Increased densities of peripheral-type benzodiazepine receptors in brain autopsy samples from cirrhotic patients with hepatic encephalopathy

Abstract

Peripheral-type benzodiazepine receptors were evaluated using the specific ligand [3H]-PK 11195 in brain homogenates from nine cirrhotic patients who died in hepatic coma and from an equal number of age-matched control subjects. Histopathological studies showed evidence of severe Alzheimer type II astrocytosis in the brains of all cirrhotic patients. Saturation-binding assays revealed a single saturable binding site for [3H]-PK 11195 in brain, with affinities in the 2- to 3-nmol/L range. Diazepam was found to be a relatively potent inhibitor of 3H-PK 11195 binding (IC50 = 253 nmol/L), whereas the central benzodiazepine antagonist Ro 15-1788 displaced 3H-PK 11195 binding with low affinity (IC50 greater than 40 mumols/L). Densities of [3H]-PK 11195 binding sites were found to be increased by 48% (p less than 0.01) and 25% (p less than 0.05) in frontal cortex and caudate nuclei, respectively, from cirrhotic patients. Densities of [3H]-PK 11195 binding sites in frontal cortex from two nonencephalopathic cirrhotic patients were not significantly different from control values. No concomitant changes of affinities of these binding sites were observed. Because it has been suggested that peripheral-type benzodiazepine receptors may be localized on mitochondrial membranes and may therefore be involved in cerebral oxidative metabolism, the alterations observed in this study could be of pathophysiological significance in hepatic encephalopathy.

Portal-Systemic Encephalopathy: A Disorder of Neuron-Astrocytic Metabolic Trafficking

“…Rather they appear to be localized in high con centration on outer mitochondrial membranes, particu larly of astrocytes where, it has been suggested, they serve as mediators of intermediary metabolism [17], There is a growing body of evidence to suggest that PT BRs and their endogenous ligands may mediate the astro cytic response to ammonia in PSE. Increased densities of the PTBR ligand 3H-PK11195 have been described in autopsied frontal cortex and caudate nucleus of cirrhotic patients who died in hepatic coma [18]. Significant re gion-selective increases of 3H -PK 11195 binding sites are also encountered in the brains of rats 4 weeks after porta caval anastomosis ( fig.…”

Low grade cerebral edema and the pathogenesis of hepatic encephalopathy in cirrhosis

“…27 Such neurosteroids have a positive GABA Areceptor modulatory activity and were identified in the brain from patients with hepatic coma. 28 This could provide an explanation for the increased GABAergic tone found in patients with HE. Although PTN interferes with protein function and signal transduction, its role in the pathogenesis of hepatic encephalopathy is unclear.…”

Management of Hepatic Encephalopathy: Role of Rifaximin

“…Ammonia toxicity does not only seem to be related to an altered brain metabolism, but more specifically to its ability to damage astrocytic cells by a glutamate-related neurotoxicity [7][8][9], which in turn may alter the entire Á-aminobutyric acid A (GABA-A) receptor system [10]. Moreover, ammonia has been shown to induce an increased production of neurosteroids that exert a positive modulatory effect on the GABA-A receptors [11] and this phenomenon has been ascribed to the upregulation of peripheral benzodiazepine receptors present in HE [12,13]. These complex metabolic cerebral events, which affect both astrocytes and neurons, result in an imbalance in the functional activity of excitatory and inhibitory receptor systems leading to a prevalence of the latter thanks to an increased tone of the GABA-A receptor system [14,15].…”