Synaptosomal glutamate transport in thioacetamide-induced hepatic encephalopathy in the rat.
Dysfunction of excitatory glutamatergic neurotransmission has been implicated in the cause of hepatic encephalopathy. Brain microdialysis studies in various animal models of portal systemic encephalopathy (PSE) and encephalopathy associated with acute liver failure, have established that an increase in extracellular glutamate occurs but the mechanisms of this are unclear. We have measured oxygen consumption, citrate synthase activity (as indices of energy state and mitochondrial content, respectively), calcium-dependent glutamate release, and high-affinity, sodium-dependent glutamate uptake by synaptosomes prepared from rats with thioacetamide-induced encephalopathy. (2 doses of thioacetamide 200 mg/kg with a 24-hour interval). Synaptosomes were prepared either by a modified P2 method (glutamate release study) or by discontinuous sucrose density gradient centrifugation (all other studies). There was no significant difference in synaptosomal oxygen consumption, citrate synthase activity, glutamate release, total synaptosomal glutamate content, or the Kd for glutamate uptake between the encephalopathy group and the controls. However, there was a marked decrease in the maximal velocity of transport (Vmax) for glutamate uptake in synaptosomes from encephalopathic rats, 2.64 versus 4.40 nmol/min/mg (P < .05). The results of this study provide evidence of impaired glutamate uptake in the rat thioacetamide model of hepatic encephalopathy, which could account for the elevated extracellular glutamate seen in the condition.
Oppong
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Department of Medicine, Medical School, University of Newcastle upon Tyne, United Kingdom.
Bartlett
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Record
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al Mardini
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D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D001921:Brain / Q000648:ultrastructure; D002118:Calcium / Q000494:pharmacology; D002950:Citrate (si)-Synthase / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D006501:Hepatic Encephalopathy / Q000139:chemically induced / Q000378:metabolism*; D008297:Male; D010101:Oxygen Consumption; D051381:Rats; D017207:Rats, Sprague-Dawley; D012964:Sodium / Q000494:pharmacology; D013574:Synaptosomes / Q000378:metabolism*; D013853:Thioacetamide
D013853:Thioacetamide; D018698:Glutamic Acid; D012964:Sodium; D002950:Citrate (si)-Synthase; D002118:Calcium