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 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- thiophenecarboximidamide], 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.
Chabrier
P E
PE
Beaufour-Ipsen Research Laboratories, Institut Henri Beaufour, 5 Avenue du Canada, 91966 Les Ulis Cedex, France. pierreet.chabrier@beaufour-ipsen.com
Auguet
M
M
Spinnewyn
B
B
Auvin
S
S
Cornet
S
S
Demerlé-Pallardy
C
C
Guilmard-Favre
C
C
Marin
J G
JG
Pignol
B
B
Gillard-Roubert
V
V
Roussillot-Charnet
C
C
Schulz
J
J
Viossat
I
I
Bigg
D
D
Moncada
S
S
D000818:Animals; D001011:Aorta / Q000378:metabolism; D001930:Brain Injuries / Q000188:drug therapy; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005849:Gerbillinae; D020128:Inhibitory Concentration 50; D007700:Kinetics; D015227:Lipid Peroxidation / Q000187:drug effects*; D008297:Male; D051379:Mice; D017202:Myocardial Ischemia / Q000188:drug therapy; D009474:Neurons / Q000201:enzymology; D018696:Neuroprotective Agents / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D009924:Organ Culture Techniques; D011719:Pyrazines / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013876:Thiophenes / Q000737:chemistry / Q000494:pharmacology*; D013997:Time Factors
D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D011719:Pyrazines; D013876:Thiophenes; C120890:BN 80933; D019001:Nitric Oxide Synthase