The nitric oxide donor LA 419 decreases ischemic brain damage

Stroke represents a major clinical problem with limited available therapeutic treatments. Nitric oxide (NO) and the enzymes that produce it are involved in the pathogenesis of this disease. Here we investigated whether the novel NO donor LA 419 was able to ameliorate the consequences of stroke in an experimental model of global ischemia. We observed a sharp increase in the amounts of inducible NO synthase (iNOS) and nitrotyrosine in the cerebral cortex of experimental rats and a moderate increase of neuronal NO synthase (nNOS), as demonstrated by immunohistochemistry, Western blotting, and enzymatic activity assays. Treatment of these animals with LA 419 completely prevented ischemia-induced upregulation of nitrergic markers. Magnetic resonance imaging of the experimental brains showed a marked decrease in apparent diffusion coefficient (ADC) following ischemia-reperfusion, which was significantly corrected by pre-treatment with LA 419. These results clearly show that LA 419 is an efficient modulator of NO-related pathophysiological events and could eventually be used for the treatment of patients with cerebrovascular pathologies.