cucurbitacin-i and Inflammation

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.

Topics: Amyloid beta-Peptides; Animals; Anti-Inflammatory Agents; Antioxidant Response Elements; Cell Survival; Cells, Cultured; Culture Media, Conditioned; Inflammation; Janus Kinases; Lipopolysaccharides; Mice, Inbred ICR; Microglia; Neurons; Neuroprotective Agents; NF-E2-Related Factor 2; NF-kappa B; Signal Transduction; STAT Transcription Factors; Teichoic Acids; Toll-Like Receptor 2; Toll-Like Receptor 4; Triterpenes

Astrocyte activation plays important roles both in physiological and pathological process in the CNS. In the latter, the process is further aggravated by hyperglycemia, leading to diabetes complications of CNS. We report here that high glucose (HG) treatment stimulated astrocytic morphological alteration coupled with changes in glial fibrillary acidic protein (GFAP) and vimentin expression. Additionally, HG upregulated the expression of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1β (IL-1β), interleukin-4 (IL-4), and vascular endothelial growth factor (VEGF); however, its effects on transforming growth factor-β (TGF-β) expression were not evident. HG treatment induced increased production of reactive oxygen species (ROS) as well as activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and signal transducer and activator transcription 3 (STAT 3). HG-induced expression of TNF-α, IL-6, IL-1β, IL-4, and VEGF was blocked by ROS scavenger and inhibitors specific for NF-κB and STAT 3, respectively. The results suggest that the aforementioned multiple inflammatory cytokines and mediators that may be linked to the pathogenesis of the diabetes complications of CNS are induced by HG via the key signaling pathways.

Topics: Animals; Astrocytes; Blotting, Western; Cell Survival; Cells, Cultured; Cytokines; Free Radical Scavengers; Glucose; Immunohistochemistry; In Situ Nick-End Labeling; Inflammation; Interleukin-1beta; Interleukin-4; Interleukin-6; Melatonin; Mice; Mice, Inbred BALB C; NF-kappa B; Proline; Reactive Oxygen Species; Real-Time Polymerase Chain Reaction; RNA; STAT3 Transcription Factor; Thiocarbamates; Transforming Growth Factor beta; Triterpenes; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A