NITRIC OXIDE-MEDIATED INHIBITION OF THE MITOCHONDRIAL RESPIRATORY-CHAIN IN CULTURED ASTROCYTES

The Ca2+-independent form of nitric oxide synthase was induced in rat neonatal astrocytes in primary culture by incubation with lipopolysacc haride (1 mu g/ml) plus interferon-gamma (100 U/ml), and the activitie s of the mitochondrial respiratory chain components were assessed. Inc ubation for 18 h produced 25% inhibition of cytochrome c oxidase activ ity. NADH-ubiquinone-1 reductase (complex I) and succinate-cytochrome c reductase (complex II-III) activities were not affected. Prolonged i ncubation for 36 h gave rise to a 56% reduction of cytochrome c oxidas e activity and a 35% reduction in succinate-cytochrome c reductase act ivity, but NADH-ubiquinone-1 reductase activity was unchanged. Citrate synthase activity was not affected by any of these conditions. The in hibition of the activities of these mitochondrial respiratory chain co mplexes was prevented by incubation in the presence of the specific ni tric oxide synthase inhibitor N-G-monomethyl-L-arginine. The lipopolys accharide/interferon-gamma treatment of the astrocytes produced an inc rease in glycolysis and lactate formation. These results suggest that inhibition of the mitochondrial respiratory chain after induction of a strocytic nitric oxide synthase may represent a mechanism for nitric o xide-mediated neurotoxicity.