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 investigated possible neurotoxic mechanisms involving astrocytes in vitro. Low concentrations of Mn2+ were toxic only in astrocyte-neuronal cocultures but not in pure astrocyte or neuronal cultures. As a possible mediator of manganese-derived neurotoxicity, we measured the production of nitric oxide in astrocytes. Manganese, but not other transition metals, dose dependently increased iNOS mRNA and protein levels and the release of nitric oxide in activated astrocytes. This effect was specific for astrocytes, since we observed no stimulation in microglial cells. The observations suggest that besides the known inhibition of mitochondrial function the neurotoxic effect of manganese in low concentrations might be mediated by the increased production of nitric oxide in astrocytes.