Multiple ammonia-induced episodes of hepatic encephalopathy provoke neuronal cell loss in bile-duct ligated rats
Notice bibliographique
Résumé
•Multiple ammonia-induced episodes of HE cause apoptosis and a reduction in neuronal cell markers in the hippocampus.•Higher levels of oxidative stress markers and decreased total antioxidant capacity in the hippocampus suggest oxidative stress-related apoptotic neuronal loss.•Multiple ammonia-induced episodes of HE lead to permanent cell damage and therefore irreversibility.•History of episodes of HE may justify persisting neurological complications observed in patients following liver transplantation. Background & AimsHepatic encephalopathy (HE) is defined as a reversible syndrome and therefore should resolve following liver transplantation (LT). However, neurological complications have been reported in up to 47% of LT recipients, which have been documented to be associated with a history of overt HE pre-LT. We hypothesise that multiple episodes of HE lead to permanent cell injury and exacerbate neurological dysfunction. Our goal was to evaluate the impact of cumulative HE episodes on neurological status and brain integrity in rats with chronic liver disease.MethodsEpisodes of overt HE (loss of righting reflex) were induced following injection of ammonium acetate in bile duct ligation (BDL) rats (BDL-Ammonia) every 4 days starting at week 3 post-BDL. Neurobehaviour was evaluated after the last episode. Upon sacrifice, plasma ammonia, systemic oxidative stress, and inflammation markers were assessed. Neuronal markers including neuron-specific nuclear antigen and SMI311 (anti-neurofilament marker) and apoptotic markers (cleaved caspase-3, Bax, and Bcl2) were measured. Total antioxidant capacity, oxidative stress marker (4-hydroxynonenal), and proinflammatory cytokines (tumour necrosis factor-alpha and interleukin-1β) were measured in brain (hippocampus, frontal cortex, and cerebellum). Proteomic analysis was conducted in the hippocampus.ResultsIn hippocampus of BDL-Ammonia rats, cleaved caspase-3 and Bax/Bcl2 ratio were significantly increased, whereas NeuN and SMI311 were significantly decreased compared with BDL-Vehicle rats. Higher levels of oxidative stress-induced post-translational modified proteins were found in hippocampus of BDL-Ammonia group which were associated with a lower total antioxidant capacity.ConclusionsAmmonia-induced episodes of overt HE caused neuronal cell injury/death in BDL rats. These results suggest that multiple bouts of HE can be detrimental on the integrity of the brain, translating to irreversibility and hence neurological complications post-LT.Impact and implicationsHepatic encephalopathy (HE) is defined as a reversible neuropsychiatric syndrome resolving following liver transplantation (LT); however, ∼47% of patients demonstrate neurological impairments after LT, which are associated with a previous history of overt HE pre-LT. Our study indicates that multiple episodes of overt HE can cause permanent neuronal damage which may lead to neurological complications after LT. Nevertheless, preventing the occurrence of overt HE episodes is critical for reducing the risk of irreversible neuronal injury in patients with cirrhosis. Hepatic encephalopathy (HE) is defined as a reversible syndrome and therefore should resolve following liver transplantation (LT). However, neurological complications have been reported in up to 47% of LT recipients, which have been documented to be associated with a history of overt HE pre-LT. We hypothesise that multiple episodes of HE lead to permanent cell injury and exacerbate neurological dysfunction. Our goal was to evaluate the impact of cumulative HE episodes on neurological status and brain integrity in rats with chronic liver disease. Episodes of overt HE (loss of righting reflex) were induced following injection of ammonium acetate in bile duct ligation (BDL) rats (BDL-Ammonia) every 4 days starting at week 3 post-BDL. Neurobehaviour was evaluated after the last episode. Upon sacrifice, plasma ammonia, systemic oxidative stress, and inflammation markers were assessed. Neuronal markers including neuron-specific nuclear antigen and SMI311 (anti-neurofilament marker) and apoptotic markers (cleaved caspase-3, Bax, and Bcl2) were measured. Total antioxidant capacity, oxidative stress marker (4-hydroxynonenal), and proinflammatory cytokines (tumour necrosis factor-alpha and interleukin-1β) were measured in brain (hippocampus, frontal cortex, and cerebellum). Proteomic analysis was conducted in the hippocampus. In hippocampus of BDL-Ammonia rats, cleaved caspase-3 and Bax/Bcl2 ratio were significantly increased, whereas NeuN and SMI311 were significantly decreased compared with BDL-Vehicle rats. Higher levels of oxidative stress-induced post-translational modified proteins were found in hippocampus of BDL-Ammonia group which were associated with a lower total antioxidant capacity. Ammonia-induced episodes of overt HE caused neuronal cell injury/death in BDL rats. These results suggest that multiple bouts of HE can be detrimental on the integrity of the brain, translating to irreversibility and hence neurological complications post-LT.
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Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,001 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».