title: Inhibition of iNOS activity by 1400W decreases glutamate release and ameliorates stroke outcome after experimental ischemia.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  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.
authors.affiliation: Centro de Investigación, Hospital Universitario La Fe, Valencia, Spain.
authors.forename: Fernando J
authors.initials: FJ
authors.lastname: Pérez-Asensio
authors.forename: Olivia
authors.initials: O
authors.lastname: Hurtado
authors.forename: María C
authors.initials: MC
authors.lastname: Burguete
authors.forename: María A
authors.initials: MA
authors.lastname: Moro
authors.forename: Juan B
authors.initials: JB
authors.lastname: Salom
authors.forename: Ignacio
authors.initials: I
authors.lastname: Lizasoain
authors.forename: Germán
authors.initials: G
authors.lastname: Torregrosa
authors.forename: Juan C
authors.initials: JC
authors.lastname: Leza
authors.forename: Enrique
authors.initials: E
authors.lastname: Alborch
authors.forename: José
authors.initials: J
authors.lastname: Castillo
authors.forename: Richard G
authors.initials: RG
authors.lastname: Knowles
authors.forename: Pedro
authors.initials: P
authors.lastname: Lorenzo
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000578:Amidines / Q000494:pharmacology* / Q000627:therapeutic use; D027322:Amino Acid Transport System X-AG / Q000378:metabolism; D000818:Animals; D001596:Benzylamines / Q000494:pharmacology* / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D002544:Cerebral Infarction / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D019610:Cytoprotection / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism*; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D002546:Ischemic Attack, Transient / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology; D009569:Nitric Oxide / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D051381:Rats; D017208:Rats, Wistar; D020521:Stroke / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D016896:Treatment Outcome
chemical_list: D000578:Amidines; D027322:Amino Acid Transport System X-AG; D001596:Benzylamines; D004791:Enzyme Inhibitors; C104820:N-(3-(aminomethyl)benzyl)acetamidine; D018696:Neuroprotective Agents; D009569:Nitric Oxide; D018698:Glutamic Acid; D000255:Adenosine Triphosphate; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat