Treatment of hypoxic-ischemic brain injury in newborn rats with TPCK 3 h after hypoxia decreases caspase-9 activation and improves neuropathologic outcome.

Abstract

N-Tosyl-L-phenylalanyl-chloromethyl ketone (TPCK) reduces apoptosis in vitro. Pretreatment with TPCK reduces brain injury. Would treatment after injury reduce damage? Seven-day-old rats had the right carotid artery ligated and were subjected to 2.5 h of 8% oxygen and were treated intraperitoneally 3 h after hypoxia with 10 mg/kg of TPCK or vehicle. Brain damage was measured 22 days after injury. bcl-2, bax, and cytochrome c where measured by Western blot 24 h after injury. Caspase-9 and caspase-3 activity were measured enzymatically 24 h after injury. Treatment with TPCK reduced the loss of the right hemisphere caused by injury from 27.6 +/- 2.8% SEM (vehicle, n = 56) to 19.8 +/- 2.8% (TPCK, n = 61, p < 0.05). Hypoxic ischemia increased cytosolic cytochrome c from 0.25 +/- 0.04 to 0.4 +/- 0.04 optical density (OD; p < 0.05), but TPCK had no effect (0.31 +/- 0.03 OD). TPCK reduced caspase-9 activity from 72 +/- 30 to 43 +/- 5 fluorescence units/h/mg (p < 0.05 vs. vehicle), and caspase-3 activity from 66 +/- 10 to 39 +/- 3.7 fluorescence units/h/mg (p < 0.05 vs. vehicle). Treatment with TPCK 3 h after hypoxic ischemia reduced brain infarct size. TPCK may act by reducing caspase-9 activation by cytochrome c.

• Authors: Yangzheng Feng, Michael H LeBlanc
• Journal: Developmental neuroscience (Dev Neurosci) 2003 Jan-Feb Vol. 25 Issue 1 Pg. 34-40 ISSN: 0378-5866 [Print] Switzerland
• PMID: 12876429 (Publication Type: Journal Article)
• Copyright: Copyright 2003 S. Karger AG, Basel

Chemical References

• Caspase Inhibitors
• Cytochrome c Group
• Neuroprotective Agents
• Serine Proteinase Inhibitors
• Tosylphenylalanyl Chloromethyl Ketone
• Casp9 protein, rat
• Caspase 9
• Caspases

Topics

• Animals
• Animals, Newborn
• Brain (drug effects, metabolism, pathology)
• Caspase 9
• Caspase Inhibitors
• Caspases (metabolism)
• Cytochrome c Group (metabolism)
• Cytosol (metabolism)
• Drug Administration Schedule
• Enzyme Activation (drug effects)
• Hypoxia-Ischemia, Brain (drug therapy, metabolism, pathology)
• Neuroprotective Agents (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Serine Proteinase Inhibitors (administration & dosage)
• Tosylphenylalanyl Chloromethyl Ketone (administration & dosage)