Attenuation of Acetic Acid-Induced Gastric Ulcer Formation in Rats by Glucosylceramide Synthase Inhibitors
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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.
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.
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.
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.
KeywordsCeramide Glucosylceramide inhibitor Gastric ulcer Acetic acid Apoptosis
This study was supported by a Grant-in-Aid for Scientific Research (B) from the Japan Society for the Promotion of Science (22300169, to H.S.), Grant-in-Aid for challenging Exploratory Research (24659103, to H.S.), a grant from the National Defense Medical College (to S.M.), a Research Fund of Mitsukoshi Health and Welfare Foundation (to H.S.), and a grant from the Smoking Research Foundation (to H.S.).
Conflict of interest
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