Ginsenoside Rg1 ameliorates hippocampal long-term potentiation and memory in an Alzheimer's disease model

Li,Fengling; Wu,Xiqing; Li,Jing; Niu,Qingliang

doi:10.3892/mmr.2016.5103

Ginsenoside Rg1 ameliorates hippocampal long-term potentiation and memory in an Alzheimer's disease model

Authors:
- Fengling Li
- Xiqing Wu
- Jing Li
- Qingliang Niu
View Affiliations

Affiliations: Department of Neurology, The Affiliated Hospital of Weifang Medical University, Weifang, Shandong 261031, P.R. China, Medical Imaging Center, Weifang Traditional Chinese Medicine Hospital, Weifang, Shandong 261041, P.R. China, Department of Orthopaedics Rehabilitation, Weifang Traditional Chinese Medicine Hospital, Weifang, Shandong 261041, P.R. China
Published online on: April 12, 2016 https://doi.org/10.3892/mmr.2016.5103
Pages: 4904-4910

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The complex etiopathogenesis of Alzheimer's disease (AD) has limited progression in the identification of effective therapeutic agents. Amyloid precursor protein (APP) and presenilin‑1 (PS1) are always overexpressed in AD, and are considered to be the initiators of the formation of β‑amyloid plaques and the symptoms of AD. In the present study, a transgenic AD model, constructed via the overexpression of APP and PS1, was used to verify the protective effects of ginsenoside Rg1 on memory performance and synaptic plasticity. AD mice (6‑month‑old) were treated via intraperitoneal injection of 0.1‑10 mg/kg ginsenoside Rg1. Long‑term memory, synaptic plasticity, and the levels of AD‑associated and synaptic plasticity‑associated proteins were measured following treatment. Memory was measured using a fear conditioning task and protein expression levels were investigated using western blotting. All the data was analyzed by one-way analysis of variance or t‑test. Following 30 days of consecutive treatment, memory in the AD mouse model was ameliorated in the 10 mg/kg ginsenoside Rg1 treatment group. As demonstrated by biochemical experiments, ginsenoside Rg1 treatment reduced the accumulations of β‑amyloid 1‑42 and phosphorylated (p)‑Tau in the AD model. Additionally, brain-derived neurotrophic factor (BDNF) and p‑TrkB synaptic plasticity‑associated proteins were upregulated following ginsenoside Rg1 application. Correspondingly, long‑term potentiation (LTP) was restored following ginsenoside Rg1 application in the AD mice model. Taken together, ginsenoside Rg1 repaired hippocampal LTP and memory, likely through facilitating the clearance of AD‑associated proteins and through activation of the BDNF‑TrkB pathway. Therefore, ginsenoside Rg1 may be a candidate drug for the treatment of AD.

View Figures

View References

1	Qiu C, Kivipelto M and von Strauss E: Epidemiology of Alzheimer's disease: Occurrence, determinants and strategies toward intervention. Dialogues Clin Neurosci. 11:111–128. 2009.
2	Salloway S: Current and future treatments for Alzheimer's disease. CNS Spectr. 14(8 Suppl 7): 4–7; discussion 16–18. 2009.PubMed/NCBI
3	Yiannopoulou KG and Papageorgiou SG: Current and future treatments for Alzheimer's disease. Ther Adv Neurol Disord. 6:19–33. 2013. View Article : Google Scholar : PubMed/NCBI
4	Aisen PS, Cummings J and Schneider LS: Symptomatic and nonamyloid/tau based pharmacologic treatment for Alzheimer disease. Cold Spring Harb Perspect Med. 2:a0063952012. View Article : Google Scholar : PubMed/NCBI
5	LaFerla FM, Green KN and Oddo S: Intracellular amyloid-beta in Alzheimer's disease. Nat Rev Neurosci. 8:499–509. 2007. View Article : Google Scholar : PubMed/NCBI
6	Li M, Chen L, Lee DH, Yu LC and Zhang Y: The role of intracellular amyloid beta in Alzheimer's disease. Prog Neurobiol. 83:131–139. 2007. View Article : Google Scholar : PubMed/NCBI
7	Carter J and Lippa CF: Beta-amyloid, neuronal death and Alzheimer's disease. Curr Mol Med. 1:733–737. 2001. View Article : Google Scholar
8	Oakley H, Cole SL, Logan S, Maus E, Shao P, Craft J, Guillozet-Bongaarts A, Ohno M, Disterhoft J, Van Eldik L, et al: Intraneuronal beta-amyloid aggregates, neurodegeneration and neuron loss in transgenic mice with five familial Alzheimer's disease mutations: Potential factors in amyloid plaque formation. J Neurosci. 26:10129–10140. 2006. View Article : Google Scholar : PubMed/NCBI
9	Chapman PF, White GL, Jones MW, Cooper-Blacketer D, Marshall VJ, Irizarry M, Younkin L, Good MA, Bliss TV, Hyman BT, et al: Impaired synaptic plasticity and learning in aged amyloid precursor protein transgenic mice. Nat Neurosci. 2:271–276. 1999. View Article : Google Scholar : PubMed/NCBI
10	Hung IC, Chang SS, Chang PC, Lee CC and Chen CY: Memory enhancement by traditional Chinese medicine? J Biomol Struct Dyn. 31:1411–1439. 2013. View Article : Google Scholar
11	May BH, Lu C, Lu Y, Zhang AL and Xue CC: Chinese herbs for memory disorders: A review and systematic analysis of classical herbal literature. J Acupunct Meridian Stud. 6:2–11. 2013. View Article : Google Scholar : PubMed/NCBI
12	Yang L, Zhang J, Zheng K, Shen H and Chen X: Long-term ginsenoside Rg1 supplementation improves age-related cognitive decline by promoting synaptic plasticity associated protein expression in C57BL/6J mice. J Gerontol A Biol Sci Med Sci. 69:282–294. 2014. View Article : Google Scholar
13	Gillis CN: Panax ginseng pharmacology: A nitric oxide link? Biochem Pharmacol. 54:1–8. 1997. View Article : Google Scholar : PubMed/NCBI
14	Lee CH and Kim JH: A review on the medicinal potentials of ginseng and ginsenosides on cardiovascular diseases. J Ginseng Res. 38:161–166. 2014. View Article : Google Scholar : PubMed/NCBI
15	Nah SY: Ginseng ginsenoside pharmacology in the nervous system: Involvement in the regulation of ion channels and receptors. Frontiers in physiology. 5:982014. View Article : Google Scholar : PubMed/NCBI
16	Lee B, Sur B, Park J, Kim SH, Kwon S, Yeom M, Shim I, Lee H and Hahm DH: Ginsenoside rg3 alleviates lipopolysaccharide-induced learning and memory impairments by anti-inflammatory activity in rats. Biomol Ther (Seoul). 21:381–390. 2013. View Article : Google Scholar
17	Song XY, Hu JF, Chu SF, Zhang Z, Xu S, Yuan YH, Han N, Liu Y, Niu F, He X and Chen NH: Ginsenoside Rg1 attenuates okadaic acid induced spatial memory impairment by the GSK3beta/tau signaling pathway and the Abeta formation prevention in rats. Eur J Pharmacol. 710:29–38. 2013. View Article : Google Scholar : PubMed/NCBI
18	Chu S, Gu J, Feng L, Liu J, Zhang M, Jia X, Liu M and Yao D: Ginsenoside Rg5 improves cognitive dysfunction and beta-amyloid deposition in STZ-induced memory impaired rats via attenuating neuroinflammatory responses. Int Immunopharmacol. 19:317–326. 2014. View Article : Google Scholar : PubMed/NCBI
19	Wang Y, Kan H, Yin Y, Wu W, Hu W, Wang M and Li W and Li W: Protective effects of ginsenoside Rg1 on chronic restraint stress induced learning and memory impairments in male mice. Pharmacol Biochem Behav. 120:73–81. 2014. View Article : Google Scholar : PubMed/NCBI
20	Nah JJ, Hahn JH, Chung S, Choi S, Kim YI and Nah SY: Effect of ginsenosides, active components of ginseng, on capsaicin-induced pain-related behavior. Neuropharmacology. 39:2180–2184. 2000. View Article : Google Scholar : PubMed/NCBI
21	Long W, Zhang SC, Wen L, Mu L, Yang F and Chen G: In vivo distribution and pharmacokinetics of multiple active components from Danshen and Sanqi and their combination via inner ear administration. J Ethnopharmacol. 156:199–208. 2014. View Article : Google Scholar : PubMed/NCBI
22	Zhang X, Wang J, Xing Y, Gong L, Li H, Wu Z, Li Y, Wang J, Wang Y, Dong L and Li S: Effects of ginsenoside Rg1 or 17β-estradiol on a cognitively impaired, ovariectomized rat model of Alzheimer's disease. Neuroscience. 220:191–200. 2012. View Article : Google Scholar : PubMed/NCBI
23	Zhu G, Wang Y, Li J and Wang J: Chronic treatment with ginsenoside Rg1 promotes memory and hippocampal long-term potentiation in middle-aged mice. Neuroscience. 292:81–89. 2015. View Article : Google Scholar : PubMed/NCBI
24	Quan Q, Wang J, Li X and Wang Y: Ginsenoside Rg1 decreases Aβ(1–42) level by upregulating PPARgamma and IDE expression in the hippocampus of a rat model of Alzheimer's disease. PloS One. 8:e591552013. View Article : Google Scholar
25	Hong X, Liu J, Zhu G, Zhuang Y, Suo H, Wang P, Huang D, Xu J, Huang Y, Yu M, et al: Parkin overexpression ameliorates hippocampal long-term potentiation and β-amyloid load in an Alzheimer's disease mouse model. Hum Mol Genet. 23:1056–1072. 2014. View Article : Google Scholar
26	Zhu G, Liu Y, Wang Y, Bi X and Baudry M: Different patterns of electrical activity lead to long-term potentiation by activating different intracellular pathways. J Neurosci. 35:621–633. 2015. View Article : Google Scholar : PubMed/NCBI
27	Liu J, Yan X, Li L, Zhu Y, Qin K, Zhou L, Sun D, Zhang X, Ye R and Zhao G: Ginsennoside rd attenuates cognitive dysfunction in a rat model of Alzheimer's disease. Neurochem Res. 37:2738–2747. 2012. View Article : Google Scholar : PubMed/NCBI
28	Qiu J, Li W, Feng SH, Wang M and He ZY: Ginsenoside Rh2 promotes nonamyloidgenic cleavage of amyloid precursor protein via a cholesterol-dependent pathway. Genet Mol Res. 13:3586–3598. 2014. View Article : Google Scholar : PubMed/NCBI
29	Zhao H, Li Q, Pei X, Zhang Z, Yang R, Wang J and Li Y: Long-term ginsenoside administration prevents memory impairment in aged C57BL/6J mice by up-regulating the synaptic plasticity-related proteins in hippocampus. Behav Brain Res. 201:311–317. 2009. View Article : Google Scholar : PubMed/NCBI
30	Zhao HF, Li Q and Li Y: Long-term ginsenoside administration prevents memory loss in aged female C57BL/6J mice by modulating the redox status and up-regulating the plasticity-related proteins in hippocampus. Neuroscience. 183:189–202. 2011. View Article : Google Scholar : PubMed/NCBI
31	Wang XY, Chen J and Zhang JT: Effect of ginsenoside Rg1 on learning and memory impairment induced by beta-amyloid peptide (25–35) and its mechanism of action. Yao Xue Xue Bao. 36:1–4. 2001.In Chinese.
32	Chen LM, Lin ZY, Zhu YG, Lin N, Zhang J, Pan XD and Chen XC: Ginsenoside Rg1 attenuates β-amyloid generation via suppressing PPARgamma-regulated BACE1 activity in N2a-APP695 cells. Eur J Pharmacol. 675:15–21. 2012. View Article : Google Scholar
33	Fang F, Chen X, Huang T, Lue LF, Luddy JS and Yan SS: Multi-faced neuroprotective effects of Ginsenoside Rg1 in an Alzheimer mouse model. Biochim Biophys Acta. 1822:286–292. 2012. View Article : Google Scholar :
34	Wang YH and Du GH: Ginsenoside Rg1 inhibits beta-secretase activity in vitro and protects against Abeta-induced cytotoxicity in PC12 cells. J Asian Nat Prod Res. 11:604–612. 2009. View Article : Google Scholar
35	Shi C, Zheng DD, Fang L, Wu F, Kwong WH and Xu J: Ginsenoside Rg1 promotes nonamyloidgenic cleavage of APP via estrogen receptor signaling to MAPK/ERK and PI3K/Akt. Biochim Biophys Acta. 1820:453–460. 2012. View Article : Google Scholar
36	Li X, Zhang X, Yuan H and Quan Q: Experimental research on effect of gensenoside Rg1 on expressions of P-Tau and caspase-3 in brain slices from AD model rats. Zhongguo Zhong Yao Za Zhi. 35:369–372. 2010.In Chinese. PubMed/NCBI
37	Shi YQ, Huang TW, Chen LM, Pan XD, Zhang J, Zhu YG and Chen XC: Ginsenoside Rg1 attenuates amyloid-beta content, regulates PKA/CREB activity and improves cognitive performance in SAMP8 mice. J Alzheimer's Dis. 19:977–989. 2010.
38	Li X, Liu Y, Zhang X, Yuan H and Quan Q: Effect of ginsenoside Rg1 on expressions of phosphory protein tau and N-methyl-D-aspartate receptor subunits NR1 and NR2B in rat brain slice model of Alzheimer's disease. Zhongguo Zhong Yao Za Zhi. 35:3339–3343. 2010.In Chinese.
39	Shi C, Na N, Zhu X and Xu J: Estrogenic effect of ginsenoside Rg1 on APP processing in post-menopausal platelets. Platelets. 24:51–62. 2013. View Article : Google Scholar