Alterations in Cortical [³H]Kainate and α‐[³H]Amino‐3‐Hydroxy‐5‐Methyl‐4‐Isoxazolepropionic Acid Binding in a Spontaneous Canine Model of Chronic Hepatic Encephalopathy

Abstract

Excitatory amino acid receptor binding parameters were investigated in a spontaneous dog model of chronic hepatic encephalopathy. L-[3H]Glutamate, (+)-[3H]-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-im ine maleate ([3H]MK-801), [3H]kainate, and alpha-[3H]-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid ([3H]AMPA) binding experiments were performed using crude cerebrocortical synaptosomal membrane preparations from dogs with congenital portosystemic encephalopathy (PSE) and control dogs. There was no change in the affinity or density of L-[3H]-glutamate or [3H]MK-801 binding sites in dogs with congenital PSE compared with control dogs. However, in the PSE dogs there was a significant reduction in the density of [3H]kainate binding sites compared with control dogs and abolition of the low-affinity [3H]AMPA binding site. The relative binding capacity of PSE synaptosomal membranes for [3H]kainate and [3H]AMPA was expressed as the ratio Bmax/KD. There was a significant inverse correlation between the Bmax/KD ratio for [3H]AMPA binding and the worst grade of encephalopathy experienced by each dog. These results suggest that there is a significant perturbation of cerebrocortical non-N-methyl-D-aspartate receptor binding in dogs with congenital PSE which may have relevance to the pathogenesis of hepatic encephalopathy.

Binding of the ligand [3H]MK-801 to the MK-801 binding site of the N-methyl-D-aspartate receptor during experimental encephalopathy from acute liver failure and from acute hyperammonemia in the rabbit

“…Thus, during experimental hepatic encephalopathy from acute liver failure there may be a selective loss of kainate receptors (Ferenci et al, 1984a), with a preservation of NMDA receptors (present study). Chronic hepatic encephalopathy appears to be associated with variable changes of the glutamate receptor populations (Peterson et al, 1990;Maddison et al, 1991). Conflicting results have also been found during hyperammonemia (Ferenci et al, 1984a;Rao et al, 1991;and present study).…”

“…However, in acute liver failure from hepatectomy and tetrachloride in the rat (Watanabe et al, 1988), thioacetamide in the rat (Zimmermann et al, 1989) and ischemic liver necrosis in the rabbit (present study) no changes were found, although in the latter we cannot exclude changes of the kainate and AMPA receptors. In rats with chronic hepatic encephalopathy glutamate binding to the NMDA receptor was diminished (Peterson et al, 1990); in dogs with chronic hepatic encephalopathy NMDA receptor binding appeared normal whereas changes occurred in the kainate and AMPA receptors (Maddison et al, 1991). No changes in glutamate receptors were found in models of acute hyperammonemia in rabbits (Ferenci et al, 1984a, present study).…”

Animal models of fulminant hepatic failure: A critical evaluation

“…Many different hepatotoxins, such as carbon tetrachloride, 20,21 thioacetamide, 22,23 nitrosamines, 24 halogenated anesthetics, 25,26 and murine hepatitis, 27,28 have been described in the literature. This review discusses two of the more widely used hepatotoxins, galactosamine [29][30][31][32][33][34][35][36] and acetaminophen.…”

Maturational Changes in the Subunit Composition of AMPA Receptors and the Functional Consequences of Their Activation in Chicken Forebrain

“…[ 3 H]AMPA (NEN-Dupont, 46.1 Ci/mmol) binding assay was performed by means of a filtration assay essentially as described by Maddison et al [1991] using 50 g P2 fraction protein. Nonspecific binding was defined as the amount of radioactivity bound in the presence of 100 M unlabelled AMPA.…”