Glia
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Manganese in excess is neurotoxic and causes CNS injury resembling that of Parkinson's disease. In brain, astrocytes predominantly take up and accumulate manganese and are thus vulnerable to its toxicity. Manganese was shown to induce cell swelling in cultured astrocytes, and oxidative/nitrosative stress (ONS) mediates such swelling. ⋯ As ONS is known to activate mitogen-activated protein kinases (MAPKs) and MAPK activation has been implicated in astrocyte swelling, we examined the effect of manganese on the activation of MAPKs and found an increased phosphorylation of extracellular signal-regulated kinase (ERK)1/2, C-Jun amino-terminal kinase (JNK)1/2/3, and p38-MAPK. Inhibitors of ERK1/2 and p38-MAPK (but not of JNK) blocked (40-60%) the manganese-induced increase in AQP4 protein content and astrocyte swelling, suggesting the involvement of these kinases in the increased AQP4 content. Inhibition of oxidative stress or MAPKs may represent potential strategies for counteracting AQP4-related neurological complications associated with manganese toxicity.