Résumés acceptés à l'AASLD 2009

Résumés acceptés

Félicitations à toute l'équipe pour les 2 résumés qui ont été acceptés à une grande conférence internationale portant sur les maladies hépatiques.

Deux résumés acceptés à l' AASLD, dont un sera présenté oralement. Ce sera la première communication scientifique à propos de l'AST-120, un nouveau traitement prometteur.

Publications connexes

Oral

AST-120 (spherical carbon adsorbent) attenuates brain edema and lowers arterial ammonia in bile duct ligated rats.

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

Background: The pathogenesis of hepatic encephalopathy (HE) is multifactorial involving gut-derived toxins such as ammonia. Liver disease leads to hyperammonemia and neurotoxic levels of ammonia which have been demonstrated to induce oxidative stress. Therefore a primary treatment target for HE is to decrease ammonia production in the gastrointestinal tract. AST-120 (spherical carbon adsorbent), an oral adsorbent of engineered activated carbon microspheres with surface areas exceeding 1600m2/g works as a sink for neuro- and hepato–toxins present in the gut. In this study, we evaluated the protective effect of AST-120 in attenuating brain edema and the capacity of AST-120 to lower arterial ammonia and oxidative stress in rats with cirrhosis. Methods: Secondary biliary cirrhosis was induced in rats by bile duct ligation (BDL) for 6 weeks. BDL and SHAM-operated rats received AST-120 by gavage in methylcellulose (MC) at a dose of 0.1 or 1g/kg/day for 6 weeks. Control BDL and SHAM-operated groups received MC only. AST and ALT were measured at the end of the treatment period to assess liver function. Ammonia and reactive oxygen species (ROS) were measured in arterial plasma using a commercially available kit and DCFDA-fluorescent technique respectively. Brain water content was measured in the frontal cortex using the specific gravimetric technique. Results: AST-120 was well-tolerated with no deaths in either of the treatment groups. Brain water content increased in BDL vs SHAM-operated rats (81.8 ± 0.1% vs 81.3 ± 0.2%, p<0.05). Both 0.1 and 1g/kg/day AST-120 treatments normalised brain water content in BDL rats. Arterial ammonia increased in the BDL control group vs SHAM-operated controls (175.5 ± 48.1uM vs 105.3 ± 27.3uM, p<0.05) and decreased significantly in BDL 0.1g/kg/day (118.0 ± 6.4uM, p<0.05) and BDL 1g/kg/day (75.4 ± 31.4uM, p<0.05). Circulating levels of ROS were significantly increased in BDL vs SHAM-operated rats (11 fold, p<0.001). AST-120 treatment did not attenuate arterial levels of ROS compared to respective SHAM-operated controls. Liver functions enzymes, AST and ALT, were increased in all BDL rats compared to their respective SHAM-operated controls (p<0.001). Conclusions: AST-120 treatment normalized brain water content and decreased arterial ammonia levels but did not demonstrate an effect on systemic ROS. Long-term treatment with AST-120 is a safe, non-antibiotic alternative demonstrating a significant ammonia-lowering effect, as well as a protective effect on the development of brain edema in rats with chronic liver failure. Additional studies are warranted to evaluate the effects of AST-120 on HE in patients with advanced liver disease.

Brain edema is associated with systemic and not central oxidative stress in rats with bile-duct ligation.

Xiaoling Yang, Cristina Bosoi, Mélanie Tremblay, Christopher F. Rose.

Background: Ammonia plays a major role in the pathogenesis of hepatic encephalopathy however oxidative stress is also believed to be involved. Two lines of evidence lead us to the following aim of our study: 1) neurotoxic levels of ammonia have demonstrated to induce oxidative stress in vitro and 2) systemic oxidative stress is believed to exacerbate the neuropsychological effects of hyperammonemia observed in patients with liver disease. Our aim was to measure oxidative stress markers systemically and centrally, in association with brain edema in rats with cirrhosis. Methods: Rats were sacrificed 6 weeks following bile-ligated induced cirrhosis. Arterial plasma and cerebrospinal fluid (CSF) were collected to measure ammonia (commercially available kit), reactive oxygen species (ROS) (DCFDA-fluorescent technique), nitric oxide (NO) (Griess method) and lipid peroxidation (malondialdehyde, MDA) (commercially available kit). Frontal cortex was dissected to measure antioxidant catalase activity (Amplex Red fluorescent technique), S-nitrosylation of cystein thiols (immunoblotting) and brain water content was determined using the specific gravimetric technique. Results: Brain water content increased in BDL rats vs SHAM-operated controls (81.91 ± 0.19% vs 81.23 ± 0.20%, p<0.05). BDL rats vs SHAM-operated controls developed an increase in plasma arterial levels of ammonia (91.8 ± 18.4uM vs 41.2 ± 13.2uM, p<0.05), ROS (4.9 fold increase), NO (2.9 fold increase), MDA (41.9 ± 7.4uM vs 9.9 ± 0.6uM, p<0.005), S-nitrosylated proteins and a decrease in catalase activity (1.3 ± 0.5U/ml vs 3.2 ± 1.4U/ml, p<0.05). Centrally, BDL rats vs SHAM-operated controls developed an increase in CSF ammonia (123.5 ± 21.7uM vs 23.3 ± 6.1uM, p<0.05) but did not develop an increase in CSF ROS and NO or in brain MDA and S-nitrosylation detection. Furthermore, catalase activity in the brain was unchanged in BDL vs SHAM-operated controls. Conclusions: Six weeks following BDL, rats developed brain edema. An increase in arterial ammonia was accompanied with an increase in lipid peroxidation, NO, ROS and S-nitrosylation with a decrease in catalase activity. However, a similar increase in ammonia levels in CSF lead to contrary results where no increase in oxidative stress markers was found in brain. Our findings suggest 1) ammonia does not induce oxidative stress in the brain, 2) systemic oxidative stress is related to a decrease in catalase activity and 3) brain edema in BDL rats is associated with systemic, and not central, oxidative stress.