Attenuation of acetic acid-induced gastric ulcer formation in rats by glucosylceramide synthase inhibitors.
BACKGROUND
Ceramide has been suggested to play a role in apoptosis during gastric ulcerogenesis. The present study is designed to investigate whether accumulated ceramide could serve as the effector molecules of ulcer formation in a rat model of acetic acid-induced gastric ulcer.


METHODS
The effect of fumonisin B1, an inhibitor of ceramide synthase, and of d,l,-threo-1-phenyl-2-hexadecanoylamino-3-morpholino-1-propanol (PPMP) and N-butyldeoxynojirimycin (NB-DNJ), both inhibitors of glucosylceramide synthase, on the accumulation of ceramide and formation of gastric ulcer were examined in the rat model of acetic acid-induced gastric ulcer.


RESULTS
Fumonisin B1 attenuated acetic acid-induced gastric ulcer formation, associated with a decrease in the number of apoptotic cells. Our results showed that it is neither the C18- nor the C24-ceramide itself, but the respective metabolites that were ulcerogenic, because PPMP and NB-DNJ attenuated gastric mucosal apoptosis and the consequent mucosal damage in spite of their reducing the degradation of ceramide.


CONCLUSIONS
The ceramide pathway, in particular, the metabolites of ceramide, significantly contributes to acetic acid-induced gastric damage, possibly via enhancing apoptosis. On the other hand, PPMP and NB-DNJ treatment attenuated gastric mucosal apoptosis and ulcer formation despite increasing the ceramide accumulation, suggesting that it was not the ceramides themselves, but their metabolites that contributed to the ulcer formation in the acetic acid-induced gastric ulcer model.
Division of Gastroentrology and Hepatology, Department of Internal Medicine, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.
Manabu
M
Nakashita
Hidekazu
H
Suzuki
Soichiro
S
Miura
Takao
T
Taki
Keita
K
Uehara
Tohru
T
Mizushima
Hiroshi
H
Nagata
Toshifumi
T
Hibi
D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives / Q000494:pharmacology; D019342:Acetic Acid / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D037341:Fumonisins / Q000494:pharmacology; D005679:G(M3) Ganglioside / Q000378:metabolism; D005753:Gastric Mucosa / Q000187:drug effects / Q000473:pathology; D005963:Glucosylceramides / Q000378:metabolism; D005964:Glucosyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013107:Sphingolipids / Q000494:pharmacology; D013276:Stomach Ulcer / Q000139:chemically induced* / Q000188:drug therapy* / Q000517:prevention & control
C095823:1-phenyl-2-palmitoylamino-3-morpholino-1-propanol; D004791:Enzyme Inhibitors; D037341:Fumonisins; D005679:G(M3) Ganglioside; D005963:Glucosylceramides; D009025:Morpholines; D013107:Sphingolipids; D017485:1-Deoxynojirimycin; C056933:fumonisin B1; C059896:miglustat; D005964:Glucosyltransferases; C023246:ceramide glucosyltransferase; D019342:Acetic Acid