The effects of ammonia and portal-systemic shunting on brain metabolism, neurotransmission and intracranial hypertension in hyperammonaemia-induced encephalopathy

Abstract

The effects of ammonia and portal-systemic shunting on brain metabolims, neurotransmission and intracranial hypertension in hyperammonaemia-induced encephalopathy Vogels, B.A.P.M.; van Steynen, B.; Maas, M.A.W.; Jorning, G.G.A.; Chamuleau, R.A.F.M. General rightsIt is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulationsIf you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: http://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. Background/Aims: The pathogenetic factors contributing to encephalopathy in portacaval shunted rats with hyperammonaemia were studied. Methods: Hyperammonaemia was induced by ammonium-acetate infusions in portacaval shunted rats (2.8 mmol-kg bw-'*h-l; AI-portacaval shunted rats) and in sham-portacaval shunted rats (6.5 mmol-kg bw-l-h-'; AI-NORM rats). Severity of encephalopathy was quantified by clinical grading and EEG spectral analysis. Changes in brain metabolites were assessed by amino acid analysis of brain cortex homogenates, whereas changes in amino acids with neurotransmitter activity were assessed in cerebrospinal fluid; brain water content was measured by subtracting dry from wet brain weights and intracranial pressure was measured by a pressure transducer connected to a cisterna magna cannula. Results:Although similar increased blood and brain ammonia concentrations were obtained in both experimental groups, only AI-portacaval shunted rats developed encephalopathy, associated with a significant increase in intracranial pressure. HEPATIC encephalopathy (HE) is generally regarded to be a reversible neuropsychiatric syndrome in patients with liver failure. It is often associated with portal-systemic shunting of blood, which may occur spontaneously or be surgically induced. Although the pathogenesis of HE is probably multi- Conclusions: These results indicate that hyperammonaemia alone does not induce encephalopathy, whereas portal-systemic shunting adds an essential contribution to the pathogenesis of encephalopathy. It is hypothesised that the larger increase in brain glutamine in AI-portacaval shunted rats than in AI-NORM rats is responsible for increased brain concentrations of aromatic amino acids, for cell swelling and for extracellular release of glutamate and aspartate. This might promote encephalopathy. If cell swelling is not restricted, intracranial hypertension will develop

Multinuclear NMR Spectroscopy Studies on NH₄Cl-Induced Metabolic Alterations and Detoxification Processes in Primary Astrocytes and Glioma Cells

“…Cerebral GS, which is primarily localized in astrocytes [18], is believed preferentially to remove excess ammonia, and this leads to an increased concentration of glutamine in brain [9,33]. The present data show that treatment of glial cells with pathologically high ammonium concentrations for 3 h increases the intracellular glutamine concentration, and are in good accord with results from previous 1 H-NMR studies of acute hyperammonemia in human and rat brain [12][13][14][15]. After an ammonia load, the glutamate concentration transiently decreases in brain during hyperammonemia (see Cooper and Plum [9] for review), as it is consumed by glutamine synthesis, but recovers after 3 h [42,43].…”

“…Since the brain lacks an effective urea cycle, cerebral ammonia removal relies mainly on glutamine formation in astrocytes [9,11]. High brain glutamine concentrations are commonly found in patients with hepatic encephalopathy as well as in induced hyperammonemia in the rat [12][13][14][15]. In contrast to the ammonia concentration [2,9,16], glutamine concentrations in the cerebrospinal fluid have been shown to correlate reasonably well with the clinical grade of hepatic encephalopathy [17].…”

Effects of Ammonia Exposition on Glioma Cells: Changes in Cell Volume and Organic Osmolytes Studied by Diffusion-Weighted and High-Resolution NMR Spectroscopy

“…Although the time course of the ammonia-induced changes suggests some metabolic differences between primary and clonal glial cells, the correlation of Gln synthesis with intracellular osmolyte content and cell volume is obvious. The observed swelling of glioma cells already 3 h after ammonia treatment and the complementary rise in intracellular Gln with simultaneous release of organic osmolytes give further evidence for the role of Gln as an accumulated osmolyte in ammonia-induced brain edema, seen in acute HE [5][6][7][8][9][10]. The concept is supported by previous results from our laboratory, where both the increase in Gln and the decrease in the osmolyte content, induced by 3 h incubation with ammonia, were prevented in primary astrocytes and F98 glioma cells by administration of MSO, although cytosolic NH 4 + levels were elevated even more [22].…”

“…It may be due to a direct action of ammonia or due to metabolic alterations induced by high ammonia concentrations, such as increased activity of glutamine synthetase (GS), known to be enriched in astrocytes [4]. Increased ammonia entry into the brain is followed by an elevation of the brain glutamine (Gln) content in various brain regions, commonly found in patients with HE as well as induced HA in the rat [5][6][7][8][9][10]. It has been postulated that an osmotic effect due to intracellular Gln accumulation could mediate brain swelling and leads to brain edema in conditions associated with HA [11,12].…”

Cerebral herniation in patients with acute E liver failure is correlated with arterial ammonia concentration

“…38,39 In different animal models, it has been consistently observed that infusion of ammonia can lead to accumulation of glutamine in the astrocytes, astrocytic swelling, increased brain water, and increased intracranial pressure. 5,8,40 It seems that mechanisms that counter-regulate astrocytic cell volume are too slow to compensate in the acute situation. 11,12 Recent research has identified a heterogeneous family of astrocytic glutamate receptors and transporters which regulate neuron-astrocytic trafficking of glutamate.…”