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NEUROPHARMACOLOGY

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

Laboratoire de Pharmacologie, Université René Descartes, Paris, France (L.D.Z., C.M.V., B.P., N.C., M.P., I.M.); and Beaufour-Ipsen Research Laboratories, Institut Henri Beaufour, Les Ulis, France

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.

Address correspondence to: Dr. Isabelle Margaill, Laboratoire de Pharmacologie, Université René Descartes, 4 Avenue de l'Observatoire, 75006 Paris, France. E-mail: margaill{at}pharmacie.univ-paris5.fr

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