Hepatic encephalopathy (HE) contains a spectrum of neuropsychiatric abnormalities observed in patients with liver disease. A quick worsening of consciousness and increasingly growing cerebral edema, high intracranial pressure, which leads to cerebral herniation and death, are characteristics of acute liver failure (ALF). Multiple factors are found responsible for the development of HE, whereas, over 100 years, hyperammonia is considered the most crucial factor in defining the pathogenesis of HE in ALF, which can increase to millimolar concentrations in the brain at the coma stages of HE.;Key words: Acute liver failure, Hepatic encephalopathy;The present thesis comprises 4 articles, which demonstrates new pathogenic mechanisms involved in the development of HE and cerebral edema in ALF, and elucidates part of the therapeutic mechanism of hypothermia and minocycline in the prevention of HE and cerebral edema during ALF. The major findings are listed below: (1) Experimental ALF leads to the increase in brain production of proinflammatory cytokines (IL-6, IL-1beta, TNF-alpha), and provides the first direct evidence that central inflammatory mechanisms play a role in the pathogenesis of the encephalopathy and brain edema in ALF (chapter 2.1 - article 1; chapter 2.1 - article 2). (2) Activation of cerebral microglia, measured by OX-42, OX-6, predicts the presence of severe encephalopathy (coma) and brain edema in rats with ischemic ALF, which accompanies the increased production of brain proinflammatory cytokines (chapter 2.1 - article 1; chapter 2.2 - article 2). (3) Oxidative/nitrosative stress participates in the pathogenesis of brain edema and its complications in experimental ALF animals with ischemic liver failure. The increases in cerebral NOS isoform expression caused by ALF were sufficient to cause increased NO production in the brain (chapter 2.3 - article 3; chapter 2.4 - article 4). (4) Anti-inflammatory treatment, such as hypothermia or antibiotics, may be beneficial in patients with ALF (chapter 2.1 - article 1; chapter 2.2 - article 2). (5) The beneficial effect of both hypothermia and minocycline on the neurological complications of experimental ALF is mediated, at least in part, by reduction of brain-derived oxidative/nitrosative stress (chapter 2.3 - article 3; chapter 2.4 - article 4).
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