Abstract

To address the role of brain gangliosides in synaptic plasticity, the synthetic ceramide analog, 1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP) was used to manipulate the biosynthesis of gangliosides in cultured cortical neurons. Spontaneous synchronized oscillatory activity of intracellular Ca(2+) between the neurons, which represents synapse formation, was suppressed by the depletion of endogenous gangliosides by d-threo-PDMP, an inhibitor of glucosylceramide synthase. On the other hand, the enantiomer of inhibitor, l-threo-PDMP, could elevate cellular levels of gangliosides by upregulating several glycosyltransferases responsible for ganglioside biosynthesis. This review presents our findings on the neurotrophic actions of l-threo-PDMP in vitro and in vivo. We found that l-PDMP could upregulate neurite outgrowth, and functional synapse formation through activating GM3, GD3, and GQ1b synthases. Simultaneously, the activity of p42 mitogen-activated protein kinase was also facilitated by l-PDMP. To evaluate the efficacy of this drug on long term memory, rats were trained for 2 weeks using an 8-arm radial maze task, and then forebrain ischemia was induced by four-vessel occlusion. Repeated treatment of l-PDMP starting 24h after the ischemia, improved the deficit of the well-learned spatial memory and prevented the ischemia-induced apoptosis in hippocampus, demonstrating the potential therapeutic use of the ceramide analog for treatment of neurodegenerative disorders.