title: Increased brain lactate is central to the development of brain edema in rats with chronic liver disease.
abstract: OBJECTIVE
  The pathogenesis of brain edema in patients with chronic liver disease (CLD) and minimal hepatic encephalopathy (HE) remains undefined. This study evaluated the role of brain lactate, glutamine and organic osmolytes, including myo-inositol and taurine, in the development of brain edema in a rat model of cirrhosis.
  
  
  METHODS
  Six-week bile-duct ligated (BDL) rats were injected with (13)C-glucose and de novo synthesis of lactate, and glutamine in the brain was quantified using (13)C nuclear magnetic resonance spectroscopy (NMR). Total brain lactate, glutamine, and osmolytes were measured using (1)H NMR or high performance liquid chromatography. To further define the interplay between lactate, glutamine and brain edema, BDL rats were treated with AST-120 (engineered activated carbon microspheres) and dichloroacetate (DCA: lactate synthesis inhibitor).
  
  
  RESULTS
  Significant increases in de novo synthesis of lactate (1.6-fold, p<0.001) and glutamine (2.2-fold, p<0.01) were demonstrated in the brains of BDL rats vs. SHAM-operated controls. Moreover, a decrease in cerebral myo-inositol (p<0.001), with no change in taurine, was found in the presence of brain edema in BDL rats vs. controls. BDL rats treated with either AST-120 or DCA showed attenuation in brain edema and brain lactate. These two treatments did not lead to similar reductions in brain glutamine.
  
  
  CONCLUSIONS
  Increased brain lactate, and not glutamine, is a primary player in the pathogenesis of brain edema in CLD. In addition, alterations in the osmoregulatory response may also be contributing factors. Our results suggest that inhibiting lactate synthesis is a new potential target for the treatment of HE.
authors: Neuroscience Research Unit, Hôpital Saint-Luc (CRCHUM), Université de Montréal, Québec, Canada.
authors: Cristina R
authors: CR
authors: Bosoi
authors: Neuroscience Research Unit, Hôpital Saint-Luc (CRCHUM), Université de Montréal, Québec, Canada.
authors: Claudia
authors: C
authors: Zwingmann
authors: Neuroscience Research Unit, Hôpital Saint-Luc (CRCHUM), Université de Montréal, Québec, Canada.
authors: Helen
authors: H
authors: Marin
authors: Neuroscience Research Unit, Hôpital Saint-Luc (CRCHUM), Université de Montréal, Québec, Canada.
authors: Christian
authors: C
authors: Parent-Robitaille
authors: Neuroscience Research Unit, Hôpital Saint-Luc (CRCHUM), Université de Montréal, Québec, Canada.
authors: Jimmy
authors: J
authors: Huynh
authors: Neuroscience Research Unit, Hôpital Saint-Luc (CRCHUM), Université de Montréal, Québec, Canada.
authors: Mélanie
authors: M
authors: Tremblay
authors: Neuroscience Research Unit, Hôpital Saint-Luc (CRCHUM), Université de Montréal, Québec, Canada. Electronic address: christopher.rose@umontreal.ca.
authors: Christopher F
authors: CF
authors: Rose
mesh_terms: D000641:Ammonia / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism*; D001929:Brain Edema / Q000209:etiology*; D002908:Chronic Disease; D005973:Glutamine / Q000378:metabolism; D006501:Hepatic Encephalopathy / Q000209:etiology* / Q000378:metabolism; D019344:Lactic Acid / Q000378:metabolism*; D008107:Liver Diseases / Q000150:complications*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D005973:Glutamine; D019344:Lactic Acid; D000641:Ammonia
keywords: BDL; Bile-duct ligation; Brain edema; CLD; DCA; Glutamine; HE; Hepatic encephalopathy; Lactate; MHE; NMR; Nuclear magnetic resonance; PC; PDH; TCA cycle; bile-duct ligation; chronic liver disease; dichloroacetate; hepatic encephalopathy; minimal hepatic encephalopathy; nuclear magnetic resonance; pyruvate carboxylase; pyruvate dehydrogenase; tricarboxylic acid cycle