Suppression of ammonia-induced astrocyte swelling by cyclosporin A

Brain edema is a serious complication of hepatic encephalopathy associated with fulminant hepatic failure (FHF). A major component of the edema seems to be cytotoxic, involving astrocyte swelling. Although the mechanism of brain edema in FHF is incompletely understood, it is generally believed that ammonia is involved critically in this process. Recent studies have shown that exposure of cultured astrocytes to ammonia results in the mitochondrial permeability transition (MPT), a phenomenon associated with mitochondrial failure and subsequent cellular dysfunction. The present study examined the potential role of the MPT in the astrocyte swelling associated with ammonia toxicity. Treatment of cultured astrocytes with ammonia (5 mM) caused a time-dependent increase in astrocyte cell volume (swelling), which was completely inhibited by the MPT inhibitor cyclosporin A (CsA). In this study, CsA also inhibited the ammonia-induced aquaporin 4 (AQP4) upregulation, which had been shown previously to be increased in cultured astrocytes by ammonia treatment. These findings suggest that the MPT plays a significant role in the ammonia-induced astrocyte swelling and may contribute to the brain edema associated with FHF.