MANGANESE AUGMENTS NITRIC-OXIDE SYNTHESIS IN MURINE ASTROCYTES - A NEW PATHOGENETIC MECHANISM IN MANGANISM

Since manganese (Mn2+) is known to be sequestered in glial cells, we i nvestigated possible neurotoxic mechanisms involving astrocytes in vit ro. Low concentrations of Mn2+ were toxic only in astrocyte-neuronal c ocultures but not in pure astrocyte or neuronal cultures. As a possibl e mediator of manganese-derived neurotoxicity, we measured the product ion of nitric oxide in astrocytes. Manganese, but not other transition metals, dose dependently increased iNOS mRNA and protein levels and t he release of nitric oxide in activated astrocytes. This effect was sp ecific for astrocytes, since we observed no stimulation in microglial cells. The observations suggest that besides the known inhibition of m itochondrial function the neurotoxic effect of manganese in low concen trations might be mediated by the increased production of nitric oxide in astrocytes. (C) 1998 Academic Press.