Development of an experimental rat model of hyperammonemic encephalopathy and evaluation of the effects of rifaximin

Abstract

Hepatic encephalopathy (HE) is a neuropsychiatric syndrome associated with hepatic dysfunction. However, the precise mechanism of HE is unclear. To elucidate the mechanism, we developed a new rat model of HE with coma using a combination of subcutaneous splenic transposition, partial hepatectomy and portal vein stenosis. In this model, blood ammonia levels increase in the postcaval vein over time and markedly increase in the cerebrospinal fluid (CSF). The distribution of ammonia in the various blood vessels in the HE model suggests that the origin of peripheral blood and CSF ammonia is the mesenteric veins that drain blood from the gastrointestinal tract. Behavioral analysis revealed decreased pain response, increased passivity, and decreased pinna and corneal reflexes, followed by the development of coma. The development of coma in this model was frequent and reproducible. Increased S100 calcium-binding protein B (S100B: a biomarker for brain injury) in venous blood, as well as damaged brain tissue, increased intracranial pressure and cerebral edema were observed in rats with coma. A very high correlation was observed between the blood ammonia concentration in the postcaval vein and the onset of coma. Rifaximin, a poorly absorbed antibiotic that targets gut flora, significantly improved symptoms of HE. Based on these results, our rat model appears to reflect the pathological state of HE associated with acute liver failure and may be a useful model for analysis of hyperammonemic encephalopathy.

Chronic Valproic Acid Administration Increases Plasma, Liver, and Brain Ammonia Concentration and Suppresses Glutamine Synthetase Activity

“…The results of this study showed that chronic VPA treatment was associated with elevation in plasma NH 4 concentration and behavioral manifestations reminiscent of mild-to-moderate hyperammonemia in animal models of hepatic encephalopathy [ 31 ]. This increase in plasma NH 4 was also accompanied by a concomitant elevation in liver and brain NH 4 concentration and a suppression of GS enzyme activity.…”

Efficacy and safety of rifaximin in Japanese patients with hepatic encephalopathy: A phase II/III, multicenter, randomized, evaluator‐blinded, active‐controlled trial and a phase III, multicenter, open trial

“…Rifaximin has in vitro bactericidal and bacteriostatic activities against Gram‐positive and ‐negative species, being able to reduce bacterial virulence and translocation and to inhibit bacterial adherence to gut mucosa . Furthermore, administration of rifaximin in a rat model of hyperammonemia improved the hyperammonemic state and reduced bacterial virulence …”

“…[48][49][50] Furthermore, administration of rifaximin in a rat model of hyperammonemia improved the hyperammonemic state and reduced bacterial virulence. 51 The gut microbiota in health and diseases including LC has recently been a focus of investigation, 52-56 because culture-independent techniques based on sequence divergences of the small subunit ribosomal RNA (16S rRNA) have been developed. 55 Several reports have shown differences in the gut microbiota of LC patients with or without HE.…”

Multimodal assessment of recovery from coma in a rat model of diffuse brainstem tegmentum injury

“…Despite extensive animal and human evidence for the role of brainstem arousal nuclei in regulation of consciousness, few studies have investigated neurological state changes during coma induction or acute recovery of consciousness following brainstem lesions in patients or in animal models. A transient coma can be caused by administration of neuro-toxins (29)(30)(31), anesthetics (18,32), or cholinergic agonists (33), but the induced coma state is brief (e.g. 5 -10 min) (30), dose-dependent, and associated with high fatality rates.…”