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Inhibition of iNOS activity by 1400W decreases glutamate release and ameliorates stroke outcome after experimental ischemia.
- Source :
-
Neurobiology of disease [Neurobiol Dis] 2005 Mar; Vol. 18 (2), pp. 375-84. - Publication Year :
- 2005
-
Abstract
- Background and Purpose: It has been shown that the reversed operation of glutamate transporters when ATP levels fall accounts for most glutamate release induced by severe cerebral ischemia. Nitric oxide (NO) is formed after ischemia and causes ATP depletion. Our purpose is to test if NO release from inducible NO synthase (iNOS) after stroke may cause a delayed glutamate release due to ATP depletion that might underlie progression of the ischemic infarct. We have studied the effect of the highly selective inhibitor of iNOS activity 1400W on brain ATP levels, extracellular glutamate, and stroke outcome after transient focal cerebral ischemia in rats.<br />Methods: To induce focal ischemia, the middle cerebral artery (MCA) was occluded by using the intraluminal thread technique (tMCAO). 1400W was administered, after tMCAO, by using an Alzet osmotic pump to yield a drug delivery rate of 2.5 mg/kg/h. Results. Postischemic treatment with 1400W induced a reduction in the neurofunctional impairment and in the total volume of brain infarct. Western blot analysis showed ischemia-induced expression of iNOS. Treatment with 1400W partially prevented delayed ATP reduction and produced inhibition of the subsequent delayed increase in glutamate levels caused by the ischemic insult.<br />Conclusions: Our data indicate that 1400W improves stroke outcome, an effect concomitant to the inhibition of both ischemia-induced decrease in brain ATP levels and increase in glutamate release. These results provide evidence indicating that the expression of iNOS induced by ischemia may contribute to the progression of the ischemic infarct and have important therapeutic implications for the management of stroke.
- Subjects :
- Adenosine Triphosphate metabolism
Amidines therapeutic use
Amino Acid Transport System X-AG metabolism
Animals
Benzylamines therapeutic use
Brain metabolism
Brain physiopathology
Cerebral Infarction drug therapy
Cerebral Infarction metabolism
Cerebral Infarction physiopathology
Cytoprotection drug effects
Cytoprotection physiology
Disease Models, Animal
Down-Regulation drug effects
Down-Regulation physiology
Enzyme Inhibitors pharmacology
Infarction, Middle Cerebral Artery drug therapy
Infarction, Middle Cerebral Artery metabolism
Infarction, Middle Cerebral Artery physiopathology
Ischemic Attack, Transient metabolism
Ischemic Attack, Transient physiopathology
Male
Neuroprotective Agents pharmacology
Nitric Oxide biosynthesis
Nitric Oxide Synthase metabolism
Nitric Oxide Synthase Type II
Rats
Rats, Wistar
Stroke metabolism
Stroke physiopathology
Treatment Outcome
Amidines pharmacology
Benzylamines pharmacology
Brain drug effects
Glutamic Acid metabolism
Ischemic Attack, Transient drug therapy
Nitric Oxide Synthase antagonists & inhibitors
Stroke drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 0969-9961
- Volume :
- 18
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Neurobiology of disease
- Publication Type :
- Academic Journal
- Accession number :
- 15686966
- Full Text :
- https://doi.org/10.1016/j.nbd.2004.10.018