Xylocoside G Reduces Amyloid-β Induced Neurotoxicity by Inhibiting NF-κB Signaling Pathway in Neuronal Cells

Article type: Research Article

Authors: Yu, Yan^{a; 1} | Zhou, Liang^{a; 1} | Sun, Miao^a | Zhou, Ting^a | Zhong, Kaiyin^a | Wang, Hecheng^a | Liu, Yi^a | Liu, Xinying^a | Xiao, RuiZhong^b | Ge, Jia^c | Tu, PengFei^c | Fan, Dong Sheng^{b; *} | Lan, Yuan^d | Hui, Chen^e | Chui, Dehua^{a; b; *}

Affiliations: [a] Neuroscience Research Institute and Department of Neurobiology, Key Laboratory for Neuroscience, Ministry of Education and Ministry of Public Health, Health Science Center, Peking University, Beijing, China | [b] Department of Neurology, Peking University Third Hospital, Beijing, China | [c] The State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, China | [d] Peking University Medical and Healthy Analytical Center, Peking University, Beijing, China | [e] China Rehabilitation Research Center, Capital University of Medical Sciences, Beijing, China

Correspondence: [*] Correspondence to: Dr. Dong Sheng Fan or Dr. Dehua Chui, Neuroscience Research Institute, Department of Neurology, Peking University Third Hospital, Peking University Health Science Center, 38 Xueyuan Road, Hai Dian District, 100191, Beijing, China. E-mail: [email protected].

Note: [1] These authors contributed equally to this paper.

Abstract: Amyloid-β (Aβ) peptide, which can invoke a cascade of inflammatory responses, is considered to play a causal role in the development and progress of Alzheimer's disease (AD). Xylocoside G (XG) is an active compound isolated from a traditional Chinese medicinal plant, Itoa orientalis. We have previously reported that XG has neuroprotective effects, of which the mechanism is yet unknown. In this study, we investigated the possible mechanisms underlying neuroprotection of XG against Aβ-induced toxicity in SH-SY5Y cells and primary neurons. Pretreatment with XG significantly attenuated the cell viability reduction induced by Aβ exposure in a dose dependent manner which was testified by 3-[4,5-Dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase release assay. In addition, pretreatment with XG countered the effect of Aβ on Bax and Bcl-2 expression and repressed Aβ-induced caspase-3 activation, suggesting that the neuroprotective effect of XG is associated with apoptosis regulation. Neuroinflammation has been implicated in Aβ-induced neuronal death. XG significantly attenuated Aβ-stimulated release of inflammatory factors such as tumor necrosis factor-α, interleukin-1β, and prostaglandin E2. It also downregulated the expression of cyclooxygenase-2 in SH-SY5Y cells. Further molecular mechanism studies demonstrated that XG inhibited Aβ-induced NF-κB p65 translocation, which was probably the result of inhibition of JNK phosphorylation but not ERK or p38 MAPK pathway by XG. This is the first study to demonstrate that XG protects SH-SY5Y cells against Aβ-induced inflammation and apoptosis by down-regulating NF-κB signaling pathways.

Keywords: Amyloid-β, apoptosis, MAPK, NF-κB, neuroinflammation, Xylocoside G

DOI: 10.3233/JAD-2012-110779

Journal: Journal of Alzheimer's Disease, vol. 30, no. 2, pp. 263-275, 2012