Pinocembrin protects against β-amyloid-induced toxicity in neurons through inhibiting receptor for advanced glycation end products (RAGE)-independent signaling pathways and regulating mitochondrion-mediated apoptosis

BMC Medicine

Research Article

Cai-xia Wu¹  Shuo Tian²  Rui Liu²  Fan Yang²  Li Zhang²  Tian-tai Zhang²  Guan-hua Du²  Dan Zhou² 

[1] National Center of Pharmacological Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, 100050, Beijing, P.R. China;Shenyang Pharmaceutical University, 110016, Shenyang, P.R. China;National Center of Pharmacological Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, 100050, Beijing, P.R. China;State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 100050, Beijing, P.R. China;

关键词: Alzheimer's disease;    amyloid-β peptide;    apoptosis;    pinocembrin;    receptor for advanced glycation end products;   

DOI  :  10.1186/1741-7015-10-105

 received in 2012-07-13, accepted in 2012-09-18,  发布年份 2012

来源: Springer

【 摘 要 】

BackgroundIt is known that amyloid-β peptide (Aβ) plays a pivotal role in the pathogenesis of Alzheimer's disease (AD). Interaction between Aβ and the receptor for advanced glycation end products (RAGE) has been implicated in neuronal degeneration associated with this disease. Pinocembrin, a flavonoid abundant in propolis, has been reported to possess numerous biological activities beneficial to health. Our previous studies have demonstrated that pinocembrin has neuroprotective effects on ischemic and vascular dementia in animal models. It has been approved by the State Food and Drug Administration of China for clinical use in stroke patients. Against this background, we investigated the effects of pinocembrin on cognitive function and neuronal protection against Aβ-induced toxicity and explored its potential mechanism.MethodsMice received an intracerebroventricular fusion of Aβ25-35. Pinocembrin was administrated orally at 20 mg/kg/day and 40 mg/kg/day for 8 days. Behavioral performance, cerebral cortex neuropil ultrastructure, neuronal degeneration and RAGE expression were assessed. Further, a RAGE-overexpressing cell model and an AD cell model were used for investigating the mechanisms of pinocembrin. The mechanisms underlying the efficacy of pinocembrin were conducted on target action, mitochondrial function and potential signal transduction using fluorescence-based multiparametric technologies on a high-content analysis platform.ResultsOur results showed that oral administration of pinocembrin improved cognitive function, preserved the ultrastructural neuropil and decreased neurodegeneration of the cerebral cortex in Aβ25-35-treated mice. Pinocembrin did not have a significant effect on inhibiting Aβ1-42 production and scavenging intracellular reactive oxygen species (ROS). However, pinocembrin significantly inhibited the upregulation of RAGE transcripts and protein expression both in vivo and in vitro, and also markedly depressed the activation of p38 mitogen-activated protein kinase (MAPK)-MAPKAP kinase-2 (MK2)-heat shock protein 27 (HSP27) and stress-activated protein kinase (SAPK)/c-Jun N-terminal kinase (JNK)-c-Jun pathways and the downstream nuclear factor κB (NFκB) inflammatory response subsequent to Aβ-RAGE interaction. In addition, pinocembrin significantly alleviated mitochondrial dysfunction through improving mitochondrial membrane potential and inhibiting mitochondrial oxidative stress, and regulated mitochondrion-mediated apoptosis by restoration of B cell lymphoma 2 (Bcl-2) and cytochrome c and inactivation of caspase 3 and caspase 9.ConclusionsPinocembrin was shown to infer cognitive improvement and neuronal protection in AD models. The mechanisms of action of the compound were illustrated on RAGE-dependent transduction inhibition and mitochondrion protection. It appears to be a promising candidate for the prevention and therapy of AD.

【 授权许可】

Unknown   
© Liu et al; licensee BioMed Central Ltd. 2012. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.