BACKGROUND & AIMS: 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.
BACKGROUND & AIMS: 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: Chantal Bémeur; Cristina Cudalbu; Gitte Dam; Alexander S Thrane; Arthur J L Cooper; Christopher F Rose Journal: Metab Brain Dis Date: 2016-06-07 Impact factor: 3.584
Authors: Cristina R Bosoi; Mariana M Oliveira; Rafael Ochoa-Sanchez; Mélanie Tremblay; Gabriella A Ten Have; Nicolaas E Deutz; Christopher F Rose; Chantal Bemeur Journal: Metab Brain Dis Date: 2016-12-15 Impact factor: 3.584
Authors: Jasmohan S Bajaj; Andrew Fagan; Melanie B White; James B Wade; Phillip B Hylemon; Douglas M Heuman; Michael Fuchs; Binu V John; Chathur Acharya; Masoumeh Sikaroodi; Patrick M Gillevet Journal: Am J Gastroenterol Date: 2019-07 Impact factor: 10.864
Authors: Dae Joong Kang; Naga S Betrapally; Siddhartha A Ghosh; R Balfour Sartor; Phillip B Hylemon; Patrick M Gillevet; Arun J Sanyal; Douglas M Heuman; Daniel Carl; Huiping Zhou; Runping Liu; Xiang Wang; Jing Yang; Chunhua Jiao; Jeremy Herzog; H Robert Lippman; Masoumeh Sikaroodi; Robert R Brown; Jasmohan S Bajaj Journal: Hepatology Date: 2016-07-29 Impact factor: 17.425