title: Cerebral inflammation contributes to encephalopathy and brain edema in acute liver failure: protective effect of minocycline.
abstract: Encephalopathy and brain edema are serious complications of acute liver failure (ALF). The precise pathophysiologic mechanisms responsible have not been fully elucidated but it has been recently proposed that microglia-derived proinflammatory cytokines are involved. In the present study we evaluated the role of microglial activation and the protective effect of the anti-inflammatory drug minocycline in the pathogenesis of hepatic encephalopathy and brain edema in rats with ALF resulting from hepatic devascularisation. ALF rats were killed 6 h after hepatic artery ligation before the onset of neurological symptoms and at coma stages of encephalopathy along with their appropriate sham-operated controls and in parallel with minocycline-treated ALF rats. Increased OX-42 and OX-6 immunoreactivities confirming microglial activation were accompanied by increased expression of interleukins (IL-1beta, IL-6) and tumor necrosis factor-alpha (TNF-alpha) in the frontal cortex at coma stage of encephalopathy in ALF rats compared with sham-operated controls. Minocycline treatment prevented both microglial activation as well as the up-regulation of IL-1beta, IotaL-6 and TNF-alpha mRNA and protein expression with a concomitant attenuation of the progression of encephalopathy and brain edema. These results offer the first direct evidence for central proinflammatory mechanisms in the pathogenesis of brain edema and its complications in ALF and suggest that anti-inflammatory agents may be beneficial in these patients.
authors.affiliation: Saint-Luc Hospital, University of Montreal, Quebec, Canada.
authors.forename: Wenlei
authors.initials: W
authors.lastname: Jiang
authors.forename: Paul
authors.initials: P
authors.lastname: Desjardins
authors.forename: Roger F
authors.initials: RF
authors.lastname: Butterworth
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D001929:Brain Edema / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000502:physiology; D006501:Hepatic Encephalopathy / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000502:physiology; D017114:Liver Failure, Acute / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008911:Minocycline / Q000494:pharmacology / Q000627:therapeutic use*; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D018836:Inflammation Mediators; D018696:Neuroprotective Agents; D008911:Minocycline