Donepezil potentiates nerve growth factor-induced neurite outgrowth in PC12 cells

Donepezil is a potent and selective acetylcholinesterase inhibitor developed for the treatment of Alzheimer's disease. To elucidate whether donepezil causes neuronal differentiation, we examined its effect on nerve growth factor (NGF)-induced neurite outgrowth in PC12 cells. Donepezil (10 microM) significantly potentiated the neurite outgrowth evoked by low (1 ng/ml) and high (50 ng/ml) concentrations of NGF. The effect of donepezil (1 - 10 microM) was concentration-dependent. The enhancement of neurite outgrowth caused by donepezil was not blocked by the acetylcholine receptor (AChR) antagonists mecamylamine and scopolamine. Furthermore, the AChR agonists nicotine and carbachol did not affect the neurite outgrowth induced by NGF. Donepezil (10 microM) also significantly potentiated neurite outgrowth evoked by dibutyryl cyclic AMP. Moreover, donepezil potentiated the NGF-induced phosphorylation of extracellular signal-regulated kinase (ERK). These results suggest that donepezil potentiated neuronal differentiation by enhancing the activation of ERK.