title: 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.
abstract: BACKGROUND
  It 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.
  
  
  METHODS
  Mice 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.
  
  
  RESULTS
  Our 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.
  
  
  CONCLUSIONS
  Pinocembrin 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.
authors.affiliation: National Center of Pharmacological Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, PR China.
authors.forename: Rui
authors.initials: R
authors.lastname: Liu
authors.forename: Cai-Xia
authors.initials: CX
authors.lastname: Wu
authors.forename: Dan
authors.initials: D
authors.lastname: Zhou
authors.forename: Fan
authors.initials: F
authors.lastname: Yang
authors.forename: Shuo
authors.initials: S
authors.lastname: Tian
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.forename: Tian-Tai
authors.initials: TT
authors.lastname: Zhang
authors.forename: Guan-Hua
authors.initials: GH
authors.lastname: Du
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis; D002540:Cerebral Cortex / Q000473:pathology; D003071:Cognition / Q000187:drug effects; D004195:Disease Models, Animal; D044950:Flavanones / Q000008:administration & dosage* / Q000494:pharmacology; D020869:Gene Expression Profiling; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology; D009410:Nerve Degeneration / Q000473:pathology; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D018696:Neuroprotective Agents / Q000008:administration & dosage* / Q000494:pharmacology; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000096:biosynthesis; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D016229:Amyloid beta-Peptides; D044950:Flavanones; D018696:Neuroprotective Agents; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; C016063:pinocembrin