat model. PLoS One, 2014, 9(2),e88019.
[http://dx.doi.org/10.1371/journal.pone.0088019] [PMID: 24505357]
[27]
Rodriguez-Rocha, H.; Garcia-Garcia, A.; Pickett, C.; Li, S.; Jones, J.; Chen, H.; Webb, B.; Choi, J.; Zhou, Y.; Zimmerman, M.C.; Franco, R. Compartmentalized oxidative stress in dopaminergic cell death induced by pesticides and complex I inhibitors: distinct roles of superoxide anion and superoxide dismutases. Free Radic. Biol. Med., 2013, 61, 370-383.
[http://dx.doi.org/10.1016/j.freeradbiomed.2013.04.021] [PMID: 23602909]
[28]
Kudin, A.P.; Augustynek, B.; Lehmann, A.K.; Kovács, R.; Kunz, W.S. The contribution of thioredoxin-2 reductase and glutathione peroxidase to H2O2 detoxification of rat brain mitochondria. Biochim. Biophys. Acta, 2012, 1817(10), 1901-1906.
[http://dx.doi.org/10.1016/j.bbabio.2012.02.023] [PMID: 22398128]
[29]
Reed, T.T. Lipid peroxidation and neurodegenerative disease. Free Radic. Biol. Med., 2011, 51(7), 1302-1319.
[http://dx.doi.org/10.1016/j.freeradbiomed.2011.06.027] [PMID: 21782935]
[30]
Li, Q.; Wu, F.; Wen, M.; Yanagita, T.; Xue, C.; Zhang, T.; Wang, Y. The protective effect of antarctic krill oil on cognitive function by inhibiting oxidative stress in the brain of Senescence-Accelerated Prone Mouse Strain 8 (SAMP8) mice. J. Food Sci., 2018, 83(2), 543-551.
[http://dx.doi.org/10.1111/1750-3841.14044] [PMID: 29350764]
[31]
Fujimura, M.; Morita-Fujimura, Y.; Noshita, N.; Sugawara, T.; Kawase, M.; Chan, P.H. The cytosolic antioxidant copper/zinc superoxide dismutase prevents the early release of mitochondrial cytochrome C in ischemic brain after transient focal cerebral ischemia in mice. J. Neurosci., 2000, 20(8), 2817-2824.
[http://dx.doi.org/10.1523/JNEUROSCI.20-08-02817.2000] [PMID: 10751433]
[32]
Huang, J.L.; Jing, X.; Tian, X.; Qin, M.C.; Xu, Z.H.; Wu, D.P.; Zhong, Z.G. Neuroprotective properties of Panax notoginseng saponins via preventing oxidative stress injury in SAMP8 mice. Evid. Based Complement. Alternat. Med., 2017, 2017,8713561.
[http://dx.doi.org/10.1155/2017/8713561] [PMID: 28250796]
[33]
Kops, G.J.; Dansen, T.B.; Polderman, P.E.; Saarloos, I.; Wirtz, K.W.; Coffer, P.J.; Huang, T.T.; Bos, J.L.; Medema, R.H.; Burgering, B.M. Forkhead transcription factor FOXO3a protects quiescent cells from oxidative stress. Nature, 2002, 419(6904), 316-321.
[http://dx.doi.org/10.1038/nature01036] [PMID: 12239572]
[34]
Rangarajan, P.; Karthikeyan, A.; Lu, J.; Ling, E.A.; Dheen, S.T. Sirtuin 3 regulates Foxo3a-mediated antioxidant pathway in microglia. Neuroscience, 2015, 311, 398-414.
[http://dx.doi.org/10.1016/j.neuroscience.2015.10.048] [PMID: 26523980]
[35]
Webb, A.E.; Brunet, A. FOXO transcription factors: Key regulators of cellular quality control. Trends Biochem. Sci., 2014, 39(4), 159-169.
[http://dx.doi.org/10.1016/j.tibs.2014.02.003] [PMID: 24630600]
[36]
Cheng, K.Y.; Guo, F.; Lu, J.Q.; Cao, Y.Z.; Wang, T.C.; Yang, Q.; Xia, Q. MnTM-4-PyP modulates endogenous antioxidant responses and protects primary cortical neurons against oxidative stress. CNS Neurosci. Ther., 2015, 21(5), 435-445.
[http://dx.doi.org/10.1111/cns.12373] [PMID: 25545542]
[37]
Brini, M.; Calì, T.; Ottolini, D.; Carafoli, E. The plasma membrane calcium pump in health and disease. FEBS J., 2013, 280(21), 5385-5397.
[http://dx.doi.org/10.1111/febs.12193] [PMID: 23413890]
[38]
Buttgereit, F.; Brand, M.D. A hierarchy of ATP-consuming processes in mammalian cells. Biochem. J., 1995, 312(Pt 1), 163-167.
[http://dx.doi.org/10.1042/bj3120163] [PMID: 7492307]
[39]
Erecińska, M.; Silver, I.A. ATP and brain function. J. Cereb. Blood Flow Metab., 1989, 9(1), 2-19.
[http://dx.doi.org/10.1038/jcbfm.1989.2] [PMID: 2642915]
[40]
Kaur, J.; Sharma, D.; Singh, R. Acetyl-L-carnitine enhances Na(+), K(+)-ATPase glutathione-S-transferase and multiple unit activity and reduces lipid peroxidation and lipofuscin concentration in aged rat brain regions. Neurosci. Lett., 2001, 301(1), 1-4.
[http://dx.doi.org/10.1016/S0304-3940(01)01576-2] [PMID: 11239702]
[41]
Singh, A.K.; Singh, S.; Tripathi, V.K.; Bissoyi, A.; Garg, G.; Rizvi, S.I. Rapamycin confers neuroprotection against aging-induced oxidative stress, mitochondrial dysfunction and neurodegeneration in old rats via activation of autophagy. Rejuvenation Res., 2019, 22(1), 60-70.
[http://dx.doi.org/10.1089/rej.2018.2070] [PMID: 29943667]
[42]
Mark, R.J.; Hensley, K.; Butterfield, D.A.; Mattson, M.P. Amyloid beta-peptide impairs ion-motive ATPase activities: Evidence for a role in loss of neuronal Ca2+ homeostasis and cell death. J. Neurosci., 1995, 15(9), 6239-6249.
[http://dx.doi.org/10.1523/JNEUROSCI.15-09-06239.1995] [PMID: 7666206]
[43]
Salminen, A.; Kaarniranta, K.; Kauppinen, A. Crosstalk between oxidative stress and SIRT1: Impact on the aging process. Int. J. Mol. Sci., 2013, 14(2), 3834-3859.
[http://dx.doi.org/10.3390/ijms14023834] [PMID: 23434668]
[44]
Godoy, J.A.; Zolezzi, J.M.; Braidy, N.; Inestrosa, N.C. Role of Sirt1 during the ageing process: Relevance to protection of synapses in the brain. Mol. Neurobiol., 2014, 50(3), 744-756.
[http://dx.doi.org/10.1007/s12035-014-8645-5] [PMID: 24496572]
[45]
Gong, H.; Pang, J.; Han, Y.; Dai, Y.; Dai, D.; Cai, J.; Zhang, T.M. Age-dependent tissue expression patterns of Sirt1 in senescence-accelerated mice. Mol. Med. Rep., 2014, 10(6), 3296-3302.
[http://dx.doi.org/10.3892/mmr.2014.2648] [PMID: 25323555]
[46]
Li, Q.; Zeng, J.; Su, M.; He, Y.; Zhu, B. Acetylshikonin from Zicao attenuates cognitive impairment and hippocampus senescence in d-galactose-induced aging mouse model via upregulating the expression of SIRT1. Brain Res. Bull., 2018, 137, 311-318.
[http://dx.doi.org/10.1016/j.brainresbull.2018.01.007] [PMID: 29325995]
[47]
Sarubbo, F.; Esteban, S.; Miralles, A.; Moranta, D. Effects of resveratrol and other polyphenols on Sirt1: Relevance to brain function during aging. Curr. Neuropharmacol., 2018, 16(2), 126-136.
[http://dx.doi.org/10.2174/1570159X15666170703113212] [PMID: 28676015]
[48]
Fanibunda, S.E.; Deb, S.; Maniyadath, B.; Tiwari, P.; Ghai, U.; Gupta, S.; Figueiredo, D.; Weisstaub, N.; Gingrich, J.A.; Vaidya, A.D.B.; Kolthur-Seetharam, U.; Vaidya, V.A. Serotonin regulates mitochondrial biogenesis and function in rodent cortical neurons via the 5-HT2A receptor and SIRT1-PGC-1α axis. Proc. Natl. Acad. Sci. USA, 2019, 116(22), 11028-11037.
[http://dx.doi.org/10.1073/pnas.1821332116] [PMID: 31072928]
[49]
Yue, L.; Zhao, L.; Liu, H.; Li, X.; Wang, B.; Guo, H.; Gao, L.; Feng, D.; Qu, Y. Adiponectin protects against glutamate-induced excitotoxicity via activating SIRT1-dependent PGC-1α expression in HT22 hippocampal neurons. Oxid. Med. Cell. Longev., 2016, 2016,2957354.
[http://dx.doi.org/10.1155/2016/2957354] [PMID: 28042384]
[50]
Hewitt, G.; Korolchuk, V.I. Repair, reuse, recycle: The expanding role of autophagy in genome maintenance. Trends Cell Biol., 2017, 27(5), 340-351.
[http://dx.doi.org/10.1016/j.tcb.2016.11.011] [PMID: 28011061]
[51]
Wu, H.; Chen, S.; Ammar, A.B.; Xu, J.; Wu, Q.; Pan, K.; Zhang, J.; Hong, Y. Crosstalk between macroautophagy and chaperone-mediated autophagy: Implications for the treatment of neurological diseases. Mol. Neurobiol., 2015, 52(3), 1284-1296.
[http://dx.doi.org/10.1007/s12035-014-8933-0] [PMID: 25330936]
[52]
Ma, Q.; Qiang, J.; Gu, P.; Wang, Y.; Geng, Y.; Wang, M. Age-related autophagy alterations in the brain of Senescence Accelerated Mouse Prone 8 (SAMP8) mice. Exp. Gerontol., 2011, 46(7), 533-541.
[http://dx.doi.org/10.1016/j.exger.2011.02.006] [PMID: 21385605]
[53]
Komatsu, M.; Waguri, S.; Chiba, T.; Murata, S.; Iwata, J.; Tanida, I.; Ueno, T.; Koike, M.; Uchiyama, Y.; Kominami, E.; Tanaka, K. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature, 2006, 441(7095), 880-884.
[http://dx.doi.org/10.1038/nature04723] [PMID: 16625205]
[54]
Pyo, J.O.; Yoo, S.M.; Ahn, H.H.; Nah, J.; Hong, S.H.; Kam, T.I.; Jung, S.; Jung, Y.K. Overexpression of Atg5 in mice activates autophagy and extends lifespan. Nat. Commun., 2013, 4, 2300.
[http://dx.doi.org/10.1038/ncomms3300] [PMID: 23939249]

Rights & Permissions Print Cite
Article Metrics
18
© 2024 Bentham Science Publishers | Privacy Policy