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

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

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

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,

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.

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

RS Clark,PD Nathaniel,X Zhang,CE Dixon,SM Alber,SC Watkins,JA Melick,PM Kochanek,SH Graham,

For similar animals: chordata: vertebrates: mammals: rodentia: muridae: murinae: rats: rats, sprague-dawley research abstracts see: animals: chordata: vertebrates: mammals: rodentia: muridae: murinae: rats: rats, sprague-dawley research

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

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Journal of cerebral blood flow and metabolism : of

VOLUME: 27

Page Numbers: 316-26

Journal Abbreviation: J. Cereb. Blood Flow Metab.

ISSN: 0271-678X

DAY: 17

MONTH: 05

YEAR: 2006

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

Number of References:

LANGUAGE: eng

NlmUniqueID: 8112566

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

KEYWORDS: Rats, Sprague-Dawley

MESH TERMS: isolation & purification

Chemical & Substance for Abstract: boc-Aspartyl(OMe)-fluoromethylketone attenuates mitochondrial release of cytochrome c and delays brain tissue loss after traumatic brain injury in rats. Information

Substance Name: Caspase 8

Registry Number: EC 3.4.22.-

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

AFFILIATION: Department of Critical Care Medicine, The Safar Center for Resuscitation Research and the Brain Trauma Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA. clarkrs@ccm.upmc.edu

Country: United States

AGENCY: United States NINDS

GRANT: R01 NS38620

ACRONYM: NS

MEDLINETA: J Cereb Blood Flow Metab

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