Involvement of nitric oxide in 3-nitropropionic acid-induced striatal toxicity in rats.

The roles of nitric oxide (NO) in 3-nitropropionic acid (3-NPA)-induced toxicity were investigated using in vivo and in vitro models. Chronic 3-NPA administration (10 mg/kg) to rats produced selective striatal lesions that were associated with abnormal motor and EMG activities. In these animals, there was loss of glial fibrillary acidic protein (GFAP)-positive cells with extravasation of IgG in the lesion center, although microtubule-associated protein (MAP)-2-positive cells remained, indicating that astrocytes were involved. 3-NPA increased the NO(2)(-)/NO(3)(-) levels in microdialysates obtained from the striatum, thalamus and cerebellum. The basal NO(3)(-) level was much higher in the striatum than in the other areas. The NO(2)(-)/NO(3)(-) levels in the striatum were much higher in animals exhibiting abnormal muscular activity. Expression of endothelial NO synthase (eNOS), but not neuronal NOS (nNOS), was greatly increased in the striatum at 5 h after a second 3-NPA exposure, but not in other areas. In astrocyte cultures, the toxic effects of 3-NPA were associated with corresponding increases in the NO(2)(-) level, and this toxicity was attenuated by hemoglobin (Hb; 20 microM), which quenches NO. The NO(2)(-) generated by 3-NPA, even without cells, was also antagonized by Hb. 3-NPA, S-nitroso-n-acetyl-dl-penicillamine (SNAP) and sodium nitroprusside (SNP) all increased the NO current (detected by NO-sensitive electrodes) in concentration-dependent manners, and Hb significantly attenuated the NO generation induced by 3-NPA, SNAP or SNP. Taken together, these results suggest that 3-NPA generates NO both directly as a donor and indirectly by enhancing NOS expression to produce toxic effects on astrocytes and neuronal toxicity.