Hypoxia-mediated neurotoxicity contributes to various neurodegenerative disorders, including Alzheimer's disease and multiple sclerosis. Tetramethylpyrazine (TMP), a major bioactive component purified from Ligusticum wallichii Franchat, exhibited potent neuroprotective effect. However, the mechanism of TMP-exerted neuroprotective effect against hypoxia was not clear. In the study, we investigated the mechanism of the neuroprotective effect of TMP against hypoxia induced by CoCl 2 in vitro and in vivo. The results showed that TMP could protect against CoCl 2 -induced neurotoxicity in PC12 cells and in rats, as evidenced by enhancement of cell viability in PC12 cells and improvement of learning and memory ability in rats treated with CoCl 2 . TMP could inhibit mitochondrial dysfunction, mitochondrial apoptotic molecular events, and thus apoptosis induced by CoCl 2 . TMP inhibited CoCl 2 -increased reactive oxygen species (ROS) level, which may contribute to hypoxia-related neurotoxicity induced by CoCl 2 . The antioxidant and neuroprotective activities of TMP involved two pathways: one was the enhancement of nuclear factor erythroid 2-related factor 2 (Nrf2)/catalytic subunit of cglutamylcysteine ligase-mediated regulation of GSH and the other was the inhibition of hypoxia-inducible factor 1 a/NADPH oxidase 2 (NOX2)-mediated ROS generation. These two pathways contributed to improvement of oxidative stress and thus the amelioration of apoptosis under hypoxic conditions. These results have appointed a new path toward the understanding of pathogenesis and TMP-related therapy of hypoxiarelated neurodegenerative diseases.

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Objectives To explore the impacts of cordycepin and underlying mechanism on the sepsis. Methods The sepsis mice model was built and treated with different concentrations of cordycepin. Then the liver and lung injury caused by cecal ligation and puncture (CLP) was assessed using H&E staining and TUNEL assay. The expression of relevant genes was detected using qRT-PCR analysis and ELISA assays. Besides, the macrophage polarization was checked by flow cytometry. Key findings Cordycepin could significantly improve the liver and lung injury. Moreover, cordycepin increased the distribution of F4/80+ CD206+ M2-like macrophages and F4/80+ iNOS+ M1-like macrophages through down-regulating the expression of relevant genes. More importantly, cordycepin could monitor the protein expression of iNOS, Arg-1, TNF-α, MCP-1, IL-4 and IL-10 in CLP mice. Meanwhile, the elevated level of p65 induced by CLP was also repressed by the increase of the cordycepin. Moreover, cordycepin played a crucial part in CLP mice through modulating the NF-κB/p65 signalling pathway. Conclusions Cordycepin played an important role in mice with sepsis via reducing the M1/M2 macrophage polarization and modulating the NF-κB/p65 signalling pathway.

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