title: Tripchlorolide protects neuronal cells from microglia-mediated beta-amyloid neurotoxicity through inhibiting NF-kappaB and JNK signaling.
abstract: Recent research has focused on soluble oligomeric assemblies of beta-amyloid peptides (Abeta) as the proximate cause of neuroinflammation, synaptic loss, and the eventual dementia associated with Alzheimer's disease (AD). In this study, tripchlorolide (T4), an extract of Tripterygium wilfordii Hook. F (TWHF), was studied as a novel agent to suppress neuroinflammatory process in microglial cells and to protect neuronal cells against microglia-mediated oligomeric Abeta toxicity. T4 significantly attenuated oligomeric Abeta(1-42)-induced release of inflammatory productions such as tumor necrosis factor-alpha, interleukin-1beta, nitric oxide (NO), and prostaglandin E2. It also downregulated the protein levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in microglial cells. Further molecular mechanism study demonstrated that T4 inhibited the nuclear translocation of nuclear factor-kappaB (NF-kappaB) without affecting I-kappaBalpha phosphorylation. It repressed Abeta-induced JNK phosphorylation but not ERK or p38 MAPK. The inhibition of NF-kappaB and JNK by T4 is correlated with the suppression of inflammatory mediators in Abeta-stimulated microglial cells. These results suggest that T4 protects neuronal cells by blocking inflammatory responses of microglial cells to oligomeric Abeta(1-42) and that T4 acts on the signaling of NF-kappaB and JNK, which are involved in the modulation of inflammatory response. Therefore, T4 may be an effective agent in modulating neuroinflammatory process in AD.
authors.affiliation: Department of Neurology, Union Hospital of Fujian Medical University, Fuzhou, Fujian, People's Republic of China.
authors.forename: Xiao-Dong
authors.initials: XD
authors.lastname: Pan
authors.forename: Xiao-Chun
authors.initials: XC
authors.lastname: Chen
authors.forename: Yuan-Gui
authors.initials: YG
authors.lastname: Zhu
authors.forename: Li-Min
authors.initials: LM
authors.lastname: Chen
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.forename: Tian-Wen
authors.initials: TW
authors.lastname: Huang
authors.forename: Qin-Yong
authors.initials: QY
authors.lastname: Ye
authors.forename: Hua-Pin
authors.initials: HP
authors.lastname: Huang
mesh_terms: D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D002478:Cells, Cultured; D004224:Diterpenes / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects* / Q000276:immunology / Q000502:physiology; D052002:NF-kappa B p50 Subunit / Q000378:metabolism*; D015213:Neuroimmunomodulation / Q000187:drug effects; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010446:Peptide Fragments / Q000633:toxicity*; D010616:Phenanthrenes / Q000494:pharmacology*
chemical_list: D016229:Amyloid beta-Peptides; D004224:Diterpenes; D052002:NF-kappa B p50 Subunit; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D010616:Phenanthrenes; C075222:amyloid beta-protein (1-42); C068051:tripchlorolide; C073701:Nfkb1 protein, mouse; D048031:JNK Mitogen-Activated Protein Kinases