Increased brain lactate is central to the development of brain edema in rats with chronic liver disease

Abstract

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.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).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.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.Canadian Institutes of Health Research. CB:Fonds de recherche du Québec – Sant

1H and 31P magnetic resonance spectroscopy in a rat model of chronic hepatic encephalopathy: in vivo longitudinal measurements of brain energy metabolism

“…Gln increased linearly reaching a 2.5 fold increase at week 8. We measured a gradual decrease of Ins together with other osmolytes as tCho and Cr, in agreement with previously published studies in BDL rats (Chavarria et al 2013;Bosoi et al 2014) and CLD patients (Kreis et al 1992;Bluml et al 1998;Taylor-Robinson et al 1999), suggesting a compensatory effect for the osmotic imbalance created by Gln accumulation,. Therefore, as expected, Gln most strongly correlated with Ins, consistent with the fact that Ins is considered as the main astrocytic osmolyte (Lien et al 1990;Flögel et al 1995).…”

“…In the present study, the sum of the main osmolytes (Gln, Ins, tCho, Cr) was not constant over time, showing a 20 % increase at week 8. This progressive yet incomplete osmotic compensation is probably the underlying cause of the observed minimal brain edema associated with chronic HE, as previously shown Bosoi et al 2014). Moreover these changes go along with the appearance of the neurological signs towards the end stage of the disease, as demonstrated by the decrease in locomotor activity in the Open Field task using the same animal model (Leke et al 2012;Rackayova et al 2015).…”

“…In addition, it is important to note that Glu and Asp play also a crucial role in malate-aspartate shuttle (Rao and Norenberg 2001). Increased brain Lac levels are considered as sign of energy disturbances (Rama Rao and Norenberg 2012;Bosoi et al 2014) with substantial evidence that increased brain Lac is associated with the development of brain edema mainly at comatose stages of HE in ALF models (Chavarria et al 2010). A recent ex vivo study showed in 6 weeks BDL rats that a rise in Lac (1.7 fold) and not Gln is a primary player in the pathogenesis of brain edema in CLD (Bosoi et al 2014).…”

“…Increased brain Lac levels are considered as sign of energy disturbances (Rama Rao and Norenberg 2012;Bosoi et al 2014) with substantial evidence that increased brain Lac is associated with the development of brain edema mainly at comatose stages of HE in ALF models (Chavarria et al 2010). A recent ex vivo study showed in 6 weeks BDL rats that a rise in Lac (1.7 fold) and not Gln is a primary player in the pathogenesis of brain edema in CLD (Bosoi et al 2014). Our in vivo longitudinal results are in contrast with these findings since we observed no significant elevation of Lac in rats 8 weeks following BDL, confirming the findings of others in the same animal model and similar brain region (Chavarria et al 2013).…”

Research progress on hepatic encephalopathy: animal models and disease mechanisms

“…This phenomenon might be attributed to hyperplasia of bile duct epithelial cells after BDL, which is a key factor and center pathological link to a series of lipid peroxidation reactions [19] . Recent animal study found that de novo synthesis of lactate in rat brain is one of the main reasons for the occurrence of cerebral edema six weeks after BDL [34] . Decreased levels of glutamine synthetase and glutaminase in the liver also contributed to cause hyperammonemia [35] .…”