dizocilpine-maleate and Hepatic-Encephalopathy

There is increasing evidence that glutamatergic neurotransmission is perturbed in hepatic encephalopathy (HE). Studies of the glutamate receptor system suggest that glutamate receptor density is reduced in different animal models of HE. Glutamate release and/or uptake is also believed to be altered in the disorder resulting in increased glutamate concentrations in the synaptic cleft. The relevance of these findings to the pathogenesis of HE remains to be clarified.

Topics: alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Brain; Dizocilpine Maleate; Dogs; Glutamic Acid; Hepatic Encephalopathy; Humans; In Vitro Techniques; Rats; Receptors, Glutamate; Synaptic Transmission

Topics: Ammonia; Animals; Brain; Dizocilpine Maleate; Hepatic Encephalopathy; Humans; Microtubule-Associated Proteins; Microtubules; Receptors, N-Methyl-D-Aspartate

Hepatic encephalopathy (HE), a neuropsychiatric disorder developing in patients with severe hepatic dysfunction, has been known for more than a century. However, pathogenetic mechanisms of cerebral dysfunction associated with liver disease are still poorly understood. There is a consensus that the primary cause of HE is accumulation of ammonia in the brain as a result of impaired liver detoxification capacity or the portosystemic shunt. Current evidence suggests that ammonia toxicity is mediated by hyperactivation of glutamate receptors, mainly N-methyl-D-aspartate receptors (NMDARs), and affects brain aerobic metabolism, which provides energy for multiple specific functions and neuronal viability. Recent reports on the presence of functional NMDARs in erythrocytes and the data on the deviations of blood parameters from their normal ranges indicate impaired hemodynamics and reduced oxygen-carrying capacity of erythrocytes in most patients with HE, thus suggesting a relationship between erythrocyte damage and cerebral dysfunction. In order to understand how hyperammonemia (HA)-induced disturbances in the energy metabolism in the brain (which needs a constant supply of large amounts of oxygen in the blood) lead to encephalopathy, it is necessary to reveal ammonia-induced impairments in the energy metabolism and antioxidant defense system of erythrocytes and to explore a potential role of ammonia in reduced brain oxygenation. To identify the said missing link, the activities of antioxidant enzymes and concentrations of reduced glutathione (GSH), oxidized glutathione (GSSG), and H2O2 were measured in the erythrocytes of rats with HA that were injected with the noncompetitive NMDAR antagonist MK-801. We found that in rats with HA, ammonia was accumulated in erythrocytes (cells lacking ammonia removal enzymes), which made them more susceptible to the prooxidant environment created during oxidative stress. This effect was completely or partially inhibited by MK-801. The data obtained might help to identify the risk factors in cognitive disorders and facilitate prediction of unfavorable outcomes of hypoperfusion in patients with a blood elevated ammonia concentration.

Topics: Ammonia; Animals; Antioxidants; Dizocilpine Maleate; Erythrocytes; Hepatic Encephalopathy; Humans; Hydrogen Peroxide; Oxygen; Rats; Receptors, N-Methyl-D-Aspartate

Treatment of patients with acute liver failure (ALF) is unsatisfactory and mortality remains unacceptably high. Blocking NMDA receptors delays or prevents death of rats with ALF. The underlying mechanisms remain unclear. Clarifying these mechanisms will help to design more efficient treatments to increase patient's survival. The aim of this work was to shed light on the mechanisms by which blocking NMDA receptors delays rat's death in ALF. ALF was induced by galactosamine injection. NMDA receptors were blocked by continuous MK-801 administration. Edema and cerebral blood flow were assessed by magnetic resonance. The time course of ammonia levels in brain, muscle, blood, and urine; of glutamine, lactate, and water content in brain; of glomerular filtration rate and kidney damage; and of hepatic encephalopathy (HE) and intracranial pressure was assessed. ALF reduces kidney glomerular filtration rate (GFR) as reflected by reduced inulin clearance. GFR reduction is due to both reduced renal perfusion and kidney tubular damage as reflected by increased Kim-1 in urine and histological analysis. Blocking NMDA receptors delays kidney damage, allowing transient increased GFR and ammonia elimination which delays hyperammonemia and associated changes in brain. Blocking NMDA receptors does not prevent cerebral edema or blood-brain barrier permeability but reduces or prevents changes in cerebral blood flow and brain lactate. The data show that dual protective effects of MK-801 in kidney and brain delay cerebral alterations, HE, intracranial pressure increase and death. NMDA receptors antagonists may increase survival of patients with ALF by providing additional time for liver transplantation or regeneration.

Topics: Animals; Blood-Brain Barrier; Body Temperature; Brain; Brain Edema; Cerebrovascular Circulation; Disease Progression; Dizocilpine Maleate; Drug Evaluation, Preclinical; Excitatory Amino Acid Antagonists; Galactosamine; Glomerular Filtration Rate; Hepatic Encephalopathy; Hyperammonemia; Intracranial Hypertension; Inulin; Kidney; Lactates; Liver Failure; Liver Regeneration; Male; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Time Factors

Developing procedures to delay the mechanisms of acute liver failure-induced death would increase patients' survival by allowing time for liver regeneration or to receive a liver for transplantation. Hyperammonemia is a main contributor to brain herniation and mortality in acute liver failure (ALF). Acute ammonia intoxication in rats leads to N-methyl-D-aspartate (NMDA) receptor activation in brain. Blocking these receptors prevents ammonia-induced death. Ammonia-induced activation of NMDA receptors could contribute to ALF-induced death. If this were the case, blocking NMDA receptors could prevent or delay ALF-induced death. The aim of this work was to assess 1) whether ALF leads to NMDA receptors activation in brain in vivo and 2) whether blocking NMDA receptors prevents or delays ALF-induced death of rats. It is shown, by in vivo brain microdialysis, that galactosamine-induced ALF leads to NMDA receptors activation in brain. Blocking NMDA receptors by continuous administration of MK-801 or memantine through miniosmotic pumps affords significant protection against ALF-induced death, increasing the survival time approximately twofold. Also, when liver injury is not 100% lethal (1.5 g/kg galactosamine), blocking NMDA receptors increases the survival rate from 23 to 62%. This supports that blocking NMDA receptors could have therapeutic utility to improve survival of patients with ALF.

Topics: Ammonia; Animals; Brain; Disease Models, Animal; Disease Progression; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Galactosamine; Hepatic Encephalopathy; Hyperammonemia; Infusion Pumps, Implantable; Liver Failure, Acute; Male; Memantine; Microdialysis; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Severity of Illness Index; Time Factors

The effects of depolarizing stimuli; high (50 mM) potassium ions and the glutamate receptor agonists N-methyl-D-aspartate, kainate and 2-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) on the release of newly-loaded [3H]dopamine were studied in frontal cortical and striatal slices from control rats and from rats with acute hepatic encephalopathy induced with a hepatotoxin, thioacetamide. Hepatic encephalopathy enhanced the stimulatory effect of potassium ions by 20% in striatal slices and by 34% in frontal cortical slices. In striatal slices the stimulatory effects of N-methyl-D-aspartate and kainate were depressed in hepatic encephalopathy by 46% and 21%, respectively, which may be taken to reflect impaired modulation of striatal dopamine release by glutamate acting at N-methyl-D-aspartate or kainate receptors. In frontal cortical slices, the stimulatory effect of kainate was enhanced by 35% in hepatic encephalopathy but N-methyl-D-aspartate-stimulated release was not affected. The release evoked by 2-amino-3-hydroxy-5-methyl-4-isoxazolepropionate was not affected in hepatic encephalopathy in either brain region. Stimulation of dopamine release in the frontal cortex by depolarization or glutamate acting at kainate receptors could inhibit the activity of descending corticostriatal glutamatergic pathways, further impairing regulation of dopamine release by glutamate in the striatum.

Topics: alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Cerebral Cortex; Corpus Striatum; Dizocilpine Maleate; Dopamine; Excitatory Amino Acid Agonists; Hepatic Encephalopathy; Kainic Acid; Male; N-Methylaspartate; Potassium; Rats; Rats, Wistar; Receptors, Glutamate; Thioacetamide; Tritium

There is increasing evidence that alterations of glutamatergic function are implicated in the pathogenesis of central nervous system consequences of acute liver failure. The aim of the study was to assess the integrity of glutamate receptors in the brain in experimental ischemic liver failure using quantitative receptor autoradiography and the selective ligands [3H]MK801 (for N-methyl-D-aspartate [NMDA] sites), [3H]5-fluorowillardiine (for non-NMDA, alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid [AMPA] subclass sites), and [3H]kainate (for non-NMDA, kainate subclass sites). At coma stages of encephalopathy, a selective loss of up to 60% of binding sites for the kainate- and AMPA-receptor ligands was observed in cerebral cortical and hippocampal structures as well as in the hypothalamus and cerebellum. The finding of a selective loss of AMPA sites at coma stages of encephalopathy in this model of acute liver failure is consistent with previous electrophysiological reports of inhibition of AMPA-mediated neuronal depolarization resulting from exposure of hippocampal neurons to millimolar concentrations of ammonia. On the other hand, the present study showed that binding sites for the NMDA-receptor ligand [3H]MK801 at coma stages of encephalopathy in acute liver failure were within normal limits in all brain structures examined. NMDA sites are uniquely neuronal, whereas kainate and AMPA sites are localized on both neurons and astrocytes. Therefore, the selective loss of non-NMDA sites in acute liver failure may also reflect astrocytic changes in this condition. Because astrocytic glutamate receptors are implicated in K+ and neurotransmitter reuptake, alterations in their density could result in altered neuronal excitability and thus be responsible for the neurological dysfunction characteristic of hepatic encephalopathy in acute liver failure.

Topics: Alanine; Animals; Binding Sites; Brain; Cerebellum; Cerebral Cortex; Dizocilpine Maleate; Hepatic Encephalopathy; Hippocampus; Kainic Acid; Male; Pyrimidines; Rats; Rats, Sprague-Dawley

Binding of the ligand [3H]MK-801 to the MK-801 binding site of the N-methyl-D-aspartate (NMDA) receptor population on brain homogenates in rabbits was studied during experimental encephalopathy from acute liver failure and from acute hyperammonemia in the rabbit. Homogenates were prepared from brain cortex, hippocampus and striatum. Hepatic encephalopathy was induced by a two-stage liver devascularization procedure and acute hyperammonemia by a prolonged ammonium-acetate infusion; rabbits receiving a sodium-potassium-acetate infusion served as controls. In these animal models extracellular brain glutamate levels are known to be elevated. However no significant alterations in the number nor the affinity of the MK-801 binding sites of the NMDA receptors were found during acute liver failure and acute hyperammonemia. These findings suggest that the NMDA receptor population remains unaltered in experimental encephalopathy from acute liver failure and acute hyperammonemia, despite alterations in extracellular brain glutamate levels.

Topics: Acute Disease; Ammonia; Animals; Binding Sites; Dizocilpine Maleate; Hepatic Encephalopathy; Liver Failure; Rabbits; Receptors, N-Methyl-D-Aspartate

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.

Topics: alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Cerebral Cortex; Chronic Disease; Dizocilpine Maleate; Dogs; Glutamates; Glutamic Acid; Hepatic Encephalopathy; Ibotenic Acid; Kainic Acid; Ligands; Tritium