Inhibition of iNOS activity by 1400W decreases glutamate release and ameliorates stroke outcome after experimental ischemia

Neurobiology of Disease

Juan B. Salom¹  Germán Torregrosa²  José Castillo²  María C. Burguete³  Pedro Lorenzo³  Enrique Alborch³  Ignacio Lizasoain³  Fernando J. Pérez-Asensio³  Juan C. Leza⁴  Richard G. Knowles⁴  Olivia Hurtado⁴  María A. Moro⁴ 

[1] Corresponding author. Fax: [phone].;Departamento de Fisiología, Universidad de Valencia, Spain;Centro de Investigación, Hospital Universitario ‘La Fe’, Valencia, Spain;Departamento de Farmacología, Facultad de Medicina, Universidad Complutense de Madrid, Ciudad Universitaria s/n, 28040 Madrid, Spain;

关键词: ATP;    Glutamate;    L-arginine;    Neuroprotection;    Nitric oxide;    Stroke;   

DOI  :  

来源: DOAJ

【 摘 要 】

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. 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.

【 授权许可】

Unknown