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.