title: 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.
authors.affiliation: Pharmacological Research Department, ASKA Pharmaceutical Co., Ltd., 5-36-1, Shimosakunobe, Takatsu-ku, Kawasaki 213-8522, Japan. Electronic address: tamaoki-s@aska-pharma.co.jp.
authors.forename: Satoru
authors.initials: S
authors.lastname: Tamaoki
authors.affiliation: Pharmacological Research Department, ASKA Pharmaceutical Co., Ltd., 5-36-1, Shimosakunobe, Takatsu-ku, Kawasaki 213-8522, Japan. Electronic address: suzuki-h3@aska-pharma.co.jp.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Suzuki
authors.affiliation: Pharmacological Research Department, ASKA Pharmaceutical Co., Ltd., 5-36-1, Shimosakunobe, Takatsu-ku, Kawasaki 213-8522, Japan. Electronic address: okada-m@aska-pharma.co.jp.
authors.forename: Mami
authors.initials: M
authors.lastname: Okada
authors.affiliation: Safety Research Department, ASKA Pharmaceutical Co., Ltd., 5-36-1, Shimosakunobe, Takatsu-ku, Kawasaki 213-8522, Japan. Electronic address: fukui-n@aska-pharma.co.jp.
authors.forename: Norio
authors.initials: N
authors.lastname: Fukui
authors.affiliation: Safety Research Department, ASKA Pharmaceutical Co., Ltd., 5-36-1, Shimosakunobe, Takatsu-ku, Kawasaki 213-8522, Japan. Electronic address: isobe-m@aska-pharma.co.jp.
authors.forename: Mitsui
authors.initials: M
authors.lastname: Isobe
authors.affiliation: Pharmacological Research Department, ASKA Pharmaceutical Co., Ltd., 5-36-1, Shimosakunobe, Takatsu-ku, Kawasaki 213-8522, Japan. Electronic address: saito-t1@aska-pharma.co.jp.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Saito
mesh_terms: D000641:Ammonia / Q000097:blood; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000473:pathology; D003128:Coma / Q000150:complications; D004195:Disease Models, Animal; D006501:Hepatic Encephalopathy / Q000097:blood* / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D022124:Hyperammonemia / Q000150:complications*; D008297:Male; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012294:Rifamycins / Q000494:pharmacology* / Q000627:therapeutic use; D000078262:Rifaximin
chemical_list: D012294:Rifamycins; D000641:Ammonia; D000078262:Rifaximin
keywords: Animal model; Antibiotics; Encephalopathy; Gastrointestinal tract; Hyperammonemia