Caspase-9 inhibition after focal cerebral ischemia improves outcome following reversible focal ischemia.

Abstract

Cerebral ischemia initiates a program of cell death known as apoptosis. Early steps in these death promoting events are the release of cytochrome c from the mitochondria and activation of caspase-9. The purpose of this report is to determine if the administration of a specific caspase-9 inhibitor, Z-Leu-Glu(Ome)-His-Asp(Ome)-FMK x TFA (Z-LEHD-FMK) would attenuate apoptosis and the resultant brain injury after ischemia. Adult Wistar rats underwent 3 h of temporary middle cerebral artery occlusion (MCAO) followed by 24 h of reperfusion. An intraventricular injection of 4.8 microg of Z-LEHD-FMK was given 15-min postreperfusion. Administration of the caspase-9 inhibitor, Z-LEHD-FMK, to the experimental group (n = 12) reduced total infarction volume by 49% (p < 0.05) and improved neurological outcome by 63% (p < 0.01) as compared to the control group (n = 12). Western blot analysis of animals that underwent ischemia-reperfusion showed the appearance of the active form of caspase-9. Inhibition of caspase-9, the apical caspase in cytochrome-c-dependent apoptosis, is an effective intervention to attenuate neurological injury after focal ischemia.

• Authors: Graham Mouw, Jennifer L Zechel, Yifang Zhou, W David Lust, Warren R Selman, Robert A Ratcheson
• Journal: Metabolic brain disease (Metab Brain Dis) Vol. 17 Issue 3 Pg. 143-51 (Sep 2002) ISSN: 0885-7490 [Print] United States
• PMID: 12322785 (Publication Type: Journal Article)

Chemical References

• Caspase Inhibitors
• Cytochrome c Group
• Enzyme Inhibitors
• Oligopeptides
• benzyloxycarbonyl-leucyl-glutamyl-histidyl-aspartic acid fluoromethyl ketone
• Casp9 protein, rat
• Caspase 9

Topics

• Animals
• Blotting, Western
• Brain Ischemia (drug therapy, pathology, physiopathology)
• Caspase 9
• Caspase Inhibitors
• Cytochrome c Group (metabolism)
• Enzyme Inhibitors (therapeutic use)
• Infarction, Middle Cerebral Artery (drug therapy, pathology)
• Male
• Oligopeptides (therapeutic use)
• Psychomotor Performance (physiology)
• Rats
• Rats, Wistar
• Reperfusion Injury (drug therapy, pathology)