Potentiation of NGF-induced neurite outgrowth in PC12 cells by papaverine: Role played by PLC-γ, IP3 receptors

Papaverine, an inhibitor of phosphodiesterase (PDE) 10A, is gaining attention for its potential in the treatment of neuropsychiatric diseases such as schizophrenia. However, the precise mechanisms underlying the putative neuroprotective/neurotrophic actions of papaverine remain unclear. Thus, we investigated the effects of papaverine on nerve growth factor (NGF)-induced neurite outgrowth in PC12 cells. Papaverine potentiated NGF-induced neurite outgrowth in PC12 cells in a concentration-dependent manner. In contrast, the selective PDE10A inhibitor MP-10 had no effect on NGF-induced neurite outgrowth. The potentiation of NGF-induced neurite outgrowth by papaverine was blocked by the PLC-γ inhibitor U73122. Furthermore, papaverine's potentiation of NGF-induced neurite outgrowth was also blocked by the co-administration of inositol 1,4,5-trisphosphate (IP3) receptor antagonists (xestospongin C and 2-aminoethoxydiphenyl borate (2-APB)) and by reduced expression of IP3 receptor gene (i.e., itpr1 and itpr3) by siRNA. Our findings suggest that papaverine could potentiate NGF-induced neurite outgrowth, and that activation of PLC-γ and IP3 receptors might be involved in the mechanism underlying papaverine's potentiation of neurite outgrowth in PC12 cells.

Research highlight
► Papaverine potentiated NGF-induced neurite outgrowth in PC12 cells.
► The selective PDE10A inhibitor MP-10 did not affect NGF-induced neurite outgrowth.
► Effect of papaverine was blocked by PLC-γ inhibitor and IP3 receptor antagonist.
► Activation of PLC-γ and IP3 receptors might be involved in mechanism of papaverine.