In vitro antioxidant neuroprotective activity of BN 80933, a dual inhibitor of neuronal nitric oxide synthase and lipid peroxidation.
BN 80933, a dual inhibitor of neuronal nitric oxide synthase and lipid peroxidation, prevents in vivo brain ischemic/reperfusion injury. In the present study, BN 80933 was shown to protect neurons from hypoxia-induced cell death in primary cultures of cortical neurons. BN 80933 prevented lactate dehydrogenase activity elevation induced by hypoxia, displaying an IC50 value of 0.15 +/- 0.05 microM. This effect was likely due to the antioxidant properties of BN 80933 because Trolox, but not NG-nitro-L-arginine, also elicited protection. The antioxidant property of BN 80933 was then further investigated on HT-22 cells subjected to buthionine sulfoximine- or glutamate-induced glutathione depletion. The relative order of potency of the various compounds to inhibit oxidative stress-induced neuronal death (BN 80933 > U104067 > butylated hydroxytoluene > 17beta-estradiol > Trolox > vitamin E) correlated with their ability to inhibit brain membrane lipid peroxidation (correlation coefficient = 0.939). BN 80933 afforded protection even when added 6 h after glutamate exposure. BN 80933 did not reverse intracellular glutathione depletion but prevented elevation of the level of beta-epiprostaglandin F2alpha (8-isoprostane), which appeared to be a delayed phenomenon. In conclusion, BN 80933 induces a potent cytoprotection that may be mediated by inhibition of delayed lipid peroxidation.
Demerlé-Pallardy
C
C
Beaufour-IPSEN Research Laboratory, Institut Henri Beaufour, Les Ulis, France.
Gillard-Roubert
V
V
Marin
J G
JG
Auguet
M
M
Chabrier
P E
PE
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D002460:Cell Line; D002540:Cerebral Cortex / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D015237:Dinoprost / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D028441:F2-Isoprostanes; D005978:Glutathione / Q000037:antagonists & inhibitors; D000860:Hypoxia / Q000201:enzymology / Q000473:pathology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008054:Lipid Peroxides / Q000037:antagonists & inhibitors*; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052248:Nitric Oxide Synthase Type I; D018384:Oxidative Stress / Q000187:drug effects; D011719:Pyrazines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013876:Thiophenes / Q000494:pharmacology*
D000975:Antioxidants; D004791:Enzyme Inhibitors; D028441:F2-Isoprostanes; D008054:Lipid Peroxides; D018696:Neuroprotective Agents; D011719:Pyrazines; D013876:Thiophenes; C075750:8-epi-prostaglandin F2alpha; C120890:BN 80933; D015237:Dinoprost; D007770:L-Lactate Dehydrogenase; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496322:Nos1 protein, rat; D005978:Glutathione