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Biomedical subjects

Roger F Butterworth

Publications and source records attributed to Roger F Butterworth.

At least 19 recordsLinked to original sources
PubMed2004

Selective alterations of brain osmolytes in acute liver failure: protective effect of mild hypothermia.

The principal cause of mortality in patients with acute liver failure (ALF) is brain herniation resulting from intracranial hypertension caused by a progressive increase of brain water. In the present study, ex vivo high-resolution 1H-NMR spectroscopy was used to investigate the effects of ALF, with or without superimposed hypothermia, on brain organic osmolyte concentrations in relation to the severity of encephalopathy and brain edema in rats with ALF due to hepatic devascularization. In normothermic ALF rats, glutamine concentrations in frontal cortex increased more than fourfold at precoma stages, i.e. prior to the onset of severe encephalopathy, but showed no further increase at coma stages. In parallel with glutamine accumulation, the brain organic osmolytes myo-inositol and taurine were significantly decreased in frontal cortex to 63% and 67% of control values, respectively, at precoma stages (p<0.01), and to 58% and 67%, respectively, at coma stages of encephalopathy (p<0.01). Hypothermia, which prevented brain edema and encephalopathy in ALF rats, significantly attenuated the depletion of myo-inositol and taurine. Brain glutamine concentrations, on the other hand, did not respond to hypothermia. These findings demonstrate that experimental ALF results in selective changes in brain organic osmolytes as a function of the degree of encephalopathy which are associated with brain edema, and provides a further rationale for the continued use of hypothermia in the management of this condition.

Animals↗
PubMed2004

Increased brain serotonin turnover correlates with the degree of shunting and hyperammonemia in rats following variable portal vein stenosis.

BACKGROUND/AIMS: Hepatic encephalopathy (HE) is a serious neuropsychiatric complication of chronic liver disease. Brain monoamines have been implicated in the pathogenesis of HE. We examined the relationship between monoamine dysfunction and the degree of portal-systemic shunting (PSS) in rats with varying degrees of PSS. METHODS: Concentrations of catecholamines, serotonin, histamine, precursors and metabolites in frontal cortex of rats with varying degrees of PSS (9-99.8%) were measured by HPLC. RESULTS: The concentrations of the serotonin precursor, tryptophan, and its metabolite, 5-HIAA were increased up to 4-fold in brains of rats with various degrees of PSS and were significantly correlated with the degree of shunting and with arterial ammonia levels. Brain levels of histamine, its precursor, l-histidine, and metabolite, tele-methylhistamine were significantly increased only following total shunting. Concentrations of catecholamines and their metabolites were not significantly correlated with degree of PSS or hyperammonemia. CONCLUSIONS: Given the established role of the serotonin system in the regulation of sleep, circadian rhythmicity and locomotion these findings suggest that selective alterations of this system could be implicated in the pathogenesis of HE. Therapeutic approaches aimed at the normalization of serotonin turnover could be beneficial in the prevention and treatment of early neuropsychiatric symptoms of HE.

Animals↗
PubMed2004

Increased brain endothelial nitric oxide synthase expression in thiamine deficiency: relationship to selective vulnerability.

Thiamine deficiency results in selective neuronal cell death in thalamic structures. Previous studies provide evidence for a role implicating nitric oxide (NO) in the pathogenesis of cell death due to thiamine deficiency. In order to ascertain the origin of increased NO in the thiamine deficient brain, expression of endothelial nitric oxide synthase isoform (eNOS), was measured in the medial thalamus and in the inferior colliculus and compared to the frontal cortex (a spared region) of rats in which thiamine deficiency was induced through a feeding protocol of thiamine-deficient diet concomitant with daily administration of pyrithiamine, a central thiamine antagonist. eNOS mRNA and protein expression were significantly increased as a function of the severity of neurological impairment and the degree of neuronal cell loss in the medial thalamus and in the inferior colliculus. These findings suggest that the vascular endothelium is a major site of NO production in the brain in thiamine deficiency and that eNOS-derived NO could account for the selective damage to the thalamic structures that are observed in this particular disorder.

Animals↗
PubMed2004

Manganese distribution in the brain and neurobehavioral changes following inhalation exposure of rats to three chemical forms of manganese.

The central nervous system is an important target for manganese (Mn) intoxication in humans; it may cause neurological symptoms similar to Parkinson's disease. Manganese compounds emitted from the tailpipe of vehicles using methylcyclopentadienyl manganese tricarbonyl (MMT) are primarily Mn phosphate, Mn sulfate, and Mn phosphate/sulfate mixture. The purpose of this study is to compare the patterns of Mn distribution in various brain regions (olfactory bulb, frontal parietal cortex, globus pallidus, striatum and cerebellum) and other tissues (lung, liver, kidney, testis) and the neurobehavioral damage following inhalation exposure of rats to three Mn species. Rats (n=15 rats per Mn species) were exposed 6 h per day, 5 days per week for 13 consecutive weeks to metallic Mn, Mn phosphate or Mn phosphate/sulfate mixture at about 3000 microgm(-3) and compared to controls. At the end of the exposure period, spontaneous motor activity was measured for 36 h using a computerized autotrack system. Mn in tissues was determined by instrumental neutron activation analysis (INAA). The Mn concentrations in the brain were significantly higher in rats exposed to Mn phosphate and Mn phosphate/sulfate mixture than in control rats or rats exposed to metallic Mn. Exposure to Mn phosphate/sulfate mixture caused a decrease in the total ambulatory count related to locomotor activity. Our results confirm that Mn species and solubility have an influence on the brain distribution of Mn in rats.

Animals↗
PubMed2003

Effects of hypothermia on brain glucose metabolism in acute liver failure: a H/C-nuclear magnetic resonance study.

BACKGROUND & AIMS: Mild hypothermia has a protective effect on brain edema and encephalopathy in both experimental and human acute liver failure. The goals of the present study were to examine the effects of mild hypothermia (35 degrees C) on brain metabolic pathways using combined (1)H and (13)C-Nuclear Magnetic Resonance (NMR) spectroscopy, a technique which allows the study not only of metabolite concentrations but also their de novo synthesis via cell-specific pathways in the brain. METHODS: (1)H and (13)C NMR spectroscopy using [1-(13)C] glucose was performed on extracts of frontal cortex obtained from groups of rats with acute liver failure induced by hepatic devascularization whose body temperature was maintained either at 37 degrees C (normothermic) or 35 degrees C (hypothermic), and appropriate sham-operated controls. RESULTS: At coma stages of encephalopathy in the normothermic acute liver failure animals, glutamine concentrations in frontal cortex increased 3.5-fold compared to sham-operated controls (P < 0.001). Comparable increases of brain glutamine were observed in hypothermic animals despite the absence of severe encephalopathy (coma). Brain glutamate and aspartate concentrations were respectively decreased to 60.9% +/- 7.7% and 42.2% +/- 5.9% (P < 0.01) in normothermic animals with acute liver failure compared to control and were restored to normal values by mild hypothermia. Concentrations of lactate and alanine in frontal cortex were increased to 169.2% +/- 15.6% and 267.3% +/- 34.0% (P < 0.01) respectively in normothermic rats compared to controls. Furthermore, de novo synthesis of lactate and alanine increased to 446.5% +/- 48.7% and 707.9% +/- 65.7% (P < 0.001), of control respectively, resulting in increased fractional (13)C-enrichments in these cytosolic metabolites. Again, these changes of lactate and alanine concentrations were prevented by mild hypothermia. CONCLUSIONS: Mild hypothermia (35 degrees C) prevents the encephalopathy and brain edema resulting from hepatic devascularization, selectively normalizes lactate and alanine synthesis from glucose, and prevents the impairment of oxidative metabolism associated with this model of ALF, but has no significant effect on brain glutamine. These findings suggest that a deficit in brain glucose metabolism rather than glutamine accumulation is the major cause of the cerebral complications of acute liver failure.

Alanine↗
PubMed2003

Increased concentrations of histamine and its metabolite, tele-methylhistamine and down-regulation of histamine H3 receptor sites in autopsied brain tissue from cirrhotic patients who died in hepatic coma.

BACKGROUND/AIMS: Hepatic encephalopathy (HE) is a serious neuropsychiatric complication of chronic liver disease. To determine whether changes in the central histaminergic system are a feature of human HE, we studied histamine, tele-methylhistamine, and presynaptic autoregulatory H(3) receptors in cerebral cortex and caudate-putamen obtained at autopsy from six cirrhotic patients and six appropriately matched controls. METHODS: Histamine was assayed by HPLC; tele-methylhistamine by GC-MS. H(3) receptors were studied by in vitro receptor binding using [3H]R-alpha-methylhistamine as ligand. RESULTS: In HE patients, there was a significant fourfold increase of histamine in caudate-putamen and a significant increase in all cortical regions studied. tele-Methyhistamine was also increased and the densities of histamine H(3) receptor sites were significantly decreased in patient material. CONCLUSIONS: These findings are consistent with activation of the histaminergic system in HE. Given that histamine participates in the regulation of arousal and circadian rhythmicity, they indicate that induction of central histamine mechanisms may contribute to the development of neuropsychiatric symptoms, such as sleep disturbances and altered circadian rhythms in chronic HE and suggest that pharmacological manipulation of the histaminergic system could be beneficial in the treatment of HE in chronic liver failure.

Adult↗
PubMed2003

Induction of astrocytic cyclooxygenase-2 in epileptic patients with hippocampal sclerosis.

Induction of cyclooxygenase-2 (COX-2) has been described in a wide range of neurological diseases including animal models of epilepsy. The present study was undertaken to assess COX-2 expression in hippocampal biopsies from patients with therapy-refractive temporal lobe epilepsy (TLE). For this purpose, hippocampal CA1 subfield was dissected from epileptic patients with (n=5) or without (n=2) hippocampal sclerosis (HS). COX-2 expression was investigated using immunohistochemistry and semi-quantitative RT-PCR. COX-2 immunoreactivity in TLE patient material in the absence of HS was restricted to a few neurons of the hippocampus. In the presence of HS, on the other hand, a significant induction of astrocytic COX-2 immunoreactivity associated with a concomitant increase in the steady-state level of COX-2 mRNA was observed in the CA1 subfield. These findings suggest that induction of astrocytic COX-2 is implicated in the pathogenesis of HS in TLE and is consistent with the previous findings of increased concentrations of prostaglandins in the cerebrospinal fluid of these patients.

Adolescent↗
PubMed2003

Effects of ammonia on high affinity glutamate uptake and glutamate transporter EAAT3 expression in cultured rat cerebellar granule cells.

Increased levels of extracellular glutamate are a consistent feature of hepatic encephalopathy (HE) associated with liver failure and other hyperammonemic pathologies. Reduction of glutamate uptake has been described in ammonia-exposed cultured astrocytes, synaptosomes, and in animal models of hyperammonemia. In the present study, we examine the effects of pathophysiological concentrations of ammonia on D-aspartate (a non-metabolizable analog of glutamate) uptake by cultured rat cerebellar granule neurons. Exposure of these cells to ammonia resulted in time-dependent (24% reduction at 24h and 60% reduction at 5 days, P<0.001) and dose-dependent (21, 37, and 57% reduction at 1, 2.5, and 5mM for 5 days, P<0.01) suppression of D-aspartate uptake. Kinetic analyses revealed significant decreases in the velocity of uptake (V(max)) (37% decrease at 2.5mM NH(4)Cl, P<0.05 and 52% decrease at 5mM NH(4)Cl, P<0.001) as well as significant reductions in K(m) values (25% reduction at 2.5mM NH(4)Cl, P<0.05 and 45% reduction at 5mM NH(4)Cl, P<0.001). Western blotting, on the other hand, showed no significant changes in the neuronal glutamate transporter EAAC1/EAAT3 protein, the only glutamate transporter currently known to be expressed by these cells. In addition, 1H combined with 13C-NMR spectroscopy studies using the stable isotope [1-13C]-glucose demonstrated a significant increase in intracellular glutamate levels derived from the oxidative metabolism of glucose, rather than from the deamidation of exogenous glutamine in cultured granule neurons exposed to ammonia. The present study provides evidence that the effects of ammonia on glutamate uptake are not solely an astrocytic phenomenon and that unlike the astrocytic glutamate transporter counterpart, EAAT3 protein expression in cultured cerebellar granule cells is not down-regulated when exposed to ammonia. Decrease of glutamate uptake in these cellular preparations may afford an additional regulatory mechanism aimed at controlling intracellular levels of glutamate and ultimately the releasable pool of glutamate in neurons.

Amino Acid Transport System X-AG↗
PubMed2003

Normal coupling of brain benzodiazepine and neurosteroid modulatory sites on the GABA-A receptor complex in human hepatic encephalopathy.

To assess the possible implication of the allosteric coupling of different modulatory sites at the GABA-A receptor complex in hepatic encephalopathy (HE), we investigated in autopsied frontal cortex of six cirrhotic patients and six appropriately-matched controls, the modulatory effects of the benzodiazepine site agonist flunitrazepam on the binding of [3H]muscimol and the effect of the neurosteroid site agonist allopregnanolone (5alpha-pregnan-3alpha-ol-20-one) on the binding of [3H]muscimol and [3H]flunitrazepam. There were no significant differences in either the magnitude E(max): 11.5+/-1.1% (controls) versus 10.2+/-2.2% (HE patients) or the efficacy EC(50): 20.2+/-5.5 nM (controls) versus 17.7+/-6.2 nM (HE patients) of flunitrazepam modulation of [3H]muscimol binding. Allopregnanolone also showed modulation of both sites to a comparable extent in brain tissue from cirrhotic patients and controls E(max): [3H]muscimol, 15.1+/-2.8% (controls) versus 13.8+/-1.9% (HE patients); [3H]flunitrazepam, 17.9+/-2.3% (controls) versus 19.1+/-2.3% (HE patients), EC(50): [3H]muscimol, 386.5+/-25.8 nM (controls) versus 373.8+/-13.1 nM (HE patients); [3H]flunitrazepam, 49.8+/-22.9 nM (controls) versus 55.5+/-14.0 nM (HE patients). These findings demonstrate unequivocally that the GABA-A sites and their benzodiazepine and neurosteroid modulatory sites manifest normal allosteric coupling in brain in human HE. Therefore, if increased "GABAergic tone" is implicated in the pathophysiology of HE, this must be the consequence of increased brain concentrations of endogenous benzodiazepine and/or neurosteroid ligands for components of the GABA-A receptor complex rather than alterations of the receptor proteins themselves.

Adult↗
PubMed2003

Role of circulating neurotoxins in the pathogenesis of hepatic encephalopathy: potential for improvement following their removal by liver assist devices.

Both acute and chronic liver failure result in impaired cerebral function known as hepatic encephalopathy (HE). Evidence suggests that HE is the consequence of the accumulation in brain of neurotoxic and/or neuroactive substance including ammonia, manganese, aromatic amino acids, mercaptans, phenols, short-chain fatty acids, bilirubin and a variety of neuroactive medications prescribed as sedatives to patients with liver failure. Brain ammonia concentrations may attain levels in excess of 2 mm, concentrations which are known to adversely affect both excitatory and inhibitory neurotransmission as well as brain energy metabolism. Manganese exerts toxic effects on dopaminergic neurones. Prevention and treatment of HE continues to rely heavily on the reduction of circulating ammonia either by reduction of gut production using lactulose or antibiotics or by increasing its metabolism using L-ornithine-L-aspartate. No specific therapies have so far been designed to reduce circulating concentrations of other toxins. Liver assist devices offer a potential new approach to the reduction of circulating neurotoxins generated in liver failure. In this regard, the Molecular Adsorbents Recirculating System (MARS) appears to offer distinct advantages over hepatocyte-based systems.

Hepatic Encephalopathy↗
PubMed2003

Selective increase of brain lactate synthesis in experimental acute liver failure: results of a [H-C] nuclear magnetic resonance study.

Acute liver failure (ALF) results in alterations of energy metabolites and of glucose-derived amino acid neurotransmitters in brain. However, the dynamics of changes in glucose metabolism remain unclear. The present study was undertaken using (1)H and (13)C nuclear magnetic resonance (NMR) spectroscopy to determine the rates of incorporation of glucose into amino acids and lactate via cell-specific pathways in relation to the severity of encephalopathy and brain edema in rats with ALF because of hepatic devascularization. Early (precoma) stages of encephalopathy were accompanied by significant 2- to 4.5-fold (P <.001) increases of total brain glutamine and lactate concentrations. More severe (coma) stages of encephalopathy and brain edema led to a further significant increase in brain lactate but no such increase in glutamine. Furthermore, (13)C isotopomer analysis showed a selective increase of de novo synthesis of lactate from [1-(13)C]glucose resulting in 2.5-fold increased fractional (13)C enrichments in lactate at coma stages. [2-(13)C]glutamine, synthesized through the astrocytic enzyme pyruvate carboxylase, increased 10-fold at precoma stages but showed no further increase at coma stages of encephalopathy. (13)C-label incorporation into [4-(13)C]glutamate, synthesized mainly through neuronal pyruvate dehydrogenase, was selectively reduced at coma stages, whereas brain GABA synthesis was unchanged at all time points. In conclusion, increased brain lactate synthesis and impaired glucose oxidative pathways rather than intracellular glutamine accumulation are the major cause of brain edema in ALF. Future NMR spectroscopic studies using stable isotopes and real-time measurements of metabolic rates could be valuable in the elucidation of the cerebral metabolic consequences of ALF in humans.

Amino Acids↗
PubMed2003

Molecular neurobiology of acute liver failure.

Acute liver failure results in encephalopathy and brain edema that is characterized by astrocytic cell swelling. Molecular biological techniques have led to the identification of alterations in expression of several genes coding for key astrocytic proteins in acute liver failure. Such proteins include amino acid transporters, structural proteins, the endothelial cell glucose transporter GLUT-1, the mitochondrial "peripheral-type" benzodiazepine receptor, and the water channel protein aquaporin IV. Magnetic resonance spectroscopic studies reveal increased brain lactate concentrations that are positively correlated with severity of encephalopathy and brain edema in acute liver failure, suggesting a deficit of cellular oxidative capacity and impending brain energy failure. Mild hypothermia prevents brain edema in acute liver failure, and mechanisms responsible for this beneficial effect include reduced blood-brain ammonia transfer as well as normalization of astrocytic amino acid transport and brain energy metabolism. Further elucidation of the molecular mechanisms responsible for brain edema and encephalopathy in acute liver failure will undoubtedly lead to novel treatment strategies for these complications.

Astrocytes↗
PubMed2003

Pathogenesis of hepatic encephalopathy: update on molecular mechanisms.

Hepatic encephalopathy (HE) is a major neuropsychiatric complication of acute and chronic liver failure. Neuropathologically, HE in chronic liver failure is characterized by astrocytic (rather than neuronal) changes known as Alzheimer type II astrocytosis and in altered expression of key astrocytic proteins. Magnetic resonance imaging in cirrhotic patients reveals bilateral signal hyperintensities in globus pallidus on T1-weighted imaging, which appear to result from manganese deposition. Proton (1H) magnetic resonance spectroscopy shows an increase in glutamine resonance in brain, a finding that confirms previous biochemical studies and is consistent with increased uptake of ammonia by the brain (glutamine synthesis). Recent molecular biological studies show an increased expression of several genes coding for neurotransmitter-related proteins in chronic liver failure. Such genes include those for monoamine oxidase (MAO-A isoform), nitric oxide synthase (nNOS isoform) and the peripheral-type benzodiazepine receptor. Activation of these systems may lead to alterations of monoamine and amino acid neurotransmitter function and changes in cerebral blood flow in chronic liver failure.

Ammonia↗
PubMed2002

Assessment of bioaccumulation, neuropathology, and neurobehavior following subchronic (90 days) inhalation in Sprague-Dawley rats exposed to manganese phosphate.

Methylcyclopentadienyl manganese tricarbonyl (MMT) is an organic manganese (Mn) compound added to unleaded gasoline. It has been suggested that the combustion products of MMT containing Mn, such as manganese phosphate, could cause neurological symptoms similar to Parkinson's disease in humans. The aim of this work was to investigate the exposure-response relationship of bioaccumulation, neuropathology, and neurobehavior following a subchronic inhalation exposure to manganese phosphate in Sprague-Dawley male rats. Rats were exposed 6 h/day, 5 days/week for 13 consecutive weeks at 30, 300, or 3000 microg/m(3) Mn phosphate and compared to controls. Some rats were implanted with chronic EMG electrodes in the gastrocnemius muscle of the hind limb to assess tremor at the end of Mn exposure. Spontaneous motor activity was measured for 36 h using a computerized autotrack system. Rats were then sacrificed by exsanguination and Mn level in different brain tissues and other organs was determined by instrumental neutron activation analysis. Neuronal cell counts were obtained by assessing the sum of five grid areas for the caudate/putamen and the sum of two adjacent areas for the globus pallidus. Increased manganese concentrations were observed in all tissues of the brain and was dose-dependent in olfactory bulb and caudate/putamen. In fact, beginning with the highest level of exposure (3000 microg/m(3)) and ending with the control group, Mn concentrations in the olfactory bulb were 2.47 vs 1.28 vs 0.77 vs 0.64 ppm (P < 0.05) while for the caudate/putamen, Mn concentrations were 1.06 vs 0.73 vs 0.62 vs 0.47 ppm (P < 0.05). The Mn concentrations in lung were also dose-dependent (10.30 vs 1.40 vs 0.42 vs 0.17 ppm; P < 0.05). No statistical difference was observed for loss of neurons in caudate/putamen and globus pallidus. Locomotor activity assessment and tremor assessment did not reveal in neurobehavioral changes between the groups. Our results reinforce the hypothesis that the olfactory bulb and caudate/putamen are the main brain tissues for Mn accumulation after subchronic inhalation exposure.

Animals↗
PubMed2002

Ammonia induces MK-801-sensitive nitration and phosphorylation of protein tyrosine residues in rat astrocytes.

Astrocytes play a key role in the pathogenesis of ammonia-induced neurotoxicity and hepatic encephalopathy. As shown here, ammonia induces protein tyrosine nitration in cultured rat astrocytes, which is sensitive to the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801. A similar pattern of nitrated proteins is produced by NMDA. Ammonia-induced tyrosine nitration depends on a rise in [Ca2+]i, IkB degradation, and NO synthase (iNOS) induction, which are prevented by MK-801 and the intracellular Ca2+ chelator 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA-AM). Moreover, the increase in tyrosine nitration is blunted by L-NMMA, 1400W, uric acid, Cu, Zn-superoxide dismutase/catalase treatment, and methionine-sulfoximine, which indicate the involvement of reactive nitrogen intermediates and intracellular glutamine accumulation. Such reactive nitrogen intermediates additionally mediate ammonia-induced phosphorylation of the MAP-kinases Erk-1/Erk-2 and p38MAPK. Among the proteins, which are tyrosine -nitrated by ammonia, glyceraldehyde-3-phosphate dehydrogenase, the peripheral-type benzodiazepine receptor, Erk-1, and glutamine synthetase are identified. Ammonia-induced nitration of glutamine synthetase is associated with a loss of enzymatic activity. Astroglial protein tyrosine nitration is found in brains from rats after acute ammonia-intoxication or after portacaval anastomosis, indicating the in vivo relevance of the present findings. The production of reactive nitrogen intermediates and protein tyrosine nitration may alter astrocyte function and contribute to ammonia neurotoxicity.

Ammonia↗
PubMed2002

Mitochondrial dysfunction in acute hyperammonemia.

Acute hyperammonemia resulting from congenital urea cycle disorders, Reye syndrome or acute liver failure results in severe neuronal dysfunction, seizures and death. Increasing evidence suggests that acute hyperammonemia results in alterations of mitochondrial and cellular energy function resulting from ammonia-induced inhibition of the tricarboxylic acid cycle enzyme alpha-ketoglutarate dehydrogenase and by activation of the NMDA receptor. Antagonists of this receptor and NOS inhibitors prevent acute ammonia-induced seizures and mortality and prevent acute ammonia-induced changes in mitochondrial calcium homeostasis and cellular energy metabolism. Acute hyperammonemia also results in decreased activities of free radical scavenging enzymes and again, free radical formation due to ammonia exposure is prevented by either NMDA receptor antagonists or NOS inhibitors. Acute hyperammonemia also results in activation of "peripheral-type" benzodiazepine receptors and monoamine oxidase-B, enzymes which are localized on the mitochondrial membranes of astrocytes in the CNS. Activation of these receptors results in mitochondrial swelling and in increased degradation of monoamines, respectively. Alterations of mitochondrial function could contribute to the neuronal dysfunction characteristic of acute hyperammonemic syndromes.

Acute Disease↗
PubMed2002

Neurobiology of ammonia.

Hyperammonemia resulting from inherited urea cycle enzyme deficiencies or liver failure results in severe central nervous system dysfunction including brain edema, convulsions and coma. Neuropathologic evaluation in these disorders reveals characteristic alterations of astrocyte morphology ranging from cell swelling (acute hyperammonemia) to Alzheimer Type II astrocytosis (chronic hyperammonemia). Having no effective urea cycle, brain relies on glutamine synthesis for the removal of excess ammonia and the enzyme responsible, glutamine synthetase, has a predominantly astrocytic localization. Accumulation of ammonia in brain results in a redistribution of cerebral blood flow and metabolism from cortical to sub-cortical structures. In addition to changes in astrocyte morphology, increased brain ammonia concentrations result in alterations in expression of key astrocyte proteins including glial fibrillary acidic protein, glutamate and glycine transporters and "peripheral-type" (mitochondrial) benzodiazepine receptors. Such changes result in alterations of astrocytic volume and increased extracellular concentrations of excitatory and inhibitory substances. In addition, the ammonium ion has direct effects on excitatory-inhibitory transmission via distinct mechanisms involving cellular chloride extrusion and postsynaptic receptor function. Acute ammonia exposure leads to activation of NMDA receptors and their signal transduction pathways. Chronic hyperammonemia also results in increased concentrations of neuroactive L-tryptophan metabolites including serotonin and quinolinic acid. Therapy in hyperammonemic syndromes continues to rely on ammonia-lowering strategies via peripheral mechanisms (reduction of ammonia production in the gastrointestinal tract, increased ammonia removal by muscle).

Ammonia↗