Na-K-Cl Cotransporter-1 as a Regulator of Manganese-induced Astrocyte Swelling

Astrocyte swelling leads to brain edema, intracranial pressure, brain herniation and acute liver failure (fulminant hepatic failure) which is the major cause of death in this condition. Manganese has been strongly implicated as an important factor in astrocyte swelling. Manganese in excess is neurotoxic and causes a CNS disorder that resembles Parkinson's disease (manganism). Manganese highly accumulates in astrocytes, which renders these cells more vulnerable to its toxicity. In addition to manganism, increased brain levels of manganese have been found in hepatic encephalopathy. In particular, activation of the Na-K-Cl cotransporter-1 (NKCC1) has been shown to be involved in cell swelling in several neurological disorders. Manganese increased NKCC activity at 24 h. Inhibition of this activity by bumetanide diminished manganese-induced astrocyte swelling. Manganese also increased total as well as phosphorylated NKCC1. These results suggest that, activation of NKCC1 is an important factor in the mediation of astrocyte swelling by manganese and that such activation appears to be mediated by NKCC1 abundance.