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Parkinson’s disease (PD) is a common neurodegenerative disorder with no cure. Astragalus membranaceus is used in Chinese culture as a food supplement to boost immunity. The present study aimed to explore the neuroprotective effects of total flavonoids extracted from A. membranaceus (TFA) and their protective mechanisms. TFA offered neuroprotection against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in the mouse model of Parkinsonism, by improving behavior performance in the gait analysis and pole test, and inhibiting the decline of tyrosine hydroxylase (TH) positive neurons and TH protein expression in substantia nigra of mice. TFA also prevented 1-methyl-4-phenylpyridinium (MPP+) induced neurotoxicity in SH-SY5Y cells, by increasing GSH and GSH/GSSG ratio, and reducing reactive oxygen species. In addition, the neuroprotective effects of TFA were associated with its ability to restore MPTP/MPP+ induced downregulation of SLC7A11 and glutathione peroxidase 4 (GPX-4). In conclusion, we demonstrated that TFA exerted significant neuroprotection against MPTP/MPP+ induced neurodegeneration by inhibiting ferroptosis through the regulation of SLC7A11/GPX-4 axis, suggesting the use of TFA as a possible food supplement in the prevention of PD.
Parkinson’s disease (PD) is a common neurodegenerative disorder with no cure. Astragalus membranaceus is used in Chinese culture as a food supplement to boost immunity. The present study aimed to explore the neuroprotective effects of total flavonoids extracted from A. membranaceus (TFA) and their protective mechanisms. TFA offered neuroprotection against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in the mouse model of Parkinsonism, by improving behavior performance in the gait analysis and pole test, and inhibiting the decline of tyrosine hydroxylase (TH) positive neurons and TH protein expression in substantia nigra of mice. TFA also prevented 1-methyl-4-phenylpyridinium (MPP+) induced neurotoxicity in SH-SY5Y cells, by increasing GSH and GSH/GSSG ratio, and reducing reactive oxygen species. In addition, the neuroprotective effects of TFA were associated with its ability to restore MPTP/MPP+ induced downregulation of SLC7A11 and glutathione peroxidase 4 (GPX-4). In conclusion, we demonstrated that TFA exerted significant neuroprotection against MPTP/MPP+ induced neurodegeneration by inhibiting ferroptosis through the regulation of SLC7A11/GPX-4 axis, suggesting the use of TFA as a possible food supplement in the prevention of PD.
K. Hu, Q. Huang, C. Liu, Y. et al., c-Jun/Bim upregulation in dopaminergic neurons promotes neurodegeneration in the MPTP mouse model of parkinson’s disease, Neuroscience. 399 (2019) 117-124. https://doi.org/10.1016/j.neuroscience.2018.12.026.
Y. Mou, J. Wang, J. Wu, et al., Ferroptosis, a new form of cell death: opportunities and challenges in cancer, J. Hematol. Oncol.J Hematol Oncol. 12 (2019) 34. https://doi.org/10.1186/s13045-019-0720-y.
O. Weinreb, S. Mandel, M.B.H. Youdim, et al., Targeting dysregulation of brain iron homeostasis in Parkinson’s disease by iron chelators, Free Radic. Biol. Med. 62 (2013) 52-64. https://doi.org/10.1016/j.freeradbiomed.2013.01.017.
A.A. Belaidi, A.I. Bush, Iron neurochemistry in Alzheimer’s disease and Parkinson’s disease: targets for therapeutics, J. Neurochem. 139 (2016) 179-197. https://doi.org/10.1111/jnc.13425.
X. Zeng, H. An, F. Yu, et al., Benefits of Iron Chelators in the Treatment of Parkinson’s Disease, Neurochem. Res. 46 (2021) 1239-1251. https://doi.org/10.1007/s11064-021-03262-9.
J.X. Ren, X. Sun, X.L. Yan, et al., Ferroptosis in Neurological Diseases, Front. Cell. Neurosci. 14 (2020) 218. https://doi.org/10.3389/fncel.2020.00218.
Y. Zhou, W. Lin, T. Rao, et al., Ferroptosis and Its Potential Role in the Nervous System Diseases, J. Inflamm. Res. Volume 15 (2022) 1555-1574. https://doi.org/10.2147/JIR.S351799.
X. Chen, C. Yu, R. Kang, et al., Cellular degradation systems in ferroptosis, Cell Death Differ. 28 (2021) 1135-1148. https://doi.org/10.1038/s41418-020-00728-1.
M. Asanuma, I. Miyazaki, Glutathione and related molecules in parkinsonism, Int. J. Mol. Sci. 22 (2021) 8689. https://doi.org/10.3390/ijms22168689.
L. Liu, S. Yang, H. Wang, α-Lipoic acid alleviates ferroptosis in the MPP+ -induced PC12 cells via activating the PI3K/Akt/Nrf2 pathway, Cell Biol. Int. 45 (2021) 422-431. https://doi.org/10.1002/cbin.11505.
F.P. Bellinger, M.T. Bellinger, L.A. Seale, et al., Glutathione peroxidase 4 is associated with neuromelanin in substantia nigra and dystrophic axons in putamen of Parkinson’s brain, Mol. Neurodegener. 6 (2011) 8. https://doi.org/10.1186/1750-1326-6-8.
Y. Bi, H. Bao, C. Zhang, et al., Quality control of Radix astragali (The root of Astragalus membranaceus var. mongholicus) Along Its Value Chains, Front. Pharmacol. 11 (2020) 562376. https://doi.org/10.3389/fphar.2020.562376.
Z. Guo, Y. Lou, M. Kong, et al., A systematic review of phytochemistry, pharmacology and pharmacokinetics on Astragali radix: implications for Astragali radix as a personalized medicine, Int. J. Mol. Sci. 20 (2019) 1463. https://doi.org/10.3390/ijms20061463.
J.Z. Song, H.H.W. Yiu, C.F. Qiao, et al., Chemical comparison and classification of Radix Astragali by determination of isoflavonoids and astragalosides, J. Pharm. Biomed. Anal. 47 (2008) 399-406. https://doi.org/10.1016/j.jpba.2007.12.036.
D. Zhang, Y. Zhuang, J. Pan, et al., Investigation of effects and mechanisms of total flavonoids of Astragalus and calycosin on human erythroleukemia cells, Oxid. Med. Cell. Longev. 2012 (2012) 1-5. https://doi.org/10.1155/2012/209843.
Q. Zhang, Y. Heng, Z. Mou, J. et al., Reassessment of subacute MPTP-treated mice as animal model of Parkinson’s disease, Acta Pharmacol. Sin. 38 (2017) 1317-1328. https://doi.org/10.1038/aps.2017.49.
H. Zhu, Y. Tao, T. Wang, et al., Long‐term stability and characteristics of behavioral, biochemical, and molecular markers of three different rodent models for depression, Brain Behav. 10 (2020). https://doi.org/10.1002/brb3.1508.
H. Zhu, G. Wang, Y. Bai, et al., Natural bear bile powder suppresses neuroinflammation in lipopolysaccharide-treated mice via regulating TGR5/AKT/NF-κB signaling pathway, J. Ethnopharmacol. 289 (2022) 115063. https://doi.org/10.1016/j.jep.2022.115063.
Q. Xu, Z. Chen, B. Zhu, et al., A-Type cinnamon procyanidin oligomers protect against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity in mice through inhibiting the P38 mitogen-activated Protein Kinase/P53/BCL-2 associated X protein signaling pathway, J. Nutr. 150 (2020) 1731-1737. https://doi.org/10.1093/jn/nxaa128.
K.B. Magalingam, A.K. Radhakrishnan, N. Haleagrahara, Protective mechanisms of flavonoids in Parkinson’s disease, Oxid. Med. Cell. Longev. 2015 (2015) 1-14. https://doi.org/10.1155/2015/314560.
N. Sharma, M. Dobhal, Y. Joshi, et al., Flavonoids: a versatile source of anticancer drugs, Pharmacogn. Rev. 5 (2011) 1. https://doi.org/10.4103/0973-7847.79093.
M. Ayaz, A. Sadiq, M. Junaid, et al., Flavonoids as prospective neuroprotectants and their therapeutic propensity in aging associated neurological disorders, Front. Aging Neurosci. 11 (2019) 155. https://doi.org/10.3389/fnagi.2019.00155.
P. Maher, The potential of flavonoids for the treatment of neurodegenerative diseases, Int. J. Mol. Sci. 20 (2019) 3056. https://doi.org/10.3390/ijms20123056.
U.J. Jung, S.R. Kim, Beneficial effects of flavonoids against parkinson’s disease, J. Med. Food. 21 (2018) 421-432. https://doi.org/10.1089/jmf.2017.4078.
L. Bai, F. Yan, R. Deng, et al., Thioredoxin-1 rescues MPP+/MPTP-induced ferroptosis by increasing glutathione peroxidase 4, Mol. Neurobiol. 58 (2021) 3187-3197. https://doi.org/10.1007/s12035-021-02320-1.
N. Geng, B.J. Shi, S.L. Li, et al., Knockdown of ferroportin accelerates erastin-induced ferroptosis in neuroblastoma cells, Eur. Rev. Med. Pharmacol. Sci. 22 (2018) 3826-3836. https://doi.org/10.26355/eurrev_201806_15267.
H. Li, R. Shi, F. Ding, et al., Astragalus polysaccharide suppresses 6-hydroxydopamine-induced neurotoxicity in Caenorhabditis elegans, Oxid. Med. Cell. Longev. 2016 (2016) 1-10. https://doi.org/10.1155/2016/4856761.
Y. Tan, L. Yin, Z. Sun, et al., Astragalus polysaccharide exerts anti-Parkinson via activating the PI3K/AKT/mTOR pathway to increase cellular autophagy level in vitro, Int. J. Biol. Macromol. 153 (2020) 349-356. https://doi.org/10.1016/j.ijbiomac.2020.02.282.
H. Liu, S. Chen, C. Guo, et al., Astragalus polysaccharide protects neurons and stabilizes mitochondrial in a mouse model of parkinson disease, Med. Sci. Monit. 24 (2018) 5192-5199. https://doi.org/10.12659/MSM.908021.
L. Yang, X. Han, F. Xing, et al., Total flavonoids of astragalus attenuates experimental autoimmune encephalomyelitis by suppressing the activation and inflammatory responses of microglia via JNK/AKT/NFκB signaling pathway, Phytomedicine. 80 (2021) 153385. https://doi.org/10.1016/j.phymed.2020.153385.
O. Ibrahim, J. O’Sullivan, Iron chelators in cancer therapy, BioMetals. 33 (2020) 201-215. https://doi.org/10.1007/s10534-020-00243-3.
A. Nair, S. Jacob, A simple practice guide for dose conversion between animals and human, J. Basic Clin. Pharm. 7 (2016) 27. https://doi.org/10.4103/0976-0105.177703.
V. Ny, M. Houška, R. Pavela, et al., Potential benefits of incorporating Astragalus membranaceus into the diet of people undergoing disease treatment: An overview, J. Funct. Foods. 77 (2021) 104339. https://doi.org/10.1016/j.jff.2020.104339.
Y.-H. Kuo, W.-J. Tsai, S.-H. Loke, et al., Astragalus membranaceus flavonoids (AMF) ameliorate chronic fatigue syndrome induced by food intake restriction plus forced swimming, J. Ethnopharmacol. 122 (2009) 28-34. https://doi.org/10.1016/j.jep.2008.11.025.
R.B. de Andrade Teles, T.C. Diniz, T.C. Costa Pinto, et al., Flavonoids as therapeutic agents in Alzheimer’s and Parkinson’s diseases: a systematic review of preclinical evidences, Oxid. Med. Cell. Longev. 2018 (2018) 1-21. https://doi.org/10.1155/2018/7043213.
A. Jäger, L. Saaby, Flavonoids and the CNS, Molecules. 16 (2011) 1471-1485. https://doi.org/10.3390/molecules16021471.
K.Y.Z. Zheng, R.C.Y. Choi, A.W.H. Cheung, et al., Flavonoids from Radix Astragali induce the expression of erythropoietin in cultured cells: a signaling mediated via the accumulation of hypoxia-inducible factor-1α, J. Agric. Food Chem. 59 (2011) 1697-1704. https://doi.org/10.1021/jf104018u.
L.Y. Luo, M.X. Fan, H.Y. Zhao, et al., Pharmacokinetics and bioavailability of the isoflavones formononetin and ononin and their in vitro absorption in ussing chamber and Caco-2 cell models, J. Agric. Food Chem. 66 (2018) 2917-2924. https://doi.org/10.1021/acs.jafc.8b00035.
X. Li, T. Zhao, J. Gu, et al., Intake of flavonoids from Astragalus membranaceus ameliorated brain impairment in diabetic mice via modulating brain-gut axis, Chin. Med. 17 (2022) 22. https://doi.org/10.1186/s13020-022-00578-8.
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