Neuroprotective Effects of (S)-N-[4-[4-[(3,4-Dihydro-6-hydroxy-2,5,7,8 -tetramethyl-2H-1-benzopyran-2-yl)carbonyl]-1-piperazinyl]phenyl]-2 -thiophenecarboximid-amide (BN 80933), an Inhibitor of Neuronal Nitric-Oxide Synthase and an Antioxidant, in Model of Transient Focal Cerebral Ischemia in Mice

Q3 · MEDICINE

Article

Author: Croci, Nicole ; Margaill, Isabelle ; Palmier, Bruno ; Chabrier, Pierre-Etienne ; Li, Ding-Zhou ; Plotkine, Michel ; Marchand-Verrecchia, Catherine

Nitric oxide (NO) and reactive oxygen species are both implicated in neuronal death due to cerebral ischemia. BN 80933, an original compound associating an inhibitor of neuronal NO synthase with an antioxidant, has been shown to reduce functional and histological damage in rat submitted to cerebral ischemia. The aim of the present study was to confirm these results in mice and to further examine the effects of BN 80933 on inflammatory response, including blood-brain barrier (BBB) disruption, brain edema, and neutrophil infiltration after transient middle cerebral artery occlusion (MCAO). Intravenous administration of BN 80933 at 3 and 10 mg/kg 3 h after MCAO significantly reduced by 26 to 36% the infarct volume evaluated 24 and 48 h after ischemia, and improved the neurological score. Furthermore, BN 80933 at both dosages decreased by 42 to 75% the extravasation of Evans blue in brain parenchyma observed 24 h after ischemia. This reduction in BBB disruption was associated with decreased brain edema as demonstrated by the 37% reduction in brain water content induced by BN 80933 at 3 mg/kg 24 h after MCAO. Neutrophil infiltration in brain parenchyma, evaluated by the myeloperoxidase activity, was also reduced by 45 to 56% in animals treated with BN 80933 at 3 and 10 mg/kg. Together, these results extend the protective capacity of BN 80933 against brain ischemic injury and confirm that BN 80933 represents a promising treatment for stroke.

01 May 2000·Journal of NeurochemistryQ2 · MEDICINE

In Vitro Antioxidant Neuroprotective Activity of BN 80933, a Dual Inhibitor of Neuronal Nitric Oxide Synthase and Lipid Peroxidation

Q2 · MEDICINE

Article

Author: Caroline Demerlé‐Pallardy ; Jean‐Grégoire Marin ; Véronique Gillard‐Roubert ; Michel Auguet ; Pierre‐Etienne Chabrier

Abstract: 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 μM. 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 > 17β‐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 8‐epiprostaglandin F2α (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.

01 Apr 2000·NeuroReportQ4 · MEDICINE

BN 80933 Inhibits F2-isoprostane elevation in focal cerebral ischaemia and hypoxic neuronal cultures

Q4 · MEDICINE

Article

Author: Cornet, Sylvie ; Chabrier, Pierre-Etienne ; Auguet, Michel ; Spinnewyn, Brigitte ; Demerle-Pallardy, Caroline ; Marin, Jean-Gregoire

Formation of the lipid peroxidation product 8-epi-prostaglandin2alpha (8-epi-PGF2alpha) a bioactive marker of oxidative stress, was quantified in in vitro and in vivo models of neuronal death. In culture media of primary rat cortical neurones exposed to hypoxia followed by reoxygenation, a 3.7-fold increase of 8-epi-PGF2alpha concentration was observed in comparison to control cells. In rats submitted to 2h middle cerebral artery occlusion followed by a 22h reperfusion period, a 27-fold increase of 8-epi-PGF2alpha was observed in the ischaemic hemisphere compared with the corresponding hemisphere of sham-operated rats. Treatment with the neuroprotective agent BN 80933 significantly reduced both 8-epi-PGF2alpha elevations in vitro and in vivo. These data suggest that 8-epi-PGF2alpha elevations might reflect the damaging free radical overproduction and subsequent lipid peroxidation during neuronal injury induced by hypoxia and ischaemia. Inhibition of 8-epi-PGF2alpha elevations participates to the neuroprotective effects of BN 80933.

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Indication	Highest Phase	Country/Location	Organization	Date
Brain Ischemia	Preclinical	FR	Beaufour Ipsen Pharma SAS	-

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