Cordycepin mediates neuroprotection against apoptosis via ERK/CREB signaling activation in Aβ(1-42)-induced neuronal cell models.

The aggregation of β-amyloid (Aβ) peptides has been associated with the onset of Alzheimer's disease (AD) by causing neurotoxicity due to oxidative stress and apoptosis. Cordycepin is a natural derivative of the nucleoside adenosine that displays potent antioxidant, antitumor, anti-inflammatory, and neuroprotective properties. However, the mechanism of the neuroprotective effect of cordycepin toward Aβ-induced neurotoxicity, as well as underlying mechanisms, is still unclear. In this study, we found that cordycepin conferred neuroprotection to catecholaminergic PC12 neuronal cell cultures exposed to Aβ(1-42)-insult by reducing the production of reactive oxygen species, restoring the mitochondrial membrane potential, and inhibiting apoptosis. Cordycepin stimulated the phosphorylation of extracellular signal-regulated kinase (ERK) and cyclic AMP-responsive element-binding protein (CREB) in a time- and concentration-dependent manner. Inhibition of the ERK pathway reduced the neuroprotective effect of cordycepin. Similar results were obtained with hippocampal HT22 neuronal cell cultures. Cumulatively, these findings suggest that cordycepin-induced neuroprotection toward Aβ(1-42) neurotoxic insult may involve activation of the ERK/CREB pathway. This study expands our knowledge of the neuroprotective function of cordycepin and suggests that it holds promise as a natural lead compound for drug development in AD.