Manganese Cytotoxicity Mediated by Potentiation of Nitric Oxide Production in Activated Glial Cell

ABSTRACT

BACKGROUND: Glial cells are generally known to support normal neuronal functions tightly regulating the extracellular environment and providing energy substrates such as glucose. Therefore, dysfunction or loss of glial cells will lead to neuonal death. Since manganese (Mn2+) is known to be sequestered in glial cells, we investigated whether nitric oxide (NO) production in the activated glial cells is potentiated by manganese and the relationship between increased NO production and manganese-induced cytotoxicity of glial cells. METHODS: Manganese toxicity was assessed by morphological examination and by measuring the release of lactate dehydrogenase. Cultured glial cells were stimulated by lipopolysaccharide (1mug/mL). NO production was determined by measuring nitrites, a stable oxidation product of NO. RESULTS: Neither a LPS nor a MnCl2 altered the viability of glial cells. A 24 hr stimulation both LPS and MnCl2, however, markedly potentiated the manganese-induced death of glial cells. Manganese significantly increased the bacterial LPS-induced NO production. Manganese-induced NO release was markedly reduced by NOS inhibitor N(G)-nitro-L-arginine (L-NNA, 1 mM), and potentiation of manganese-induced cell death by activated glial cells was partially prevented by L-NNA. CONCLUSION: It is concluded that manganese could induce sustained production of neurotoxic nitric oxide by the activated glial cells and manganese-induced cytotoxicity is partially mediated by potentiation of LPS-induced nitric oxide in the glial cell culture model.