boc-Aspartyl(OMe)-fluoromethylketone attenuates mitochondrial release of cytochrome c and delays brain tissue loss after traumatic brain injury in rats.

Abstract

The pathobiology of traumatic brain injury (TBI) includes activation of multiple caspases followed by cell death with a spectrum of apoptotic phenotypes. There are initiator (e.g. caspase-2, -8, and -9) and effector (e.g. caspase-3 and -7) caspases. Recently, caspase-2 and -8 have been shown to regulate cell death via provoking cytochrome c release from the mitochondria upstream of caspase-9. Here, we show that an intracerebral injection of the pan-caspase inhibitor boc-Aspartyl(OMe)-fluoromethylketone (BAF; 1 micromol) 1 min after TBI in rats reduces caspase-3-like activity, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) and tissue damage, and cytochrome c release in ipsilateral cortex at 24 h versus vehicle. To investigate whether either caspase-2 and/or caspase-8 activation may contribute to cytochrome release, the effect of BAF treatment on caspase-2 and caspase-8 proteolysis was also examined. boc-aspartyl(OMe)-fluoromethylketone treatment inhibited proteolysis of caspase-2 but not caspase-8 24 h after TBI in rats versus vehicle. However, BAF with or without nerve growth factor (12.5 ng/h x 14 days intracerebrally via osmotic pump) did not result in differences in motor function, Morris water maze performance, hippocampal neuron survival, nor contusion volume at 14 days. These data suggest that BAF treatment reduces acute cell death after TBI by inhibiting mitochondrial release of cytochrome c, possibly via a mechanism involving initiator caspases; however, BAF appears to delay cell death, rather than result in permanent protection.

• Authors: Robert S B Clark, Paula D Nathaniel, Xiaopeng Zhang, C Edward Dixon, Sean M Alber, Simon C Watkins, John A Melick, Patrick M Kochanek, Steven H Graham
• Journal: Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism (J Cereb Blood Flow Metab) Vol. 27 Issue 2 Pg. 316-26 (Feb 2007) ISSN: 0271-678X [Print] United States
• PMID: 16736044 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Amino Acid Chloromethyl Ketones
• Nerve Tissue Proteins
• Neuroprotective Agents
• butyloxycarbonyl-O-methyl-aspartyl-fluoromethyl ketone
• Cytochromes c
• Nerve Growth Factor
• Caspase 2
• Caspase 3
• Caspase 8

Topics

• Amino Acid Chloromethyl Ketones (pharmacology)
• Animals
• Blotting, Western
• Brain (enzymology, pathology)
• Brain Injuries (drug therapy, enzymology, pathology)
• Caspase 2 (metabolism)
• Caspase 3 (metabolism)
• Caspase 8 (metabolism)
• Cell Survival (drug effects)
• Cytochromes c (metabolism)
• In Situ Nick-End Labeling
• Male
• Maze Learning (physiology)
• Mitochondria (drug effects, enzymology)
• Nerve Growth Factor (metabolism)
• Nerve Tissue Proteins (biosynthesis, isolation & purification)
• Neuroprotective Agents
• Rats
• Rats, Sprague-Dawley