Facilitatory roles of novel compounds designed from cyclopentenone prostaglandins on neurite outgrowth-promoting activities of nerve growth factor

Cyclopentenone prostaglandins (PGs) are known to arrest the cell cycle at t he G(1) phase in vitro and to suppress tumor growth in vivo. However, their effects on neurons are unclear. Here, we report that some cyclopentenone P Gs function as neurite outgrowth-promoting factors. They promoted neurite o utgrowth from PC12 cells and from dorsal root ganglion explants but only in the presence of nerve growth factor (NGF), We refer to these PGs as neurit e outgrowth-promoting PGs (NEPPs), Through study of the structure-function relationship of NEPP1-10 and related compounds, we found that the cross-con jugated dienone moiety of NEPPs was essential for promoting neurite outgrow th, and NEPP10 was concluded to be the best candidate for drug development. We also investigated the intracellular mechanism of the promotion by NEPPs and obtained evidence that immunoglobulin heavy chain binding protein/gluc ose-regulated protein 78 (BiP/GRP78) plays a role in the promotion, based o n the following observations: Antisense nucleotides for BiP/GRP78 gene bloc ked the promotion of neurite outgrowth; BiP/GRP78 protein level increased i n response to NEPPs; and overexpression of BiP/GRP78 protein by adenoviral gene transfer promoted the neurite outgrowth by NGF.