ISHEN 2012

Conférence ISHEN

Dr Rose et Cristina Bosoi sont présentement en route vers la conférence du ISHEN, à Grenaa, au Danemark.

Ce 15e Symposium de l'International society for Hepatic Encephalopathies and Nitrogen Metabolism (ISHEN) regroupe tous les spécialistes du domaine de l'encéphalopathie hépatique. Cristina Bosoi et Dr Rose y feront des présentations orales portant sur nos plus récents résultats.

***MISE À JOUR : Cristina a remporté le prix de la meilleure communication orale. Félicitations!

Publications connexes

Oral

Systemic oxidative stress induction leads to brain edema in hyperammonemic portacaval-shunted rats.

Cristina Bosoi, Christian Parent-Robitaille, Mélanie Tremblay, Christopher F. Rose.

Aims: Although ammonia is the central component in the pathogenesis of hepatic encephalopathy, it is believed oxidative stress (OS) plays a role in the pathogenesis of brain edema during liver disease. We previously demonstrated that portacaval shunted hyperammonemic rats do not develop OS or brain edema (Bosoi et al., FRBM, 2012). To define whether a synergistic effect exists between hyperammonemia and OS in the development of brain edema, the present study investigates the role of OS in the pathogenesis of brain edema in PCA rats following glutathione depletion by diethyl maleate (DEM). Methods: We evaluated the effect of DEM (1 mg/kg/day intraperitoneally for 10 days starting day 18 after surgery) in PCA and SHAM-operated rats. Rats were sacrificed at day 28 and OS was evaluated by measuring arterial and cerebral malon-dialdehyde (MDA, commercial kit), reactive oxygen species (ROS, DCFDA fluorescence), and 4-hydroxy-2-nonenal (HNE, Western blot). Ammonia levels (commercial kit) were also assessed. Frontal cortex brain water was measured using a specific gravimetric technique. Results: DEM induced a significant increase in plasma MDA, ROS and HNE levels in PCA rats. No increase was detected in DEM-treated SHAM-operated controls. No changes in cerebral OS markers were observed in any group. Ammonia levels increased in non-treated and DEM-treated PCA vs SHAM-operated rats (p<0.001) and remained unchanged between non-treated and DEM-treated PCA groups. Brain water content increased in DEM-treated PCA rats vs non-treated PCA rats (PCA+DEM: 78.45±0.13% vs PCA: 77.38±0.11%, p< 0.001). Conclusions: DEM treatment in PCA rats induced systemic, not central OS. This, superimposed on hyperammonemia, led to the development of brain edema. Similar DEM doses did not result in increased OS and brain edema in SHAM-operated rats, suggesting PCA rats are more susceptible to OS. Our findings support a synergistic effect between hyperammonemia and systemic OS in the pathogenesis of brain edema in hepatic encephalopathy.

Oral

Role of oxidative stress in prevention of brain edema during an acute deterioration of chronic liver failure.

Cristina R. *Bosoi, Chantal Bémeur, Cristina R. Bosoi, Mélanie Tremblay, Christopher F. Rose.

Aims: Acute-on-chronic liver failure (ACLF) represents an acute decompensation of liver cirrhosis. End-to-side portacaval anastomosis (PCA) followed by hepatic artery ligation (HAL) performed after 4 weeks represents a model of liver decompensation. In this model, the onset of coma is delayed compared to acute liver failure induced by hepatic devascularisation. As oxidative stress plays a role in brain edema in chronic liver failure, the objective of this study was to investigate the role of oxidative stress in the pathogenesis of brain edema in ACLF. Methods: Male Sprague-Dawley rats were subjected to PCA followed by hepatic artery ligation (HAL) either concomitantly (HAL-0) or 4 weeks (HAL-4W) following shunt surgery or to a SHAM intervention. Body temperature and blood glucose were monitored and maintained throughout the experiments. Brain edema (specific gravimetric technique) and glutathione levels (spectrophotometry) were measured in brain tissue of all groups. Results: Brain water content was significantly attenuated in “acute-on-chronic” rats (SHAM: 80.12±0.09 %; HAL-0: 81.39±0.15 % (p<0.01 vs SHAM); HAL-4W: 80.04±0.13 % (ns vs SHAM; p<0.01 vs HAL-0)). Arterial ammonia concentration followed a similar pattern (control: 0.060±0.007 mM; HAL-0: 1.340±0.090 mM (p<0.001 vs SHAM); HAL-4W: 0.350±0.070 mM (p<0.001 vs SHAM; p<0.001 vs HAL-0)). Glutathione levels did not change in HAL-4W compared to SHAM and were significantly decreased in the brains of HAL-0 rats (by 36% vs SHAM, p<0.05 and by 25% vs HAL-4W). These effects were not due to an improvement in liver function, as liver necrosis markers AST and ALT did not differ between HAL-4W and HAL-0 rats. Conclusions: Brain edema, ammonia levels and oxidative stress are reduced in ACLF rats compared to acute liver failure rats. These findings suggest that during chronic liver failure compensatory mechanisms are developed that prevent the apparition of brain edema and attenuate oxidative stress during an acute deterioration.

Oral

Increased cerebral lactate contributes to brain edema in cirrhotic rats.

Cristina Bosoi, Mélanie Tremblay, Christopher F. Rose.

Aims: Neurotoxic effects of ammonia have been shown to induce numerous metabolic alterations such as increased brain glutamine and lactate. In brain edema associated with acute liver failure, glutamine plays a controversial role and a few studies demonstrated lactate is also involved. Brain edema is also present in patients with chronic liver failure; in this situation roles of lactate and glutamine are less understood. We previously demonstrated an increase in lactate de novo synthesis in bile-duct ligated rats (BDL), a known model of chronic liver failure/minimal hepatic encephalopathy. To define the role of lactate in the pathogenesis of brain edema, the present study investigates the effects of inhibiting lactate production. Methods: BDL rats were treated with dichloroacetate (DCA, 25 mg/kg for 7 days starting at week 5 after intervention, intraperitoneally), a pyruvate dehydrogenase kinase inhibitor that leads to pyruvate dehydrogenase stimulation, therefore to a shift of pyruvate from glycolysis to oxidation and consequently to a decrease in lactate production. Brain edema (specific gravimetric technique) and glutamine (HPLC) were measured in brain tissue of BDL rats vs sham operated controls. Results: 6 weeks following BDL, rats develop brain edema and increased brain lactate compared to SHAM-operated controls. DCA treatment normalized brain lactate in BDL rats. DCA-treated BDL rats demonstrated a significant reduction of brain water content reaching values similar to those seen in SHAM-operated rats. Glutamine levels were increased in BDL vs sham operated rats and remained high in DCA-treated BDL rats (569.20±80.44 µM vs BDL: 796.60±71.50 µM, and vs SHAM: 442.80±33.79 µM). Conclusions: Inhibition of lactate production attenuated brain edema while cerebral glutamine levels remained high. Our findings suggest increased brain lactate, not glutamine, is associated with brain edema. Impaired lactate metabolism contributes to the pathogenesis of brain edema in minimal hepatic encephalopathy.