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Astrocyte swelling (cytotoxic edema) represents a critical component of the brain edema in acute form of hepatic encephalopathy (acute liver failure, ALF). Although mechanisms of astrocyte swelling by ammonia are not completely understood, cultured astrocytes exposed to pathophysiological levels of ammonia develop the mitochondrial permeability transition (mPT), a process that was shown to result in astrocyte swelling. Cyclosporin A (CsA), a traditional inhibitor of the mPT, was previously shown to completely block ammonia\u2010induced astrocyte swelling in culture. However, the efficacy of CsA to protect cytotoxic brain edema in ALF is problematic because it poorly crosses the blood\u2013brain barrier, which is relatively intact in ALF. We therefore examined the effect of agents that block the mPT but are also known to cross the blood\u2013brain barrier, including pyruvate, magnesium, minocycline, and trifluoperazine on the ammonia\u2010induced mPT, as well as cell swelling. Cultured astrocytes exposed to ammonia for 24 hr displayed the mPT as demonstrated by a CsA\u2010sensitive dissipation of the mitochondrial inner membrane potential. Pyruvate, minocycline, magnesium, and trifluoperazine significantly blocked the ammonia\u2010induced mPT. Ammonia resulted in a significant increase in cell volume, which was blocked by the above\u2010mentioned agents to a variable degree. A regression analysis indicated a high correlation between the effectiveness of reducing the mPT and cell swelling. Our data suggest that all these agents have therapeutic potential in mitigating brain edema in ALF. \u00a9 2009 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/jnr.22097","type":"journal-article","created":{"date-parts":[[2009,4,21]],"date-time":"2009-04-21T05:06:15Z","timestamp":1240290375000},"page":"2677-2685","source":"Crossref","is-referenced-by-count":25,"title":["Inhibitors of the mitochondrial permeability transition reduce ammonia\u2010induced cell swelling in cultured astrocytes"],"prefix":"10.1002","volume":"87","author":[{"given":"Pichili V. 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