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1.
J Cereb Blood Flow Metab ; 21(1): 15-21, 2001 Jan.
Article in English | MEDLINE | ID: mdl-11149663

ABSTRACT

Nitric oxide (NO) has been suspected to mediate brain damage during ischemia. Here the authors studied the effects of an antisense oligodeoxynucleotide (ODN) directed against the inducible isoform of NO synthase (iNOS) in a model of transient focal cerebral ischemia in rats. Treatment consisted of seven intracerebroventricular injections of a phosphodiester/phosphorothioate chimera ODN (3 nmol each) at 12-hour intervals, and was initiated 12 hours before a 2-hour occlusion of the left middle cerebral artery and common carotid artery. Outcomes were measured three days after ischemia. When compared with animals treated with vehicle or an appropriate random non-sense control ODN sequence, the antisense treatment reduced the lesion volume by 30% and significantly improved recovery of sensorimotor functions, as assessed on a neuroscore. This effect was associated with a decrease in iNOS expression, as assessed by Western blot, a 39% reduction in iNOS enzymatic activity evaluated as Ca2+-independent NOS activity, and a 37% reduction in nitrotyrosine formation, reflecting protein nitration by NO-derived peroxynitrite. These findings provide new evidence that inhibition of iNOS may be of interest for the treatment of stroke.


Subject(s)
Brain Damage, Chronic/prevention & control , Brain/pathology , Cerebral Infarction/prevention & control , Ischemic Attack, Transient/physiopathology , Nitric Oxide Synthase/genetics , Oligodeoxyribonucleotides, Antisense/pharmacology , Animals , Brain/drug effects , Brain Damage, Chronic/pathology , Cerebral Infarction/pathology , Cerebral Ventricles/physiology , Injections, Intraventricular , Ischemic Attack, Transient/pathology , Male , Nitric Oxide Synthase Type II , Oligodeoxyribonucleotides, Antisense/administration & dosage , Rats , Rats, Sprague-Dawley
2.
Br J Pharmacol ; 127(2): 546-52, 1999 May.
Article in English | MEDLINE | ID: mdl-10385257

ABSTRACT

1. The aim of this study was to investigate the effect of N-(3-(aminomethyl)benzyl)acetamidine (1400W), a selective inhibitor of inducible calcium-independent nitric oxide synthase (iNOS), on the functional and histopathological outcomes of experimental transient focal cerebral ischaemia in rats. 2. Transient ischaemia was produced by the occlusion for 2 h of both the left middle cerebral artery and common carotid artery. Treatments with 1400W (20 mg kg(-1)) or vehicle were started 18 h after occlusion of the arteries and consisted in seven subcutaneous injections at 8 h interval. Ischaemic outcomes and NOS activities (constitutive and calcium-independent NOS) were evaluated 3 days after ischaemia. 3. 1400W significantly reduced ischaemic lesion volume by 31%, and attenuated weight loss and neurological dysfunction. 4. 1400W attenuated the calcium-independent NOS activity in the infarct by 36% without affecting the constitutive NOS activity. 5. These findings suggest that iNOS activation contributes to tissue damage and that selective inhibitors of this isoform may be of interest for the treatment of stroke.


Subject(s)
Amidines/therapeutic use , Benzylamines/therapeutic use , Brain Ischemia/drug therapy , Enzyme Inhibitors/therapeutic use , Nitric Oxide Synthase/antagonists & inhibitors , Animals , Brain Ischemia/enzymology , Brain Ischemia/pathology , Cerebral Infarction/pathology , Cerebral Infarction/prevention & control , Cerebrovascular Circulation/drug effects , Lipopolysaccharides/pharmacology , Male , Movement/drug effects , Nitric Oxide Synthase Type II , Rats , Rats, Sprague-Dawley , Weight Loss/drug effects
3.
Neurosci Lett ; 202(1-2): 21-4, 1995 Dec 29.
Article in English | MEDLINE | ID: mdl-8787821

ABSTRACT

In the present study, using the microdialysis technique, we provided evidence of the existence of hydroxyl radicals (.OH) in the striatum of awake rats under physiological conditions. This .OH generation was virtually abolished by the N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine. On the contrary, it was significantly enhanced by the .NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME). The effect of L-NAME was completely reversed by L-arginine. These results suggest that the basal .OH production is largely the consequence of an NMDA receptor-mediated glutamatergic tone. Moreover, it is likely that endogenous .NO exerts an antioxidant activity in brain by preventing the rise in .OH levels.


Subject(s)
Arginine/analogs & derivatives , Enzyme Inhibitors/metabolism , Hydroxyl Radical/metabolism , Neostriatum/enzymology , Animals , Antioxidants/pharmacology , Arginine/metabolism , Chromatography, High Pressure Liquid , Consciousness , Dizocilpine Maleate/pharmacology , Excitatory Amino Acid Antagonists/pharmacology , Hydroxybenzoates/pharmacology , Male , Microdialysis , NG-Nitroarginine Methyl Ester , Rats , Rats, Sprague-Dawley
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