piperidines and Liver-Failure--Acute

Betaine/γ-aminobutyric acid (GABA) transporter 1 (BGT-1 or Slc6a12) is a transporter for the neurotransmitter GABA and osmolyte betaine. To date, most studies on BGT-1 have focused on its functions in the nervous system and renal osmotic homeostasis. Despite its dominant distribution in the liver, the function of BGT-1 in hepatic physiology or disease remains unknown. Here, we report that BGT-1 was significantly downregulated in patients with liver failure as well as in mice with experimental acute liver failure (ALF). Furthermore, mice deficient in BGT-1 showed significant resistance to ALF compared with wild type (WT) mice, manifesting as improved survival rate, reduced alanine transaminase/aspartate aminotransferase levels, better histopathological symptoms and fewer apoptotic cells in the liver. Similarly, in primary hepatocytes, BGT-1 deficiency or treatment with a BGT-1 inhibitor, NNC 05-2090, attenuated TNF-α mediated apoptosis. In addition, BGT-1 deficiency or dosing with NNC 05-2090 stimulated the expression of the anti-apoptotic gene, c-Met in the liver, suggesting the involvement of c-Met in the function on hepatocytes of BGT-1 apoptosis. Our findings suggest BGT-1 is a promising candidate drug target to prevent and treat hepatocyte apoptosis related diseases, such as ALF.

Topics: Animals; Apoptosis; Down-Regulation; GABA Plasma Membrane Transport Proteins; gamma-Aminobutyric Acid; Hepatocytes; Homeostasis; Humans; Liver; Liver Failure, Acute; Mice; Mice, Inbred C57BL; Mice, Knockout; Piperidines

Topics: Adenine; Biomarkers; Combined Modality Therapy; Female; Humans; Liver Failure, Acute; Middle Aged; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Treatment Outcome; Waldenstrom Macroglobulinemia

FK866 exhibits a protective effect on D-galactosamine (GaIN)/lipopolysaccharide (LPS) and concanavalin A (ConA)-induced acute liver failure (ALF), but the mechanism by which FK866 affords this benefit has not yet been elucidated. Autophagy has a protective effect on acute liver injury. However, the contribution of autophagy to FK866-conferred hepatoprotection is still unclear. This study aimed to investigate whether FK866 could attenuate GaIN/LPS and ConA-induced ALF through c-jun-N-terminal kinase (JNK)-dependent autophagy. In vivo, Mice were pretreated with FK866 at 24, 12, and 0.5 h before treatment with GaIN/LPS and ConA. 3-methyladenine (3MA) or rapamycin were used to determine the role of autophagy in FK866-conferred hepatoprotection. In primary hepatocytes, autophagy was inhibited by 3MA or autophagy-related protein 7 (Atg7) small interfering RNA (siRNA). JNK was suppressed by SP600125 or Jnk siRNA. FK866 alleviated hepatotoxicity and increased autophagy while decreased JNK activation. Suppression of autophagy abolished the FK866-conferred protection. Inhibition of JNK increased autophagy and exhibited strongly protective effect. Collectively, FK866 could ameliorate GaIN/LPS and ConA-induced ALF through induction of autophagy while suppression of JNK. These findings suggest that FK866 acts as a simple and applicable preconditioning intervention to protect against ALF; autophagy and JNK may also provide therapeutic targets for ALF treatment.

Topics: Acrylamides; Animals; Autophagy; Autophagy-Related Protein 7; Disease Models, Animal; Gene Knockdown Techniques; Hepatocytes; JNK Mitogen-Activated Protein Kinases; Lipopolysaccharides; Liver Failure, Acute; Liver Function Tests; Mice; Piperidines; Protective Agents; Signal Transduction

Endocannabinoids function as neurotransmitters and neuromodulators in the central nervous system via specific receptors and apparently have a neuroprotective role. We assumed that the endocannabinoid system could be involved in the pathogenesis of hepatic encephalopathy (HE), a neuropsychiatric syndrome due to liver disease. We used a mouse model of a thioacetamide induced fulminant hepatic failure. We found that the levels of the endocannabinoid 2-arachidonoyl-glycerol (2-AG) were elevated in the brain. Treatment with either 2-AG or with the CB1 receptor antagonist, SR141716A, improved a neurological score, activity and cognitive function. Activation of the CB2 receptor by a selective agonist, HU308, also improved the neurological score. 2-AG activity could be blocked with the specific CB2 receptor antagonist SR144528A. The CB1 receptor agonist noladin ether was inactive. We conclude that the endocannabinoid system may play an important role in the pathogenesis of HE. Modulation of this system either by exogenous agonists specific for the CB2 receptors or possibly also by antagonists to the CB1 receptors may have therapeutic potential.

Topics: Animals; Arachidonic Acids; Cannabinoid Receptor Modulators; Cognition; Dose-Response Relationship, Drug; Endocannabinoids; Female; Glycerides; Hepatic Encephalopathy; Liver; Liver Failure, Acute; Maze Learning; Mice; Mice, Inbred Strains; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Thioacetamide

To describe a case of fulminant hepatitis possibly related to concomitant donepezil and seratriline therapy.. An 83-year-old woman treated in a dementia care facility and later in a tertiary medical center.. Discontinuation of donepezil and sertraline therapy with subsequent improvement evidenced by liver biopsy and liver function tests.. An older woman with Alzheimer's disease was admitted to a dementia care facility because of aggressive behavior. Treatment with sertraline was initiated in February 1998. Sertraline doses were increased gradually to 200 mg daily by May 1998, and some improvement in behavior was seen. Concomitant therapy with donepezil 5 mg qhs was initiated June 26, 1998. Ten days later, confusion and jaundice were noted. Total bilirubin was 5.6 mg/dL, GGTP was 1,208 IU/L, and alkaline phosphatase was 369 IU/L. Computed tomography revealed cholelithiasis without ductal dilation. Liver, spleen, and pancreas seemed normal. Donepezil and sertraline were discontinued. The patient was admitted to our institution and treated for dehydration. A liver biopsy revealed scattered portal eosinophils and prominent cholestasis consistent with acute chemical hepatitis. The GGTP and total bilirubin of this patient peaked at 2,235 IU/L and 22.6 mg/dL, respectively. The patient improved, and her liver function tests normalized over the next 2 months.

Topics: Aged; Aged, 80 and over; Alkaline Phosphatase; Alzheimer Disease; Bilirubin; Biopsy; Chemical and Drug Induced Liver Injury; Cholestasis; Donepezil; Drug Monitoring; Drug Therapy, Combination; Female; gamma-Glutamyltransferase; Humans; Indans; Liver Failure, Acute; Liver Function Tests; Nootropic Agents; Piperidines; Selective Serotonin Reuptake Inhibitors; Sertraline; Tomography, X-Ray Computed

Enteric bacterial overgrowth resulting from compromised gastrointestinal motility has been suggested to be important for the development of enteric bacterial translocation. In the present study, the effect of cisapride, a 5-hydroxytryptamine-4-receptor agonist and stimulant of intestinal motility, was evaluated concerning intestinal motility, as measured by intestinal transit time, enteric bacterial overgrowth, and bacterial translocation from the gut in rats with acute liver failure induced by 90% hepatectomy. The results demonstrated that (1) the incidence of bacterial translocation to the systemic and portal circulation as well as to the liver, spleen, kidneys, and lungs was nil, and 17-33% to MLN in hepatectomized animals treated with cisapride, i.e. significantly lower than in hepatectomized rats administered saline; (2) overgrowth of E. coli in the intestine was noted in hepatectomized animals given saline, but not following cisapride treatment; (3) cisapride improved the otherwise delayed intestinal transit time following hepatectomy as shown by an increase in the leading edge of isotopic propulsion and the linear slope of the cumulative percent of radioactivity through each intestinal segment. Thus, we conclude that intravenous administration of cisapride prevents enteric bacterial overgrowth and bacterial translocation by improving intestinal motility in rats with acute liver failure induced by subtotal hepatectomy.

Topics: Animals; Bacterial Physiological Phenomena; Cisapride; Gastrointestinal Motility; Intestines; Liver Failure, Acute; Male; Movement; Piperidines; Rats; Rats, Sprague-Dawley; Serotonin Receptor Agonists