UP-REGULATION OF GANGLIOSIDE BIOSYNTHESIS, FUNCTIONAL SYNAPSE FORMATION, AND MEMORY RETENTION BY A SYNTHETIC CERAMIDE ANALOG (L-PDMP)

To address the role of brain gangliosides in synaptic activity, the ce ramide analogs, o-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (D- PDMP) and its enantiomer, L-PDMP, were used to inhibit and stimulate g anglioside biosynthesis in cultured cortical neurons. Prolonged treatm ent with both PDMP isomers exhibited opposite effects on functional sy napse formation measured by spontaneous synchronized oscillatory activ ity of intracellular Ca2+ between the neurons: suppression by D-PDMP a nd facilitation by L-PDMP. Up-regulation of synaptic activity by L-PDM P could be correlated with the slow but robust stimulation of ganglios ide biosynthesis through activating GM3, GD3 and GQ1b synthases. In a similar time course, the activity of p42 mitogen-activated protein kin ase was also enhanced by L-PDMP. To evaluate the efficacy of this drug in long-term memory, rats were trained for 2 weeks using an 8-arm rad ial maze task, and then forebrain ischemia was induced by 4-vessel occ lusion. Treatment with L-PDMP starting 24 hours after the transient is chemia ameliorated the deficit of a well-learned spatial memory, demon strating the potential therapeutic intervention of the ceramide analog for neurodegenerative disorders. (C) 1997 Academic Press.