Reversing ROS-mediated neurotoxicity by chlorogenic acid involves its direct antioxidant activity and activation of Nrf2-ARE signaling pathway.

Chlorogenic acid (CA), the ester of caffeic acid and quinic acid, is one of the most abundant polyphenols in coffee, and has multiple pharmacological functions. The present study is designed to explore the protection provided by CA against hydrogen peroxide (H O )-induced oxidative damages in the rat pheochromocytoma cells, and the underlying mechanisms engaged in this process. CA displays robust free radical-scavenging activity in vitro. More importantly, CA strikingly rescues the cells from the H O -mediated oxidative insults. Mechanistic studies revealed that CA upregulates a panel of phase II cytoprotective species, such as heme oxygenase-1, NAD(P)H: quinone oxidoreductase 1, glutathione, thioredoxin reductase 1, and thioredoxin 1. This neuroprotection is dependent on the activation of the transcription factor Nuclear factor erythroid 2-related factor 2 (Nrf2), as knockdown of Nrf2 abolishes such effect. Our results demonstrate that CA provides dual neuroprotection via directly neutralizing free radicals and indirectly inducing expression of Nrf2-driven cytoprotective enzymes, and suggest a potential therapeutic usage of CA as a neuroprotective agent. Coffee is one of the most popular drinks in the world, and our discovery may also contribute to understanding the beneficial effects of regular coffee consumption. © 2019 BioFactors, 45 (4):616-626, 2019.