Details

Autor(en) / Beteiligte

• 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

Titel

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

Ist Teil von

• Proceedings of the National Academy of Sciences - PNAS, 1999-09, Vol.96 (19), p.10824-10829

Ort / Verlag

United States: National Academy of Sciences of the United States of America

Erscheinungsjahr

1999

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.