Selective inhibition of inducible nitric oxide synthase prevents ischaemic brain injury.
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.
Parmentier
S
S
Department of Pharmacology, University René Descartes, Paris, France.
Böhme
G A
GA
Lerouet
D
D
Damour
D
D
Stutzmann
J M
JM
Margaill
I
I
Plotkine
M
M
D000578:Amidines / Q000627:therapeutic use*; D000818:Animals; D001596:Benzylamines / Q000627:therapeutic use*; D002545:Brain Ischemia / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D002544:Cerebral Infarction / Q000473:pathology / Q000517:prevention & control; D002560:Cerebrovascular Circulation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D009068:Movement / Q000187:drug effects; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052247:Nitric Oxide Synthase Type II; D051381:Rats; D017207:Rats, Sprague-Dawley; D015431:Weight Loss / Q000187:drug effects
D000578:Amidines; D001596:Benzylamines; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; C104820:N-(3-(aminomethyl)benzyl)acetamidine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat