Role of peripheral benzodiazepine receptors in mitochondrial, cellular, and cardiac damage induced by oxidative stress and ischemia-reperfusion.

Abstract

Mitochondrial dysfunction has been identified as a possible early event in ischemia-reperfusion damage. The peripheral benzodiazepine receptor, a mitochondrial inner membrane protein, has already been proposed to play a role in mitochondrial regulation, although its exact function remains unclear. The aim of this work was to determine the role of peripheral benzodiazepine receptor in ischemia-reperfusion injury and to test the potential beneficial effect of a novel potent peripheral benzodiazepine receptor ligand, 7-chloro-N,N,5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide (SSR180575). To characterize and link the mitochondrial, cellular, and cardiac consequences of ischemia-reperfusion, we examined the effects of SSR180575 in several in vitro and in vivo models of oxidative stress. Hydrogen peroxide decreased mitochondrial membrane potential, reduced oxidative phosphorylation capacities, and caused cytochrome c release, caspase 3 activation, and DNA fragmentation. SSR180575 (100 nM-1 microM) prevented all these effects. In perfused rat hearts, SSR180575 administered in vitro (100 nM-1 microM) or by oral pretreatment (3-30 mg/kg) greatly reduced the contractile dysfunction associated with ischemia-reperfusion. Furthermore, in anesthetized rats, SSR180575 (3-30 mg/kg p.o.) produced significant reductions in infarct size after coronary artery occlusion/reperfusion. In conclusion, we have demonstrated that peripheral benzodiazepine receptor play a major role in the regulation of cardiac ischemia-reperfusion injury and that SSR180575, a novel peripheral benzodiazepine receptor ligand, is of potential interest in these indications.

• Authors: Nathalie Leducq, Françoise Bono, Thierry Sulpice, Valérie Vin, Philip Janiak, Gérard Le Fur, Steve E O'Connor, Jean-Marc Herbert
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 306 Issue 3 Pg. 828-37 (Sep 2003) ISSN: 0022-3565 [Print] United States
• PMID: 12928523 (Publication Type: Journal Article)

Chemical References

• Receptors, GABA-A

Topics

• Anesthesia
• Animals
• Apoptosis
• Disease Models, Animal
• Heart Injuries (etiology, pathology)
• In Vitro Techniques
• Male
• Mitochondria, Heart (physiology)
• Myoblasts, Cardiac (metabolism)
• Myocardial Infarction (pathology)
• Myocardial Reperfusion Injury (complications, pathology)
• Oxidative Phosphorylation
• Oxidative Stress (physiology)
• Rabbits
• Rats
• Rats, Sprague-Dawley
• Receptors, GABA-A (physiology)
• Transfection