Amino Acid Changes in Autopsied Brain Tissue from Cirrhotic Patients with Hepatic Encephalopathy

Abstract

Brain tissue was obtained at autopsy from nine cirrhotic patients dying in hepatic coma and from an equal number of controls, free from neurological, psychiatric, or hepatic diseases, matched for age and time interval from death to freezing of dissected brain samples. Glutamine, glutamate, aspartate, and gamma-aminobutyric acid (GABA) levels were measured in homogenates of cerebral cortex (prefrontal and frontal), caudate nuclei, hypothalamus, cerebellum (cortex and vermis), and medulla oblongata as their o-phthalaldehyde derivatives by HPLC using fluorescence detection. Glutamine concentrations were found to be elevated two- to fourfold in all brain structures, the largest increases being observed in prefrontal cortex and medulla oblongata. Glutamate levels were selectively decreased in prefrontal cortex (by 20%), caudate nuclei (by 27%), and cerebellar vermis (by 17%) from cirrhotic patients. On the other hand, GABA content of autopsied brain tissue from these patients was found to be within normal limits in all brain structures. It is suggested that such region-selective reductions of glutamate may reflect loss of the amino acid from the releasable (neurotransmitter) pool. These findings may be of significance in the pathogenesis of hepatic encephalopathy resulting from chronic liver disease.

Brain metabolism of13N-ammonia during acute hepatic encephalopathy in cirrhosis measured by positron emission tomography

“…Hence, further analyses were performed for 3 combined VOIs: cortex, basal ganglia, and cerebellum. The VOIs were subsequently placed on images of the mean radioactivity concentrations of the second 13 N-ammonia scan and of the 15 O-water scans. Finally, the VOIs were transferred to the respective dynamic images, and time courses of tissue radioactivity concentrations were extracted (Fig.…”

“…Before scanning, a short catheter (Artflon, Becton Dickinson, Swindon, UK) was placed percutaneously in a radial artery under local anesthesia. During the 15 O-water scans, arterial blood was sampled by an automated blood sampling system 28 cross-calibrated with the tomograph. Radioactivity concentrations were measured every 0.5 seconds and corrected for external delay and dispersion in the sampling catheter and for radioactive decay to start of the scan.…”

“…Dynamic 13 N-ammonia PET in conjunction with individual measurements of blood contents of 13 N-ammonia and 13 Nmetabolites were employed for optimal kinetic modeling of the ammonia metabolism. In addition, regional cerebral blood flow was measured by dynamic 15 O-water scans to obtain parameters of regional cerebral ammonia kinetics based on individual estimates of cerebral 13 Nammonia clearances and cerebral blood flow.…”

“…[1][2][3][4] The effects of experimental porta-caval anastomosis with or without pharmacological manipulations of ammonia metabolism have been examined in rat brain, [5][6][7][8][9][10][11][12][13] and the effects of excess ammonia have been tested in astrocyte cell cultures. 14 Human studies of cerebral uptake and metabolism of ammonia included postmortem examinations of brain tissue from patients dying of HE 15 and biochemical analysis of jugular vein blood samples. [16][17][18] More recently, ammonia metabolism has been tested in positron emission tomography (PET) studies of monkeys, 19 healthy humans, [19][20][21][22] and patients with cirrhosis and minimal HE.…”

Brain Alanine Formation as an Ammonia-Scavenging Pathway during Hyperammonemia: Effects of Glutamine Synthetase Inhibition in Rats and Astrocyte—Neuron Co-Cultures

“…1,2 In the brain, the predominant route for ammonia metabolism is by glutamine synthesis via the enzyme glutamine synthetase (GS), which is exclusively located in the astrocytes. 3 Consequently, during acute hyperammonemic conditions, brain glutamine levels are increased in HE patients, [4][5][6] which has been suggested as the principal cause leading to astrocyte swelling and cerebral edema. [7][8][9] In vivo studies have shown that administration of methionine sulfoximine (MSO), which specifically inhibits GS, ameliorates astrocyte swelling and brain edema observed during acute hyperammonemia.…”