The action of ammonia on astrocyte glycogen and glycogenolysis

Abstract

Most of the brain glycogen, a major energy reserve that can be mobilized in response to increased neuronal activity, resides in the astrocyte, the site of the neuropathological abnormality found in hepatic encephalopathy (HE). Ammonia, a neurotoxin implicated in the pathogenesis of HE, has been reported to cause a depletion of glycogen in primary astrocyte cultures. To further investigate the action of ammonia on glycogen levels, cultured astrocytes were exposed to ammonium chloride (1-5 mM) for various times up to 7 d. Treatment with ammonia for 24 h did not alter deoxyglucose uptake, but significantly lowered peak glycogen values (found at 1.5 h following feeding with medium containing 5.5 mM glucose) in a concentration-dependent manner. This inhibitory effect was not observed after longer exposure times to ammonia. Three day treatment of cells did, however, significantly reduce norepinephrine-stimulated glycogenolysis, an effect not seen after 1 d of ammonia treatment. Part of the neurotoxic action of long term ammonia exposure in humans and experimental animals may be to inhibit the breakdown of glycogen. The effect of ammonia on astrocyte glycogen synthesis and/or breakdown may disrupt glial neuronal signaling and thus play a role in the pathogenesis of HE.

Osmosignalling in C6 glioma cells

“…Apart from hepatocytes [31], hepatoma cells [32], astrocytes [12] and C6 glioma cells (this paper), hypo-osmolarity-induced stimulation of Erk-type MAP kinases is also observed in the human intestine 407 cell line [35], in RAW 264.7 mouse macrophages, skin fibroblasts, vascular endothelial cells (F. Schliess and D. Haussinger, unpublished work) and yeast [36], and thus seems to be a general feature, which is in line with the growth factor-like action of cell swelling in many aspects [1,4,5].…”

“…Astrocyte swelling was shown to stimulate glycogen synthesis [4] and was suggested to be a signal for proliferation and thus to play a role in gliosis [5]. In F98 glioma cells osmolarity affects the intracellular nucleoside triphosphate level, the rate of fatty acid biosynthesis and cytoplasmic pH [6].…”

Portal-Systemic Encephalopathy: A Disorder of Neuron-Astrocytic Metabolic Trafficking

“…This evidence can be summarized as follows: (1) As already stated in this arti cle, exposure o f cultured astrocytes to concentrations of ammonia equivalent to those reported in brain in experi mental PSE results in decreased capacity for glutamate uptake [28]; (2) blood extracts from patients with PSE inhibit the high affinity glutamate uptake system in rat hippocampal slices [35]; (3) high-affinity uptake of gluta mate into rat brain synaptosomes is significantly de creased by exposure to 5 mM ammonia [36]; (4) electri cally stimulated, Ca2 f-dependent (i.e., neuronal) release of glutamate from hippocampal slices from portacaval shunted rats is significantly increased [37], consistent with decreased reuptake into the presynaptic terminal and perineuronal astrocyte; (5) K 4 -stimulated release of glutamate in vivo has been shown to be increased from the brains of portacaval shunted rats measured using either the cortical cup technique [38] or in vivo cerebral microdialysis [39], and (6) densities of 3H-glutamate binding sites are decreased in the brains of portacaval shunted rats [40] consistent with down-regulation of these sites following prolonged exposure to increased concentrations of endogenous ligand (glutamate).…”

“…Ammonia also has the potential to interfere with glycogen metabolism in astrocytes by a direct effect on glycogen synthesis [28].…”

The Activity of the Na+/Ca2+ Exchanger Largely Modulates the Ca2+i Signal Induced by Hypo-Osmotic Stress in Rat Cerebellar Astrocytes. The Effect of Osmolarity on Exchange Activity

“…Astrocyte swelling occurs in different types of brain injuries and is accompanied, among others, by volume regulatory osmolyte fl uxes [29], stimulation of glycogen synthesis [30], proliferation and gliosis [31], increases in protein tyrosine nitration [32], and elevation in the intracellular [Ca 2+ ] [3,29]. The Ca 2+ signaling triggered by astrocyte swelling is thought to impair astrocyte function by effects on gene expression, protein phosphorylation, and intervention in Ca 2+ signal-mediated receptor function [3].…”