[Synthesis of sphingomyelin analogues as a sphingomyelinase inhibitor and the application as a blocking agent of extracellular stress signaling].
Sphingomyelin (SM) pathway, where sphingomyelinase (SMase) hydrolyzes SM to produce ceramide, has recently been suggested to link to the signaling pathway that determines cell death. Therefore, elucidation of the mechanism by which SMase is activated and the regulation of SMase activity will be an important therapeutic strategy for various cytokine-related and ischemic diseases. We have synthesized nine difluoromethylene analogues of SM as SMase inhibitors and evaluated their inhibitory potencies. In this study, we show that the inhibitor suppresses ceramide production and cell death of PC-12 neurons that have been induced by deprivation of serum from the culture medium. The SMase inhibitor could also suppress neuronal cell death in a mouse model of brain ischemia. These results suggest a possibility that the prevention of various extracellular stress-induced cell death signalings is accomplished by inhibiting the cell membrane SMase.
Tsuji
Yoshiaki
Y
Department of Biochemistry, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka 814-0180, Japan.
Soeda
Shinji
S
Ochiai
Takashi
T
Mishima
Ken-ichi
K
Iwasaki
Katsunori
K
Fujiwara
Michihiro
M
Yokomatsu
Tsutomu
T
Murano
Tetsuo
T
Akiyama
Takesi
T
Shibuya
Shiroshi
S
Shimeno
Hiroshi
H
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002545:Brain Ischemia / Q000188:drug therapy; D002478:Cells, Cultured; D002518:Ceramides / Q000096:biosynthesis; D003864:Depression, Chemical; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000201:enzymology; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D013108:Sphingomyelin Phosphodiesterase / Q000037:antagonists & inhibitors* / Q000502:physiology; D013109:Sphingomyelins / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D013312:Stress, Physiological / Q000503:physiopathology* / Q000517:prevention & control
D002518:Ceramides; D004791:Enzyme Inhibitors; D013109:Sphingomyelins; D013108:Sphingomyelin Phosphodiesterase