Production of nerve growth factor enhanced in cultured mouse astrocytes by glycerophospholipids, sphingolipids, and their related compounds

The NGF secretion from cultured mouse astrocytes was enhanced by sublethal concentrations of phosphatidic acid (PA), ceramide, or sphingosine (Sph), and concentration dependently by lysophosphatidic acid (LPA), sphingosylphosphorylcholine (SPC), or sphingosine-1-phosphate (S1P), but was unaffected by any concentrations of phosphatidylcholine (PC), phosphatidylethanolamine (PE) or sphingomyelin (SM). The enhancement of NGF synthesis by Sph was completely inhibited by the addition of ceramide synthase inhibitor, fumonisin B-1. LPA and S1P showed similar hyperbolic curves with maximum NGF secretion at concentrations of more than 50 mu M, but they showed no proliferative effect on quiescent astrocytes. The mechanisms underlying the stimulation of NGF synthesis by 50 mu M LPA and 50 mu M S1P were further investigated by using various inhibitors. One of the protein kinase C (PKC) inhibitors, Go6976, suppressed the LPA- and S1P-stimulated NGF synthesis by 70 and 80%, respectively. LPA and S1P were found to activate common multiple signaling pathways for NGF production, involving the activation of the protein kinase C (PKC), mitogen-activated protein (MAP) kinase, and phosphatidylinositol 3-kinase (PI-3K) pathways.