Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0085584 (encephalopathy)
 18,178 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

There is increasing evidence to suggest that hepatic encephalopathy in acute liver failure is the result of altered glutamatergic function. In particular, the high affinity uptake of glutamate is decreased in brain slices and synaptosomes from rats with acute liver failure as well as by exposure of cultured astrocytes to concentrations of ammonia equivalent to those reported in brain in acute liver failure. Both protein and gene expression of the recently cloned and sequenced astrocytic glutamate transporter GLT-1 are significantly reduced in the brains of rats with acute liver failure. Decreased expression of GLT-1 in brain in acute liver failure results in increased extracellular brain glutamate concentrations which correlates with arterial ammonia concentrations and with the appearance of severe encephalopathy and brain edema in these animals. Ammonia-induced reductions in expression of GLT-1 resulting in increased extracellular glutamate concentrations could explain some of the symptoms (hyperexcitability, cerebral edema) characteristic of hepatic encephalopathy in acute liver failure.
 ...
PMID:Evidence for an astrocytic glutamate transporter deficit in hepatic encephalopathy. 1055 80

Glutamate transporters have the important function of removing glutamate released from synapses and keeping extracellular glutamate concentrations below excitotoxic levels. Extracellular glutamate increases in portocaval anastomosis (PCA), so we used a portacaval anastomosis model in rats to analyze the expression of glutamate transporters (GLAST, GLT-1 and EAAC1) in rat cerebellum, 1 and 6 months after PCA, using immunohistochemical methods. In controls, EAAC1 immunoreactivity in Purkinje cells and glial GLAST and GLT-1 immunoreactivities in the molecular layer (ML) increased from young to old rats. One month after PCA, Purkinje cell bodies were not immunostained for neuronal EAAC1 glutamate transporter, whereas glial glutamate transporter expressions (GLAST and GLT-1) were decreased when compared to young controls. In rats with long-term PCA (6 months post-PCA), neuronal and glial glutamate transporter expressions were increased. The expression of the neuronal glutamate transporter EAAC1 was less intense than old controls, whereas glial glutamate transporters (GLAST and GLT-1) increased more than their controls. Since the level of the neuronal glutamate transporter (EAAC1) in long-term PCA did not reach that of the controls, GLAST and GLT-1 glutamate transporters seemed to be required to ensure the glutamate uptake in this type of encephalopathy. EAAC1 immunoreactivity also was expressed by Bergmann glial processes in long-term PCA, but this increase did not suffice to reverse the alterations caused at the early stage. The present findings provide evidence that transitory alteration of glutamate transporter expressions could be a significant factor in the accumulation of excess glutamate in the extracellular space in PCA, which probably makes Purkinje cells more vulnerable to glutamate effect.
 ...
PMID:Modulation of glutamate transporters (GLAST, GLT-1 and EAAC1) in the rat cerebellum following portocaval anastomosis. 1071 77

Hepatic Encephalopathy (HE) is a serious neuropsychiatric condition of both acute and chronic liver failure. Acute liver failure is characterized by rapid evolution of HE and by brain edema. Portal-Systemic encephalopathy (PSE) is particularly prevalent following treatment of portal hypertension or ascites by the TIPS procedure. Available evidence currently suggests that neurotransmission changes rather than brain energy failure are the primary cause of HE. Recent studies both in autopsied brain tissue from HE patients as well as in experimental animal models of HE reveal that liver failure results in altered expression of several genes coding for proteins having key roles in the control of neuronal excitability. Such alterations include decreased expression of the glutamate transporter GLT-1, and increased expression of monoamine oxidase (MAO-A isoform), the "peripheral-type" benzodiazepine receptor (PTBR) as well as constitutive neuronal nitric oxide synthase (nNOS). Such changes result in altered protein expression and in increased extracellular brain glutamate, increased degradation of monoamine neurotransmitters, increased synthesis of neurosteroids with inhibitory properties, and increased production of nitric oxide (respectively) in brain in chronic liver failure. In the case of GLT-1, PTBR, and nNOS, alterations in expression result from exposure to ammonia and/or manganese, two neurotoxic agents shown previously to be increased in brain in liver failure.
 ...
PMID:Neurotransmitter dysfunction in hepatic encephalopathy: new approaches and new findings. 1172 89

Glutamate transporters are essential for maintaining the extracellular levels of glutamate at synaptic clefts and are regulated developmentally in a subtype-specific manner. We investigated chronological changes of immunoreactivities for glial glutamate transporters GLAST and GLT-1 and a neuronal glutamate transporter, EAAC1, in postnatal 7-day-old rat neocortices and hippocampi at 12, 24, 48 and 72 h after hypoxia-ischemia. Glutamate transporter subtypes are differentially expressed in the ischemic core and the boundary area of the neonatal rat brain with hypoxia-ischemia. Expressions of these glutamate transporters decreased in the ischemic core at 12 h, then immunoreactivities for GLAST and GLT-1 were recovered at the hippocampus. This was accompanied by a GFAP-positive gliosis at 72 h, whereas these immunoreactivities were reduced at the neocortex in the ischemic core. Glial glutamate transporters, especially GLAST, were noted in some astrocytes appearing as apoptosis as well as shrunken pyramidal neurons mainly in the boundary area of the neocortex. Increased perikaryal expression of EAAC1 was associated with that of MAP2 at the border of the boundary area. These temporal and regional expressions of glutamate transporters may contribute towards understanding the excitotoxic cell death mechanism in hypoxic-ischemic encephalopathy during the perinatal period.
 ...
PMID:Altered expressions of glutamate transporter subtypes in rat model of neonatal cerebral hypoxia-ischemia. 1174 17

Cerebral edema and hepatic encephalopathy are major complications of acute liver failure. Brain herniation caused by increased intracranial pressure as a result of cell swelling is the major cause of death in this condition. Evidence available currently suggests that the rapid accumulation of ammonia by the brain is the major cause of the central nervous system complications of acute liver failure. Increased brain ammonia may cause cell swelling via the osmotic effects of an increase in astrocytic glutamine concentrations or by inhibition of glutamate removal from brain extracellular space. Acute liver failure results in altered expression of several genes in brain, some of which code for important proteins involved in CNS function such as the glucose (GLUT-1) and glutamate (GLT-1) transporters, the astrocytic structural protein glial fibrillary acidic protein (GFAP) the "peripheral-type" benzodiazepine receptor (PTBR) and the water channel protein, aquaporin IV. Loss of expression of GLT-1 results in increased extracellular brain glutamate in acute liver failure. Experimental acute liver failure also results in post-translational modifications of the serotonin and noradrenaline transporters resulting in increased extracellular concentrations of these monoamines. Therapeutic measures currently used to prevent and treat brain edema and encephalopathy in patients with acute liver failure include mild hypothermia and the ammonia-lowering agent L-ornithine-L-aspartate.
 ...
PMID:Alterations in expression of genes coding for key astrocytic proteins in acute liver failure. 1174 25

The major regulators of synaptic glutamate in the cerebral cortex are the excitatory amino acid transporters 1-3 (EAAT1-3). In this study, we determined the cellular and temporal expression of EAAT1-3 in the developing human cerebral cortex. We applied single- and double-label immunocytochemistry to normative frontal or parietal (associative) cortex samples from 14 cases ranging in age from 23 gestational weeks to 2.5 postnatal years. The most striking finding was the transient expression of EAAT2 in layer V pyramidal neuronal cell bodies up until 8 postnatal months prior to its expression in protoplasmic astrocytes at 41 postconceptional weeks onward. EAAT2 was also expressed in neurons in layer I (presumed Cajal-Retzius cells), and white matter (interstitial) neurons. This expression in neurons in the developing human cortex contrasts with findings by others of transient expression exclusively in axon tracts in the developing sheep and rodent brain. With western blotting, we found that EAAT2 was expressed as a single band until 2 postnatal months, after which it was expressed as two bands. The expression of EAAT2 in pyramidal neurons during human brain development may contribute to cortical vulnerability to excitotoxicity during the critical period for perinatal hypoxic-ischemic encephalopathy. In addition, by studying the expression of EAAT1 and EAAT2 glutamate transporters, it was possible to document the development of protoplasmic astrocytes.
 ...
PMID:Expression of EAAT2 in neurons and protoplasmic astrocytes during human cortical development. 2252 66