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Inflammation and oxidative stress play important roles in the pathogenesis of neurodegenerative disorders such as stroke, traumatic injury, Parkinson disease, and Alzheimer disease. Paeonol, a natural compound extracted from Moutan cortex, is a potent anti-inflammatory and antioxidative agent. The aim of this study was to investigate the neuroprotective mechanisms of paeonol on lipopolysaccharide (LPS)-induced inflammation in rat primary microglia and 6-hydroxydopamine-induced oxidative damage in cortical neurons. In LPS-treated microglia, paeonol attenuated the overexpression of inducible nitric oxide synthase and cyclooxygenase 2, leading to the decrease in nitric oxide and prostaglandin E2 production, respectively. Paeonol also suppressed LPS-induced phosphorylation of extracellular signal-regulated kinase and Jun N-terminal kinase. In addition, LPS-stimulated NADPH oxidase activation and reactive oxygen species production were attenuated by paeonol. Paeonol-induced upregulation of heme oxygenase 1 was also observed. Moreover, paeonol attenuated LPS-treated microglia culture medium-induced neuron cells death. Posttreatment with paeonol also reduced inflammatory responses in LPS-activated microglia and increased cell viability in LPS-treated microglia culture medium-treated neurons. Furthermore, in 6-hydroxydopamine-treated cortical neurons, paeonol not only decreased reactive oxygen species production but also increased cell viability, superoxide dismutase activity, and the antiapoptotic protein B-cell lymphoma 2 expression. Taken together, the present results suggest that paeonol might be a potential neuroprotective agent via inhibiting microglia-mediated inflammation and oxidative stress-induced neuronal damage.

Background and Aims: A recent neuroimaging study discovered the neurotoxicity effects of homocysteine (Hcy), which is only seen in elderly women. Estrogens exert a variety of actions on brain function that influence cognitive function, mood, and neuroprotection. The Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2) antioxidant defense pathway has been well-known to afford neuroprotection. Here, we first demonstrate the roles of Nrf2-Keap1 in 17β-estradiol (E₂) cytoprotection and Hcy toxicity and the protective mechanisms of E₂ on Hcy cytotoxicity in human dopaminergic SH-SY5Y cells. Methods: Cell viability was determined by trypan blue method. Protein expression was determined by Western blot analysis. Superoxide dismutase (SOD) activity was determined by ELISA. Reactive oxygen species (ROS) production was determined by flow cytometry. Results: In Hcy-treated SH-SY5Y cells, E₂ increased cell viability, attenuated ROS production, activated Akt signaling and inhibited glycogen synthase kinase-3β (GSK-3β), a kinase known to participate in neurodegeneration. Moreover, E₂ treatment led to Nrf2 dissociation from Keap1, the main negative regulator of Nrf2 activity in the cytoplasm, and increased the protein level of Nrf2 in the nucleus, with a significant increase in HO-1 expression and SOD activity in Hcy-treated cells. E₂-induced Nrf2 activation was attenuated by the PI3K inhibitor LY294002 and the estrogen receptor antagonist ICI 182,780. Further, E₂ decreased Hcy-induced apoptotic death by upregulating the antiapoptotic protein Bcl-2, decreasing cytochrome c release from mitochondria, and attenuating apoptotic cascade activation (Bax, caspase-9, and caspase-3). Conclusion: E₂ activates cell survival signaling and Nrf2-Keap1 antioxidant defense pathway and attenuates Hcy cytotoxicity.

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Propofol is a widely used intravenous anesthetic. The aim of this study was to investigate the roles of nuclear factor erythroid-2-related factor 2 (Nrf2) and NADPH oxidase (NOX) in propofol protection in inflammatory conditions induced by lipopolysaccharide (LPS). Human alveolar epithelial cells (A549 cell line) were incubated with propofol (10, 25, and 50 μmol/L) for 1 h and then treated with LPS (100 ng/mL) for 24 h. Results indicated that propofol not only attenuated LPS-induced expression of iNOS, NOX, and COX2, but decreased the production of ROS, NO, and PGE2 as well. Propofol also increased the GSH levels and the mRNA and protein levels of Nrf2. Notably, Nrf2 siRNA and the inhibitors of COX-2 and NOX attenuated the inhibition of propofol on ROS production. In conclusion, propofol reduced LPS-induced ROS production via inhibition of inflammatory factors and enhancement of Nrf2-related antioxidant defense, providing its cytoprotective evidence under inflammatory conditions.