Figure 2.

General scheme of the signaling pathways modulated by anthocyanins in neuroinflammation, oxidative stress, and excitotoxicity. In neuroinflammation, the activation of microglia (upper left) leads to the release of proinflammatory cytokines, promoting ROS generation. Exogenous or endogenous ROS can induce Oxidative stress in neurons, activating multiple pathways. Active Nrf2 promotes the expression of antioxidant enzymes by transactivating the antioxidant response element (ARE), whereas activation of the JNK/p53 pathway promotes apoptosis. Glutamate-driven excitotoxicity is promoted by an imbalance in the glutamate/cystine (XC-) antiporter system. An increased glutamate concentration induces the release of cytochrome-C (Cyto-C) and inhibits the entry of cystine, a key element for the formation of the antioxidant glutathione (GSH). GSH protects against ROS-mediated oxidative damage and mitochondrial dysregulation. Anthocyanins act in multiple stages of these pathways, decreasing proinflammatory signals, eliciting an antioxidant effect, or modulating the activation of proteins in the pathways (see text for details). Consequently, anthocyanins reduce neuroinflammation, oxidative stress, and/or apoptosis. Black arrows indicate direct or indirect stimulation, while red arrows represent inhibition or reduction. NMDA-R: NMDA receptor; AMPA-R: AMPA receptor; XC-: glutamate/cystine antiporter; Cyto-C: cytochrome-C.