FK506 prevents stroke-induced generation of ceramide and apoptosis signaling.
Ceramide is a key mediator of apoptosis during the cellular stress response which is also involved in stroke-induced death. Transient occlusion of the middle cerebral artery (MCA) in rats led to a strong generation of ceramide as measured in thalamus and entorhinal cortex of the ischemic brain tissue. Enhanced levels of ceramide may be involved in apoptosis signaling following stroke since exogenously added synthetic C2-ceramide increased expression of c-jun and the death-inducing ligands (DILs) CD95-L, TRAIL and TNF-alpha in neuroblastoma cells. DILs in turn mediated death via binding to their respective receptors as concluded from diminished apoptosis upon blocking of the common pathway by dominant negative FADD. C2-ceramide induced both necrosis and apoptosis in a concentration-dependent manner corresponding to the situation present in the ischemic brain. The immunosuppressant FK506 inhibited the release of ceramide, expression of CD95-L and apoptosis in an in vitro and in vivo model for ischemia/reperfusion. These data suggest that ceramide is a crucial initiator of death, e.g., by induction of DILs following stroke.
Herr
I
I
Division of Molecular Oncology, German Cancer Research Center, Heidelberg, Germany. i.herr@dkfz-heidelberg.de
Martin-Villalba
A
A
Kurz
E
E
Roncaioli
P
P
Schenkel
J
J
Cifone
M G
MG
Debatin
K M
KM
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins; D001923:Brain Chemistry / Q000187:drug effects / Q000235:genetics; D002561:Cerebrovascular Disorders / Q000188:drug therapy* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000378:metabolism* / Q000494:pharmacology; D053222:Fas Ligand Protein; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D002546:Ischemic Attack, Transient / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics; D009336:Necrosis; D009447:Neuroblastoma; D009474:Neurons / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000188:drug therapy / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000494:pharmacology; D053221:TNF-Related Apoptosis-Inducing Ligand; D016559:Tacrolimus / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects
D051017:Apoptosis Regulatory Proteins; D004791:Enzyme Inhibitors; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505662:Faslg protein, rat; D007166:Immunosuppressive Agents; D008562:Membrane Glycoproteins; C064769:N-acetylsphingosine; D016755:Proto-Oncogene Proteins c-jun; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C505655:Tnfsf10 protein, rat; D014409:Tumor Necrosis Factor-alpha; D013110:Sphingosine; D016559:Tacrolimus