Lysophosphatidylethanolamine in Grifola frondosa as a neurotrophic activator via activation of MAPK

We found that Grifola frondosa extracts induced theactivation ofmitogen-activatedprotein kinase(MAPK)in cultured PC12 cells, a line of rat pheochromocytoma cells. The active substance was isolated by a few chromatographic steps, including high-performance liquid chromatography, and was identified to be lysophosphatidylethanolamine (LPE)fromvariousstructuralanalyses.LPEfromG.frondosa (GLPE) was confirmed to induce the activation of MAPK of cultured PC12 cells and was found to suppress cell conden- sation and DNA ladder generation evoked by serum depri- vation, suggesting that the GLPE had antiapoptotic effects. Moreover, GLPE caused morphological changes in and up- regulation of neurofilament M expression of PC12 cells, demonstrating that the GLPE could induce neuronal dif- ferentiation of these cells. The activation of MAPK by GLPE was suppressed by AG1478, an antagonist of epider- mal growth factor receptor (EGFR), and by U0126, an in- hibitor of MAPK kinase (MEK1/2), but not by K252a, an inhibitorofTrkA,orbypertussistoxin. Theseresultsdem- onstrate that GLPE induced the MAPK cascade (EGFR- MEK1/2-extracellular signal-regulated protein kinases (ERK1/2)) of PC12 cells, the activation of which induced neuronal differentiation and suppressed serum deprivation- induced apoptosis. This study has clarified for the first time the involvement of the MAPK signal cascade in LPE ac-