An ICE inhibitor, z-VAD-DCB attenuates ischaemic brain damage in the rat.
Interleukin-1 beta (IL-1 beta) converting enzyme (ICE) cleaves pro-IL-1 beta to produce mature IL-beta, and is a member of a family of proteases implicated in apoptosis. Intracerebroventricular (i.c.v.) administration of an irreversible ICE inhibitor, z-VAD-DCB (1 pmol, 30 min before and 15 min, 2, 4, 6 and 8 h after surgery) markedly reduced (50 +/- 4%, p < 0.001) infarct volume measured 24 h after focal cerebral ischaemia (middle cerebral artery occlusion, MCAo) in the rat. Inhibition of damage was observed in the cortex (51 +/- 5% reduction) and striatum (42 +/- 6% reduction). These data implicate ICE in ischaemic neuronal death in vivo. Inhibition of ICE could reduce ischaemic damage either by preventing IL-1 beta synthesis or by inhibiting apoptosis or by both of these processes, and may provide a useful therapeutic approach to the inhibition of ischaemic brain damage.
Loddick
S A
SA
School of Biological Sciences, University of Manchester, UK.
MacKenzie
A
A
Rothwell
N J
NJ
D000818:Animals; D020170:Caspase 1; D002460:Cell Line; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases / Q000187:drug effects*; D015853:Cysteine Proteinase Inhibitors / Q000627:therapeutic use*; D004789:Enzyme Activation; D007375:Interleukin-1 / Q000378:metabolism*; D002546:Ischemic Attack, Transient / Q000517:prevention & control*; D008297:Male; D008970:Molecular Weight; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D009842:Oligopeptides / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors
D015853:Cysteine Proteinase Inhibitors; D007375:Interleukin-1; D018696:Neuroprotective Agents; D009842:Oligopeptides; D011994:Recombinant Proteins; C104205:z-VAD-DCB; D003546:Cysteine Endopeptidases; D020170:Caspase 1