Ishima_2008_Prog.Neuropsychopharmacol.Biol.Psychiatry_32_1656

In addition to acetylcholinesterase (AChE) inhibition, donepezil binds to sigma-1 receptors. In this study, we examined the effects of donepezil on nerve growth factor (NGF)-induced neurite outgrowth in PC12 cells. Donepezil significantly potentiated the NGF-induced neurite outgrowth in a concentration-dependent manner whereas the AChE inhibitor physostigmine did not alter NGF-induced neurite outgrowth. Potentiation of NGF-induced neurite outgrowth by donepezil was significantly blocked by co-administration of the selective sigma-1 receptor antagonist NE-100 or the inositol 1,4,5-triphosphate (IP3) receptor antagonist xestospongin C. These findings suggest that sigma-1 receptors and interaction with IP3 receptors may be involved in the pharmacological action of donepezil.