Selective inhibition of inducible nitric oxide synthase prevents ischaemic brain injury

Abstract

1 The aim of this study was to investigate the e ect 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 71 ) 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 signi®cantly 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 a ecting the constitutive NOS activity. 5 These ®ndings suggest that iNOS activation contributes to tissue damage and that selective inhibitors of this isoform may be of interest for the treatment of stroke.

The Involvement of Glucose Metabolism in the Regulation of Inducible Nitric Oxide Synthase Gene Expression in Glial Cells: Possible Role of Glucose-6-Phosphate Dehydrogenase and CCAAT/Enhancing Binding Protein

“…Although the exact mechanism is not known, the animal data indicate that insulin may provide protection by direct interaction with IGF-1 receptor and/or an indirect action by reducing the blood glucose levels. Although NO produced by iNOS is believed to play a role in the pathophysiology of cerebral ischemic injury (Iadecola et al, 1997;Nagayama et al, 1998;Iadecola, 1999;O'Mahony and Kendall, 1999;Parmentier et al, 1999), little information is available about the possible regulation of iNOS gene expression by glucose. This study reports that signals for upregulation of the LPS-induced expression of iNOS by glucose were mediated via C/EBP-␦.…”

Excess nitric oxide decreases cytochromeP-450 2J4 content andP-450-dependent arachidonic acid metabolism in lungs of rats with acute pneumonia

“…Animals were cared for until 40 h after surgery, at which time the rats were treated with either saline or a bolus of 10 mg/kg of 1400W, followed by a constant infusion of 1400W (10 mg⅐kg Ϫ1 ⅐h Ϫ1 ) for 4 h before death. The dose of 1400W was determined based on evidence from the literature (4,5,24) and preliminary experiments done in our laboratory. At 44 h, rats were anesthetized with pentobarbital sodium (30 mg/kg iv), and the thorax was opened.…”

Oxidants, antioxidants and the ischemic brain

“…Use of selective nNOS antagonists (O'Neill et al, 2000) and nNOS knockout mice (Huang et al, 1994), confirmed that neuronal production of nitric oxide contributes to ischemic cell death. iNOS has been associated with oxidative stress , and modifying its activity may have therapeutic potential (Parmentier et al, 1999). However, nitric oxide may also serve as an antioxidant against products of the Fenton reaction (Chiueh, 1999).…”