Ginsenoside Compound K Regulates Amyloid β via the Nrf2/Keap1 Signaling Pathway in Mice with Scopolamine Hydrobromide-Induced Memory Impairments
- 140 Downloads
The objective of this study was to investigate the neuroprotective and antioxidant effects of ginsenoside compound K (CK) in a model of scopolamine hydrobromide-induced, memory-impaired mice. The role of CK in the regulation of amyloid β (Aβ) and its capacity to activate the Nrf2/Keap1 signaling pathway were also studied due to their translational relevance to Alzheimer’s disease. The Morris water maze was used to assess spatial memory functions. Levels of superoxide dismutase, glutathione peroxidase, and malondialdehyde in brain tissues were tested. Cell morphology was detected by hematoxylin and eosin staining and terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling assay. Immunohistochemistry and western blotting were used to determine expression levels of Nrf2/Keap1 signaling pathway-related factors and Aβ. Ginsenoside CK was found to enhance memory function, normalize neuronal morphology, decrease neuronal apoptosis, increase superoxide dismutase and glutathione peroxidase levels, reduce malondialdehyde levels, inhibit Aβ expression, and activate the Nrf2/Keap1 signaling pathway in scopolamine-exposed animals. Based on these results, we conclude that CK may improve memory function in scopolamine-injured mice by regulating Aβ aggregation and promoting the transduction of the Nrf2/Keap1 signaling pathway, thereby reducing oxidative damage to neurons and inhibiting neuronal apoptosis. This study suggests that CK may serve as a future preventative agent or treatment for Alzheimer’s disease.
KeywordsGinsenoside compound K Scopolamine Amyloid β Alzheimer’s disease Spatial memory
The work was supported by the Project of the National Natural Science Foundation of China, 2018 (No. 81704001); “Shi San Wu” Science and Technology Project, Ministry of Education, Jilin Province, 2017 (No. JJKH20170713KJ); and Funded Project for Natural Science, Department of Science and Technology, Jilin Province, 2016 (No. 20160101229JC).
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflict of interest.
All experiments were approved by the Experimental Animal Ethics Committee of Changchun University of Chinese Medicine (approval number, 20180095).
- Alotaibi MR, Hassan ZK, Al-Rejaie SS, Alshammari MA, Almutairi MM, Alhoshani AR, Alanazi WA, Hafez MH, Al-Shabanah OA (2018) Characterization of apoptosis in a breast cancer cell line after IL-10 silencing. Asian Pac J Cancer Prev 19:777–783. https://doi.org/10.1186/s12882-017-0601-y CrossRefPubMedPubMedCentralGoogle Scholar
- Bao J, Qin M, Mahaman YA, Zhang B, Huang F, Zeng K, Xia Y, Ke D, Wang Q, Liu R, Wang JZ (2018) BACE1 SUMOylation increases its stability and escalates the protease activity in Alzheimer’s disease. Proc Natl Acad Sci U S A 22:201800498–201803959. https://doi.org/10.1073/pnas.1800498115 CrossRefGoogle Scholar
- Bellezza I, Giambanco I, Minelli A, Donato R (2018) Nrf2-Keap1 signaling in oxidative and reductive stress. Biochim Biophys Acta-Mol. Cell Res 5:721–733Google Scholar
- Birnbaum JH, Wanner D, Gietl AF, Saake A, Kündig TM, Hock C, Nitsch RM, Tackenberg C (2018) Oxidative stress and altered mitochondrial protein expression in the absence of amyloid-β and tau pathology in iPSC-derived neurons from sporadic Alzheimer’s disease patients. Stem Cell Res 27:121–130. https://doi.org/10.1016/j.scr.2018.01.019 CrossRefPubMedGoogle Scholar
- Hou XQ, Wu DW, Zhang CX, Yan R, Yang C, Rong CP, Zhang L, Chang X, Su RY, Zhang SJ, He WQ (2014) Bushen-Yizhi formula ameliorates cognition deficits and attenuates oxidative stress-related neuronal apoptosis in scopolamine-induced senescence in mice. Int J Mol Med 34:429–439. https://doi.org/10.3892/ijmm.2014.1801 CrossRefPubMedPubMedCentralGoogle Scholar
- Hui Y, Chengyong T, Cheng L, Haixia H, Yuanda Z, Weihua Y (2018) Resveratrol attenuates the cytotoxicity induced by amyloid-β 1–42 in PC12 cells by upregulating heme oxygenase-1 via the PI3K/Akt/Nrf2 pathway. Neurochem Res 43:297–305. https://doi.org/10.1007/s11064-017-2421-7 CrossRefPubMedGoogle Scholar
- Jairajpuri ZS, Ghai R, Saluja S, Kapur S, Bhowmik KT (2017) Expression of apoptosis related and proliferative proteins in malignant lympho-proliferative disorders. Iranian J Pathol 12:231Google Scholar
- Jia L, Zhao Y, Liang XJ (2009) Current evaluation of the millennium phytomedicine-ginseng (II): collected chemical entities, modern pharmacology, and clinical applications emanated from traditional Chinese medicine. Curr Med Chem 16:2924–2942. https://doi.org/10.2174/092986709788803204 CrossRefPubMedPubMedCentralGoogle Scholar
- Lv H, Liu Q, Zhou J, Tan G, Deng X, Ci X (2017) Daphnetin-mediated Nrf2 antioxidant signaling pathways ameliorate tert-butyl hydroperoxide (t-BHP)-induced mitochondrial dysfunction and cell death. Free Radic Biol Med 106:38–52. https://doi.org/10.1016/j.freeradbiomed.2017.02.016 CrossRefPubMedGoogle Scholar
- Matthes F, Hettich MM, Schilling J, Flores-Dominguez D, Blank N, Wiglenda T, Buntru A, Wolf H, Weber S, Vorberg I, Dagane A (2018) Inhibition of the MID1 protein complex: a novel approach targeting APP protein synthesis. Cell Death Disc 4:4. https://doi.org/10.1038/s41420-017-0003-8 CrossRefGoogle Scholar
- Oguchi T, Ono R, Tsuji M, Shozawa H, Somei M, Inagaki M, Mori Y, Yasumoto T, Ono K, Kiuchi Y (2017) Cilostazol suppresses Aβ-induced neurotoxicity in SH-SY5Y cells through inhibition of oxidative stress and MAPK signaling pathway. Front Aging Neurosci 9:337. https://doi.org/10.3389/fnagi.2017.00337 CrossRefPubMedPubMedCentralGoogle Scholar
- Tzeng TT, Chen CC, Chen CC, Tsay HJ, Lee LY, Chen WP, Shen CC, Shiao YJ (2018) The cyanthin diterpenoid and sesterterpene constituents of Hericium erinaceus mycelium ameliorate Alzheimer’s disease-related pathologies in APP/PS1 transgenic mice. Int J Mol Sci 19:598. https://doi.org/10.3390/ijms19020598 CrossRefPubMedCentralGoogle Scholar
- Van Maanen EM, van Steeg TJ, Ahsman MJ, Michener MS, Savage MJ, Kennedy ME, Kleijn HJ, Stone J, Danhof M (2018) Extending a systems model of the APP pathway: separation of β-and γ-secretase sequential cleavage steps of APP. J Pharmacol Exp Therapeut 365:507–518. https://doi.org/10.1124/jpet.117.244699 CrossRefGoogle Scholar
- Vida C, Martinez de Toda I, Garrido A, Carro E, Molina JA, De La Fuente M (2017) Impairment of several immune functions and redox state in blood cells of Alzheimer’s disease patients. Relevant role of neutrophils in oxidative stress. Front Immunol 8:1974. https://doi.org/10.3389/fimmu.2017.01974 CrossRefPubMedGoogle Scholar
- Xu T, Gu J, Li C, Guo X, Tu J, Zhang D, Sun W, Kong X (2018) Low-intensity pulsed ultrasound suppresses proliferation and promotes apoptosis via p38 MAPK signaling in rat visceral preadipocytes. American J Transl Res 10:948Google Scholar
- Yan Y, Ren Y, Li X, Zhang X, Guo H, Han Y, Hu J (2018) A polysaccharide from green tea (Camellia sinensis L.) protects human retinal endothelial cells against hydrogen peroxide-induced oxidative injury and apoptosis. Int J Biol Macromol 115:600–607. https://doi.org/10.1016/j.ijbiomac.2018.04.011 CrossRefPubMedGoogle Scholar
- Zhang SJ, Luo D, Li L, Tan RR, Xu QQ, Qin J, Zhu L, Luo NC, Xu TT, Zhang R, Yang L (2017) Ethyl acetate extract components of Bushen-Yizhi formula provides neuroprotection against scopolamine-induced cognitive impairment. Sci Rep 7:9824. https://doi.org/10.1038/s41598-017-10437-4 CrossRefPubMedPubMedCentralGoogle Scholar