piperidines and Hepatic-Encephalopathy

Hepatic encephalopathy (HE) is a complex neuropsychiatric syndrome. Paracetamol (APAP) causes, in high doses, a hepatic injury. Alogliptin (ALO), with its 100% oral bioavailability, may be able to reverse the acute hepatic injury and memory impairments.. Forty rats were divided into four groups as follows; Normal Control Group, APAP intoxicated group, ALO and SIL groups. Behavioral tests (Morris water maze, Y-maze spontaneous alteration, and novel object recognition test) were performed together with evaluating HE score. Neurotransmitters (gamma-aminobutyric acid, glutamate, dopamine, serotonin, norepinephrine and acetylcholine), as well as acetylcholinesterase activity, were determined in the hippocampus. Also, hepatotoxicity markers (alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and ammonia) were measured in blood. Additionally, transforming growth factor beta 1, tumor necrosis factor alpha, cytochrome c, granzyme B and caspase-3, coiled-coil Moesin-like BCL-interacting protein 1 "beclin-1", cellular FLICE-like inhibitory protein, protein 53, TNF-α related apoptosis-inducing ligand, Fas-ligand and alpha-smooth muscle actin were measured in liver homogenate. Moreover, the histopathological investigation was performed.. APAP was able to disturb neurotransmitters which were mirrored in the performance of rats in the behavioral test. Most hepatotoxicity, apoptosis and inflammation indicators were elevated after APAP administration, while beclin-1 (autophagy marker) was declined. The tested drugs, both, reversed most of the last mentioned parameters but ALO was more efficient in reducing TGF-β1, α-SMA, TNF-α and ALP as well as increasing % alteration.. ALO and SIL elicited anti-apoptotic, anti-inflammatory and autophagic effects on paracetamol-damaged liver cells and improved memory impairments of HE.

Topics: Acetaminophen; Analgesics, Non-Narcotic; Animals; Anti-Inflammatory Agents; Apoptosis; Autophagy; Behavior, Animal; Biomarkers; Chemical and Drug Induced Liver Injury; Dipeptidyl-Peptidase IV Inhibitors; Hepatic Encephalopathy; Hydroxyethylrutoside; Male; Maze Learning; Memory; Memory Disorders; Piperidines; Rats; Rats, Wistar; Uracil

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

Lubeluzole is a newly designed neuroprotectant which has proved effective in the treatment of experimental stroke in rats, mainly by inhibition of the glutamate-activated NO pathway, but also by counteracting osmotic stress by a mechanism associated with the release of the osmotically active amino acid taurine (Tau). Here we show that lubeluzole administered i.p. decreases by 25% the high (50 mM) K+-evoked accumulation of Tau in striatal microdialysates of healthy rats and by 34% in rats with thioacetamide-induced hepatic failure, where the increased extracellular accumulation of Tau signifies ongoing hepatic encephalopathy. Lubeluzole does not affect the nonstimulated accumulation of Tau in either group of rats. The results indicate that lubeluzole may be effective in ameliorating ionic or osmotic stress in a range of pathological conditions involving the rise of extracellular K+, and also in decreasing the vulnerability to stress in rats with hepatic failure.

Topics: Animals; Extracellular Space; Glutamic Acid; Hepatic Encephalopathy; Male; Microdialysis; Neostriatum; Neurons; Neuroprotective Agents; Osmotic Pressure; Piperidines; Potassium Chloride; Rats; Rats, Wistar; Taurine; Thiazoles; Thioacetamide

Accumulated neurochemical data in different animal models of fulminant hepatic failure and in humans with hepatic encephalopathy suggest that serotoninergic tone is increased in the brain in hepatic encephalopathy. Since neurochemical alterations may not have behavioural or electrophysiological consequences the contribution of the serotoninergic system to the pathogenesis of hepatic encephalopathy was explored.. The effects of drugs modulating serotoninergic neurotransmission, the nonselective serotonin receptor antagonist methysergide and the serotonin2 receptor antagonist seganserin were tested neuropharmacologically in thioacetamide-induced acute liver failure in rats.. Methysergide had no effect in control rats, but dose dependently increased motor activity in stage II-III hepatic encephalopathy by 232% (5 mg/kg methysergide), 531% (10 mg/kg) and 507% (20 mg/kg). In contrast, seganserin had no effect in encephalopathic rats.. It is suggested that the beneficial effects of methysergide are serotonin, receptor mediated. Overall the results suggest that serotoninergic mechanisms contribute to some of the behavioural manifestations of hepatic encephalopathy in this animal model.

Topics: Animals; Dose-Response Relationship, Drug; Hepatic Encephalopathy; Male; Methysergide; Motor Activity; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Serotonin; Serotonin; Serotonin Antagonists; Thioacetamide

The authors report the cases of 2 patients who died from cirrhosis after receiving perhexiline maleate, a drug widely used in Europe for the treatment of angina pectoris. Perhexiline maleate had been ingested for 24 and 28 mo, respectively. Manifestations of cirrhosis included jaundice, hepatic encephalopathy, ascites, and portal hypertension. Associated manifestations of intolerance to perhexiline maleate included peripheral neuropathy in 1 patient and marked weight loss in both. Histologic lesions resembled those observed in patients with alcoholic liver disease. Ultrastructural lesions included numerous enlarged lysosomes containing myeloid figures. Histochemical stains demonstrated increased phospholipid content of the hepatocytes. These findings are consistent with the view that prolonged administration of perhexiline maleate may induce both histologic lesions resembling those of alcoholic liver disease and ultrastructural and histochemical lesions resembling those of phospholipidosis.

Topics: Aged; Angina Pectoris; Chemical and Drug Induced Liver Injury; Cytoplasmic Granules; Female; Hepatic Encephalopathy; Humans; Inclusion Bodies; Liver; Liver Cirrhosis; Male; Middle Aged; Necrosis; Perhexiline; Piperidines

Topics: Adult; Aged; Female; Hepatic Encephalopathy; Hepatitis; Humans; Male; Middle Aged; Piperidines; Tosyl Compounds

Topics: Aged; Amides; Ammonia; Aspartic Acid; Chlorothiazide; Clopamide; Depression, Chemical; Diuretics; Female; Furosemide; Hepatic Encephalopathy; Humans; Liver Cirrhosis; Liver Diseases; Magnesium; Male; Middle Aged; Piperidines; Potassium; Pulmonary Heart Disease; Stimulation, Chemical