BN 80933, a Dual Inhibitor of Neuronal Nitric Oxide Synthase and Lipid Peroxidation: A Promising Neuroprotective Strategy

Nitric oxide (NO) and reactive oxygen species (ROS) act independently as well as cooperatively to induce neuronal death in acute neurological disorders. Inhibition of neuronal nitric oxide synthase (nNOS) and inhibition of lipid peroxidation induced by ROS have both been proposed as neuroprotective...

Full description

Saved in:
Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 1999-09, Vol.96 (19), p.10824-10829
Main Authors: Chabrier, Pierre-Etienne, Auguet, Michel, Spinnewyn, Brigitte, Auvin, Serge, Cornet, Sylvie, Demerle-Pallardy, Caroline, Guilmard-Favre, Christine, Marin, Jean-Gregoire, Pignol, Bernadette, Gillard-Roubert, Veronique, Roussillot-Charnet, Christelle, Schulz, Jocelyne, Viossat, Isabelle, Bigg, Dennis, Moncada, Salvador
Format: Article
Language:English
Subjects:
Animals
Antioxidants
Aorta - metabolism
Biological Sciences
Blood flow
Brain
Brain damage
Brain Injuries - drug therapy
Dose-Response Relationship, Drug
Enzyme Inhibitors - pharmacology
Gerbillinae
Inhibitory Concentration 50
Ischemia
Kinetics
Lipid Peroxidation - drug effects
Lipids
Male
Mice
Myocardial Ischemia - drug therapy
Neurologic manifestations
Neurology
Neurons
Neurons - enzymology
Neuroprotective Agents - pharmacology
Nitric Oxide Synthase - antagonists & inhibitors
Organ Culture Techniques
Oxides
Pyrazines - chemistry
Pyrazines - pharmacology
Rats
Rats, Sprague-Dawley
Reactive oxygen species
Stroke
Thiophenes - chemistry
Thiophenes - pharmacology
Time Factors
Vehicles
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Nitric oxide (NO) and reactive oxygen species (ROS) act independently as well as cooperatively to induce neuronal death in acute neurological disorders. Inhibition of neuronal nitric oxide synthase (nNOS) and inhibition of lipid peroxidation induced by ROS have both been proposed as neuroprotective strategies in stroke and trauma. Recently, in our laboratory, the combination of the two strategies was found to be synergistic in reducing neuronal damage. Here, we report that BN 80933 [(S)-N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]-1-piperazinyl]phenyl}-2-thiophenecarboxi midamide], a compound that combines potent antioxidant and selective nNOS inhibitory properties in vitro, affords remarkable neuronal protection in vivo. Intravenous administration of BN 80933 significantly reduced brain damage induced by head trauma in mice, global ischemia in gerbils, and transient focal ischemia in rats. Treatment with BN 80933 (0.3-10 mg/kg) significantly reduced infarct volume (>60% protection) and enhanced behavioral recovery in rats subjected to transient (2-h) middle cerebral artery occlusion and 48-h or 7-day reperfusion. Furthermore, treatment with BN 80933 commencing up to 8 h after the onset of ischemia resulted in a significant improvement of neurological outcome. All these results indicate that BN 80933 represents a class of potentially useful therapeutic agents for the treatment of stroke or trauma and possibly neurodegenerative disorders that involve both NO and ROS.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.96.19.10824