Inhibition of interleukin 1beta converting enzyme family proteases reduces ischemic and excitotoxic neuronal damage.

Abstract

The interleukin 1beta converting enzyme (ICE) family plays a pivotal role in programmed cell death and has been implicated in stroke and neurodegenerative diseases. During reperfusion after filamentous middle cerebral artery occlusion, ICE-like cleavage products and tissue immunoreactive interleukin 1beta (IL-1beta) levels increased in ischemic mouse brain. Ischemic injury decreased after intracerebroventricular injections of ICE-like protease inhibitors, N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (z-VAD.FMK), acetyl-Tyr-Val-Ala-Asp-chloromethylketone, or a relatively selective inhibitor of CPP32-like caspases, N-benzyloxycarbonyl-Asp-Glu-Val-Asp-fluoromethylketone, but not a cathepsin B inhibitor, N-benzyloxycarbonyl-Phe-Ala-fluoromethylketone. z-VAD.FMK decreased ICE-like cleavage products and tissue immunoreactive IL-1beta levels in ischemic mouse brain and reduced tissue damage when administered to rats as well. Only z-VAD.FMK and acetyl-Tyr-Val-Ala-Asp-chloromethylketone reduced brain swelling, and N-benzyloxycarbonyl-Asp-Glu-Val-Asp-fluoromethylketone did not attenuate the ischemia-induced increase in tissue IL-1beta levels. The three cysteine protease inhibitors significantly improved behavioral deficits, thereby showing that functional recovery of ischemic neuronal tissue can follow blockade of enzymes associated with apoptotic cell death. Finally, we examined the effect of z-VAD.FMK on excitotoxicity and found that it protected against alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate-induced or to a lesser extent N-methyl-D-aspartate-induced excitotoxic brain damage. Thus, ICE-like and CPP32-like caspases contribute to mechanisms of cell death in ischemic and excitotoxic brain injury and provide therapeutic targets for stroke and neurodegenerative brain damage.

• Authors: H Hara, R M Friedlander, V Gagliardini, C Ayata, K Fink, Z Huang, M Shimizu-Sasamata, J Yuan, M A Moskowitz
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 94 Issue 5 Pg. 2007-12 (Mar 04 1997) ISSN: 0027-8424 [Print] United States
• PMID: 9050895 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Cysteine Proteinase Inhibitors
• Interleukin-1
• Neurotoxins
• Receptors, Glutamate
• Casp3 protein, mouse
• Casp3 protein, rat
• Caspase 3
• Caspases
• Cysteine Endopeptidases
• Cathepsin B
• Caspase 1

Topics

• Animals
• Blotting, Western
• Brain (drug effects, metabolism)
• Brain Ischemia (drug therapy, enzymology)
• Caspase 1
• Caspase 3
• Caspases
• Cathepsin B (antagonists & inhibitors)
• Cerebrovascular Disorders (drug therapy)
• Cysteine Endopeptidases (metabolism)
• Cysteine Proteinase Inhibitors (pharmacology)
• Gene Expression (genetics)
• Interleukin-1 (metabolism)
• Male
• Mice
• Neurons (drug effects, metabolism)
• Neurotoxins (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Receptors, Glutamate (metabolism)
• Reperfusion