Ginsenoside Rg1 exerts a protective effect against Aβ25-35-induced toxicity in primary cultured rat cortical neurons through the NF-κB/NO pathway

Wu,Jiaying; Yang,Hongyu; Zhao,Qingwei; Zhang,Xingguo; Lou,Yijia

doi:10.3892/ijmm.2016.2485

Ginsenoside Rg1 exerts a protective effect against Aβ25-35-induced toxicity in primary cultured rat cortical neurons through the NF-κB/NO pathway

Authors:
- Jiaying Wu
- Hongyu Yang
- Qingwei Zhao
- Xingguo Zhang
- Yijia Lou
View Affiliations

Affiliations: Department of Pharmacy, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China, Division of Cardio-Cerebral Vascular and Hepatic Pharmacology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, P.R. China
Published online on: February 8, 2016 https://doi.org/10.3892/ijmm.2016.2485
Pages: 781-788

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

Ginsenoside Rg1 (Rg1) is a multipotent triterpene saponin extracted from ginseng, and has been proven to act as a nootropic agent against various types of neurological damage. The present study was designed to investigate the neuroprotective effect and the underlying mechanisms of Rg1 on apoptosis induced by β-amyloid peptide 25-35 (Aβ25-35) in primary cultured cortical neurons. The primary neurons were preincubated with 20 µM Rg1 for 24 h and exposed to 10 µM Aβ25-35 for 72 h. In the present study, we found that Rg1 prevented nuclear factor κ-light-chain‑enhancer of activated B cells (NF-κB) nuclear translocation and IκB-α phosphorylation in primary cultured cortical neurons after Aβ25-35 exposure by scavenging excess reactive oxygen species (ROS); ROS was measured using DCFDA and examined using a fluorescence microscope. In addition, Rg1 successfully suppressed Aβ25‑35-inducible nitric oxide synthase (iNOS) expression and nitric oxide (NO) production in a NF-κB-dependent manner; the suppression of NO was clearly illustrated by the NO production assay. Pretreatment of the cells with Rg1 elevated the proportion of Bcl-2/Bax, lessened the release of cytochrome c from mitochondria into cytoplasm and then blocked mitochondrial apoptotic cascades after Aβ25-35 insult by lowering NO generation. Taken together, our data demonstrate that Rg1 rescues primary cultured cortical neurons from Aβ25-35-induced cell apoptosis through the downregulation of the NF-κB/NO signaling pathway.

View Figures

View References

1	Cummings JL: Alzheimer's disease. N Engl J Med. 351:56–67. 2004. View Article : Google Scholar : PubMed/NCBI
2	Hampel H: Amyloid-β and cognition in aging and Alzheimer's disease: molecular and neurophysiological mechanisms. J Alzheimers Dis. 33(Suppl 1): S79–S86. 2013.
3	Ingelsson M, Fukumoto H, Newell KL, Growdon JH, Hedley-Whyte ET, Frosch MP, Albert MS, Hyman BT and Irizarry MC: Early Abeta accumulation and progressive synaptic loss, gliosis, and tangle formation in AD brain. Neurology. 62:925–931. 2004. View Article : Google Scholar : PubMed/NCBI
4	Mormino EC, Brandel MG, Madison CM, Marks S, Baker SL and Jagust WJ: Aβ deposition in aging is associated with increases in brain activation during successful memory encoding. Cereb Cortex. 22:1813–1823. 2012. View Article : Google Scholar :
5	Huang Y and Mucke L: Alzheimer mechanisms and therapeutic strategies. Cell. 148:1204–1222. 2012. View Article : Google Scholar : PubMed/NCBI
6	Ardah MT, Paleologou KE, Lv G, Menon SA, Abul Khair SB, Lu JH, Safieh-Garabedian B, Al-Hayani AA, Eliezer D, Li M and El-Agnaf OM: Ginsenoside Rb1 inhibits fibrillation and toxicity of alpha-synuclein and disaggregates preformed fibrils. Neurobiol Dis. 74:89–101. 2015. View Article : Google Scholar
7	Wu J, Pan Z, Wang Z, Zhu W, Shen Y, Cui R, Lin J, Yu H, Wang Q, Qian J, et al: Ginsenoside Rg1 protection against β-amyloid peptide-induced neuronal apoptosis via estrogen receptor α and glucocorticoid receptor-dependent anti-protein nitration pathway. Neuropharmacology. 63:349–361. 2012. View Article : Google Scholar : PubMed/NCBI
8	Xie CL, Li JH, Wang WW, Zheng GQ and Wang LX: Neuroprotective effect of ginsenoside-Rg1 on cerebral ischemia/reperfusion injury in rats by downregulating protease-activated receptor-1 expression. Life Sci. 121:145–151. 2015. View Article : Google Scholar
9	Zhu J, Mu X, Zeng J, Xu C, Liu J, Zhang M, Li C, Chen J, Li T and Wang Y: Ginsenoside Rg1 prevents cognitive impairment and hippocampus senescence in a rat model of D-galactose-induced aging. PLoS One. 9:e1012912014. View Article : Google Scholar : PubMed/NCBI
10	Gilmore TD: Introduction to NF-kappaB: players, pathways, perspectives. Oncogene. 25:6680–6684. 2006. View Article : Google Scholar : PubMed/NCBI
11	Mattson MP and Camandola S: NF-kappaB in neuronal plasticity and neurodegenerative disorders. J Clin Invest. 107:247–254. 2001. View Article : Google Scholar : PubMed/NCBI
12	Merlo E, Freudenthal R and Romano A: The IkappaB kinase inhibitor sulfasalazine impairs long-term memory in the crab Chasmagnathus. Neuroscience. 112:161–172. 2002. View Article : Google Scholar : PubMed/NCBI
13	Karin M: NF-kappaB as a critical link between inflammation and cancer. Cold Spring Harb Perspect Biol. 1:a0001412009. View Article : Google Scholar
14	Boissière F, Hunot S, Faucheux B, Duyckaerts C, Hauw JJ, Agid Y and Hirsch EC: Nuclear translocation of NF-kappaB in cholinergic neurons of patients with Alzheimer's disease. Neuroreport. 8:2849–2852. 1997. View Article : Google Scholar : PubMed/NCBI
15	Kaltschmidt B, Uherek M, Volk B, Baeuerle PA and Kaltschmidt C: Transcription factor NF-kappaB is activated in primary neurons by amyloid beta peptides and in neurons surrounding early plaques from patients with Alzheimer disease. Proc Natl Acad Sci USA. 94:2642–2647. 1997. View Article : Google Scholar : PubMed/NCBI
16	Kitamura Y, Shimohama S, Ota T, Matsuoka Y, Nomura Y and Taniguchi T: Alteration of transcription factors NF-kappaB and STAT1 in Alzheimer's disease brains. Neurosci Lett. 237:17–20. 1997. View Article : Google Scholar : PubMed/NCBI
17	Du J, Cheng B, Zhu X and Ling C: Ginsenoside Rg1, a novel glucocorticoid receptor agonist of plant origin, maintains glucocorticoid efficacy with reduced side effects. J Immunol. 187:942–950. 2011. View Article : Google Scholar : PubMed/NCBI
18	Liu Q, Kou JP and Yu BY: Ginsenoside Rg1 protects against hydrogen peroxide-induced cell death in PC12 cells via inhibiting NF-κB activation. Neurochem Int. 58:119–125. 2011. View Article : Google Scholar
19	Wang Z, Zhang X, Wang H, Qi L and Lou Y: Neuroprotective effects of icaritin against beta amyloid-induced neurotoxicity in primary cultured rat neuronal cells via estrogen-dependent pathway. Neuroscience. 145:911–922. 2007. View Article : Google Scholar : PubMed/NCBI
20	Cristina de Assis M, Cristina Plotkowski M, Fierro IM, Barja-Fidalgo C and de Freitas MS: Expression of inducible nitric oxide synthase in human umbilical vein endothelial cells during primary culture. Nitric Oxide. 7:254–261. 2002. View Article : Google Scholar : PubMed/NCBI
21	Brasier AR: The NF-kappaB regulatory network. Cardiovasc Toxicol. 6:111–130. 2006. View Article : Google Scholar
22	Perkins ND: Integrating cell-signalling pathways with NF-kappaB and IKK function. Nat Rev Mol Cell Biol. 8:49–62. 2007. View Article : Google Scholar
23	Ola MS, Nawaz M and Ahsan H: Role of Bcl-2 family proteins and caspases in the regulation of apoptosis. Mol Cell Biochem. 351:41–58. 2011. View Article : Google Scholar : PubMed/NCBI
24	Li YB, Wang Y, Tang JP, Chen D and Wang SL: Neuroprotective effects of ginsenoside Rg1-induced neural stem cell transplantation on hypoxic-ischemic encephalopathy. Neural Regen Res. 10:753–759. 2015. View Article : Google Scholar : PubMed/NCBI
25	Wu J, Pan Z, Cheng M, Shen Y, Yu H, Wang Q and Lou Y: Ginsenoside Rg1 facilitates neural differentiation of mouse embryonic stem cells via GR-dependent signaling pathway. Neurochem Int. 62:92–102. 2013. View Article : Google Scholar
26	Li W, Chu Y, Zhang L, Yin L and Li L: Ginsenoside Rg1 attenuates tau phosphorylation in SK-N-SH induced by Aβ-stimulated THP-1 supernatant and the involvement of p38 pathway activation. Life Sci. 91:809–815. 2012. View Article : Google Scholar : PubMed/NCBI
27	Kabe Y, Ando K, Hirao S, Yoshida M and Handa H: Redox regulation of NF-kappaB activation: distinct redox regulation between the cytoplasm and the nucleus. Antioxid Redox Signal. 7:395–403. 2005. View Article : Google Scholar : PubMed/NCBI
28	Tuppo EE and Arias HR: The role of inflammation in Alzheimer's disease. Int J Biochem Cell Biol. 37:289–305. 2005. View Article : Google Scholar
29	Chen CH, Zhou W, Liu S, Deng Y, Cai F, Tone M, Tone Y, Tong Y and Song W: Increased NF-κB signalling up-regulates BACE1 expression and its therapeutic potential in Alzheimer's disease. Int J Neuropsychopharmacol. 15:77–90. 2012. View Article : Google Scholar
30	Aktan F: iNOS-mediated nitric oxide production and its regulation. Life Sci. 75:639–653. 2004. View Article : Google Scholar : PubMed/NCBI
31	Surh YJ1, Chun KS, Cha HH, Han SS, Keum YS, Park KK and Lee SS: Molecular mechanisms underlying chemopreventive activities of anti-inflammatory phytochemicals: down-regulation of COX-2 and iNOS through suppression of NF-kappa B activation. Mutat Res. 480–481:243–268. 2001. View Article : Google Scholar
32	Zara S, Di Stefano A, Nasuti C, Rapino M, Patruno A, Pesce M, Sozio P, Cerasa LS and Cataldi A: NOS-mediated morphological and molecular modifications in rats infused with Aβ (1–40), as a model of Alzheimer's disease, in response to a new lipophilic molecular combination codrug-1. Exp Gerontol. 46:273–281. 2011. View Article : Google Scholar
33	Mendes AF, Carvalho AP, Caramona MM and Lopes MC: Role of nitric oxide in the activation of NF-kappaB, AP-1 and NOS II expression in articular chondrocytes. Inflamm Res. 51:369–375. 2002. View Article : Google Scholar : PubMed/NCBI
34	Pahan K, Sheikh FG, Liu X, Hilger S, McKinney M and Petro TM: Induction of nitric-oxide synthase and activation of NF-kappaB by interleukin-12 p40 in microglial cells. J Biol Chem. 276:7899–7905. 2001. View Article : Google Scholar
35	Katsuyama K, Shichiri M, Marumo F and Hirata Y: NO inhibits cytokine-induced iNOS expression and NF-kappaB activation by interfering with phosphorylation and degradation of IkappaB-alpha. Arterioscler Thromb Vasc Biol. 18:1796–1802. 1998. View Article : Google Scholar : PubMed/NCBI
36	Camins A, Pallas M and Silvestre JS: Apoptotic mechanisms involved in neurodegenerative diseases: experimental and therapeutic approaches. Methods Find Exp Clin Pharmacol. 30:43–65. 2008. View Article : Google Scholar : PubMed/NCBI
37	Tillement L, Lecanu L and Papadopoulos V: Alzheimer's disease: effects of β-amyloid on mitochondria. Mitochondrion. 11:13–21. 2011. View Article : Google Scholar
38	Burlacu A: Regulation of apoptosis by Bcl-2 family proteins. J Cell Mol Med. 7:249–257. 2003. View Article : Google Scholar : PubMed/NCBI