title: Cucurbitacins attenuate microglial activation and protect from neuroinflammatory injury through Nrf2/ARE activation and STAT/NF-κB inhibition.
abstract: Emerging evidence suggests that neuroinflammatory responses are involved in the neuronal injury. Neuroinflammatory response is mediated by cellular components such as microglia and molecular components, including nitric oxide, prostaglandins and inflammatory cytokines, activation of complement proteins etc. Cucurbitacins is a class of highly oxidized tetracyclic triterpenoids isolated mainly from Cucurbitaceae but also from other plan families and has been reported to have pharmacological activities. The present study aimed to investigate the anti-neuroinflammatory effects of Cucurbitacins on TLR 2/4 agonists (amyloid-β, LTA, and LPS)-induced neuroinflammatory response in microglia and the underlying mechanism for Nrf2/ARE pathways. Results indicates that pretreatment with Cucurbitacins significantly reduced the pro-inflammatory cytokine (TNF-α, IL-1β and IL-6) and attenuated iNOS and COX-2 expression in TLR 2/4 agonists-stimulated microglia. In addition, Cucurbitacins inhibited JNK and p38 MAPKs activation and attenuated JAK-STAT and NF-κB activation in TLR 2/4 agonists-stimulated microglia. Next, we evaluate the potential involvement of Cucurbitacins in the activation of Nrf2/ARE signaling pathways and phase II detoxification enzymes activity. Results indicate that Cucurbitacins markedly promoted the activation of Nrf-2/ARE pathway-related downstream factors including NQO-1 and HO-1. Furthermore, anti-neuroinflammatory effects of Cucurbitacins are attenuated in the knockdown of Nrf2, HO-1 and NQO-1 respectively. Cucurbitacins also has neuroprotective effect against microglia over-activation related neuronal damage. This study demonstrates that Cucurbitacins is potent activator of the Nrf2/ARE pathway and is therapeutically relevant not only to neuroinflammatory responses of microglia but also neuroinflammation mediated neuronal injury.
authors.affiliation: Bio-IT Fusion Technology Research Institute, Busan, Republic of Korea.
authors.forename: Sun Young
authors.initials: SY
authors.lastname: Park
authors.affiliation: Bio-IT Fusion Technology Research Institute, Busan, Republic of Korea.
authors.forename: Young Hun
authors.initials: YH
authors.lastname: Kim
authors.affiliation: Bio-IT Fusion Technology Research Institute, Busan, Republic of Korea; Department of Nanomaterials Engineering, Pusan National University, Busan, Republic of Korea. Electronic address: gtpark@pusan.ac.kr.
authors.forename: Geuntae
authors.initials: G
authors.lastname: Park
mesh_terms: D016229:Amyloid beta-Peptides / Q000494:pharmacology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D061745:Antioxidant Response Elements; D002470:Cell Survival; D002478:Cells, Cultured; D017077:Culture Media, Conditioned; D007249:Inflammation / Q000378:metabolism; D053612:Janus Kinases / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008813:Mice, Inbred ICR; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology*; D050791:STAT Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction; D013682:Teichoic Acids / Q000494:pharmacology; D051195:Toll-Like Receptor 2 / Q000819:agonists; D051197:Toll-Like Receptor 4 / Q000819:agonists; D014315:Triterpenes / Q000494:pharmacology*
chemical_list: D016229:Amyloid beta-Peptides; D000893:Anti-Inflammatory Agents; D017077:Culture Media, Conditioned; D008070:Lipopolysaccharides; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; D018696:Neuroprotective Agents; C495636:Nfe2l2 protein, mouse; D050791:STAT Transcription Factors; D013682:Teichoic Acids; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D014315:Triterpenes; C041246:cucurbitacin B; C009900:lipoteichoic acid; D053612:Janus Kinases; C038106:cucurbitacin I; C102326:cucurbitacin E
keywords: Cucurbitacin; Microglia; Neuroinflammation; Nuclear factor erythroid 2-related factor 2; PKA; STAT