L-PDMP improves glucosylceramide synthesis and behavior in rats with focal ischemia.
BACKGROUND
It has been shown that exogenic administration of glycosphingolipids (GSLs) induces outgrowth of neurites from cultured nerve cells. Furthermore, the activator of glucosylceramide synthase, L-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (L-PDMP), is thought to exhibit stimulatory effects on both the biosynthesis and neurotrophic actions of GSL in the same culture system. To investigate the effect of GSLs on focal cerebral ischemia in vivo, L-PDMP was injected into the intraperitoneal space of rats during the chronic phase following permanent occlusion of the left middle cerebral artery (MCA) and thereafter, the levels of GSLs and their effects on behavioral changes were examined Methods: The levels of cerebrosides, sphingomyelin (SM) and ceramide in the ischemic cortex were measured by gas-liquid chromatography (GLC) after separation by high-performance thin-layer chromatography, using the internal standards N-heptadecanoyl-D-cerebroside, N-heptadecanoyl-D-sphingomyelin and N-heptadecanoyl-D-sphingosine, respectively. To determine the sugar components of the cerebrosides, the trimethylsilylated derivatives of their methylglycosides after methanolysis were analysed directly by GLC.


RESULTS
The L-PDMP treatment induced a 2.4-fold increase in glucosylceramide, the precursor of gangliosides, but no changes were evident in the levels of SM and ceramide in the ischemic cerebral cortex. The ischemic rats treated with L-PDMP showed improved re-acquisition of memory and learning in the Morris water maze task.


CONCLUSIONS
These results suggest that the pharmacological effects of L-PDMP include significant facilitation of glucosylceramide biosynthesis and improvement of neural function.
Hisaki
Harumi
H
Department of Biochemistry, Teikyo University School of Medicine, Tokyo, Japan.
Okazaki
Tomoki
T
Kubota
Masaru
M
Nakane
Makoto
M
Fujimaki
Takamitsu
T
Nakayama
Hitoshi
H
Nakagomi
Tadayoshi
T
Tamura
Akira
A
Masuda
Hiroyuki
H
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects* / Q000502:physiology; D002545:Brain Ischemia / Q000150:complications / Q000503:physiopathology*; D002518:Ceramides / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D002554:Cerebrosides / Q000378:metabolism; D002849:Chromatography, Gas; D002908:Chronic Disease; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D005962:Glucosylceramidase / Q000037:antagonists & inhibitors / Q000378:metabolism; D005963:Glucosylceramides / Q000096:biosynthesis* / Q000378:metabolism; D006028:Glycosphingolipids / Q000378:metabolism; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000503:physiopathology; D007274:Injections, Intraperitoneal; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008568:Memory / Q000187:drug effects / Q000502:physiology; D009025:Morpholines / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013037:Spatial Behavior / Q000187:drug effects / Q000502:physiology; D013109:Sphingomyelins / Q000378:metabolism
D002518:Ceramides; D002554:Cerebrosides; D004791:Enzyme Inhibitors; D005963:Glucosylceramides; D006028:Glycosphingolipids; D009025:Morpholines; D013109:Sphingomyelins; C033110:RV 538; D005962:Glucosylceramidase