Neurotrophic and neuroprotective actions of an enhancer of ganglioside biosynthesis.
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.
Inokuchi
Jin-Ichi
J
Division of Glycopathology, Institute of Molecular Biomembranes and Glycobiology, Tohoku Pharmaceutical University, 4-4-1, komatsushima, Aoba-ku, Sendai 981-8558, Miyagi, Japan.
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001921:Brain / Q000201:enzymology*; D002545:Brain Ischemia / Q000188:drug therapy / Q000503:physiopathology / Q000523:psychology; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D005732:Gangliosides / Q000096:biosynthesis*; D008569:Memory Disorders / Q000188:drug therapy / Q000503:physiopathology; D019950:Mitogen-Activated Protein Kinase 1 / Q000096:biosynthesis*; D008954:Models, Biological; D015394:Molecular Structure; D009025:Morpholines / Q000737:chemistry / Q000494:pharmacology*; D016501:Neurites / Q000187:drug effects* / Q000502:physiology; D013569:Synapses / Q000187:drug effects / Q000502:physiology; D015854:Up-Regulation
D004791:Enzyme Inhibitors; D005732:Gangliosides; D009025:Morpholines; C033110:RV 538; D019950:Mitogen-Activated Protein Kinase 1