Up-Regulation of Ganglioside Biosynthesis, Functional Synapse Formation, and Memory Retention by a Synthetic Ceramide Analog (l-PDMP)

Abstract

To address the role of brain gangliosides in synaptic activity, the ceramide analogs,d-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (d-PDMP) and its enantiomer,l-PDMP, were used to inhibit and stimulate ganglioside biosynthesis in cultured cortical neurons. Prolonged treatment with both PDMP isomers exhibited opposite effects on functional synapse formation measured by spontaneous synchronized oscillatory activity of intracellular Ca2+between the neurons: suppression byd-PDMP and facilitation byl-PDMP. Up-regulation of synaptic activity byl-PDMP could be correlated with the slow but robust stimulation of ganglioside biosynthesis through activating GM3, GD3 and GQ1b synthases. In a similar time couurse, the activity of p42 mitogen-activated protein kinase was also enhanced byl-PDMP. To evaluate the efficacy of this drug in long-term memory, rats were trained for 2 weeks using an 8-arm radial maze task, and then forebrain ischemia was induced by 4-vessel occlusion. Treatment withl-PDMP starting 24 hours after the transient ischemia ameliorated the deficit of a well-learned spatial memory, demonstrating the potential therapeutic intervention of the ceramide analog for neurodegenerative disorders.