Aβ1–42‐induced apoptosis, cordycepin, ERK/CREB pathway, neuronal cell lines, neuroprotection, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571

Abstract 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 Aβ1–42‐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 Aβ1–42 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.