Evaluation of Phenazine Derivatives from the Lichen-Associated as Potent Antineuroinflammatory Agents In Vitro and In Vivo.

Eighteen nitrogen-containing compounds (-) were isolated from cultures of the lichen-associated collected from the Qinghai-Tibet Plateau, including seven phenazine derivatives with three new ones, named subphenazines A-C (-), two new furan pyrrolidones (-), and nine known alkaloids. The structures were elucidated by spectroscopic data analysis, and absolute configurations were determined by single-crystal X-ray diffraction and ECD calculations. The phenazine-type derivatives, in particular compound , exhibited significantly better antineuroinflammatory activity than other isolated compounds (-). Compound inhibited the release of proinflammatory cytokines including IL-6, TNF-α, and PGE, and the nuclear translocation of NF-κB; it also reduced the oxidative stress and activated the Nrf2 signaling pathway in LPS-induced BV2 microglia cells. In vivo anti-inflammatory activity in zebrafish indicated that inhibited LPS-stimulated ROS generation. These findings suggested that compound might be a potent antineuroinflammatory agent through the regulation of the NF-κB/Nrf2 signaling pathways.