boc-Aspartyl(OMe)-Fluoromethylketone Attenuates Mitochondrial Release of Cytochrome <i>c</i> and Delays Brain Tissue Loss after Traumatic Brain Injury in Rats

Journal of Cerebral Blood Flow and Metabolism - Tập 27 Số 2 - Trang 316-326 - 2007
Robert S. B. Clark1,2,3, Paula D. Nathaniel1, Xiaopeng Zhang1, C. Edward Dixon4, Sean Alber5, Simon C. Watkins5, John Mendeloff1, Patrick M. Kochanek1,2,3, Steven H. Graham6,7
1Department of Critical Care Medicine, The Safar Center for Resuscitation Research and the Brain Trauma Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
2Department of Pediatrics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
3the Children's Hospital of Pittsburgh Pittsburgh, Pennsylvania, USA
4Department of Neurological Surgery, The Safar Center for Resuscitation Research and the Brain Trauma Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
5Department of Cell Biology and Physiology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
6Department of Neurology and the Brain Trauma Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
7Geriatric Research Educational and Clinical Center, VA Pittsburgh Health System, Pittsburgh, Pennsylvania, USA

Tóm tắt

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 μmol) 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/hx14 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.

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Journal of Cerebral Blood Flow and Metabolism

Tập 27 Số 2

316-326

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