Changes in the extracellular profiles of neuroactive amino acids in the rat striatum at the asymptomatic stage of hepatic failure

Abstract

Rats were treated with a hepatotoxin thioacetamide (TAA) and examined 21 days later, when they showed moderate fatty metamorphosis of the liver and morphological changes in brain indicative of excitotoxic neuronal damage, but no evident biochemical or neurophysiological symptoms of hepatic encephalopathy (HE). High-performance liquid chromatography (HPLC) analysis of extracellular amino acids in striatal microdialysates of TAA-treated rats revealed a significant increase in the excitatory amino acids glutamate (Glu) and aspartate (Asp) and their amino acid metabolites glutamine (Gln) and alanine (Ala). Microdialysis in the presence of 50 mM K+ triggered in TAA-treated rats an accumulation of Asp and Glu, and diminished the accumulation of Gln. These effects were virtually absent in control rats. None of the treatments affected the accumulation of the nontransmitter amino acid leucine (Leu). The above changes mirror those previously described in symptomatic HE and are likely to contribute to excitotoxic damage. The basal microdialysate content of taurine (Tau), an amino acid with antioxidant and volume regulatory properties, was 60% lower in TAA-treated rats than in control rats despite its increased blood-to-brain transport. The decrease in extracellular Tau may thus reflect Tau redistribution to adjacent central nervous system (CNS) cells manifesting a cell-protective response. Stimulation with 50 mM K+ increased extracellular Tau in control rats by 182% and in TAA-treated rats by 322%. Stimulation with 100 microM N-methyl-D-aspartate (NMDA) increased extracellular Tau in control rats by 27 % and in TAA-treated rats by as much as 250%. The increase of K+- or NMDA-dependent Tau release may reflect improved cell volume regulation and neuroprotection and contribute to attenuation of neurologic symptoms in rats with liver failure.

Association of reduced extracellular brain ammonia, lactate, and intracranial pressure in pigs with acute liver failure

“…An increase in extracellular brain glutamate has been consistently demonstrated in different animal models of ALF, 24,[35][36][37][38] which could be the result of decreased glutamate uptake or increased glutamate release. 39 It has been recently demonstrated that an acute insult of ammonia leads to glutamate release from astrocytes.…”

Chronic and acute ammonia toxicity in mudskippers,Periophthalmodon schlosseriandBoleophthalmus boddaerti: brain ammonia and glutamine contents, and effects of methionine sulfoximine and MK801

“…In patients suffering from acute liver failure, glutamatergic dysfunction (Hilgier et al, 1999;Michalak et al, 1996) resulted from high levels of brain ammonia (1-3·mmol·l…”

Hypothermia in Acute Liver Failure

“…A consistent finding in experimental animal models of ALF is that of increased extracellular brain glutamate (Bosman et al, 1992;de Knegt et al, 1994;Hilgier et al, 1999;Michalak et al, 1996). This increased extracellular brain glutamate leads to increased glutamatergic neurotransmission which has been suggested to be implicated in the pathogenesis of CNS complications of ALF (Butterworth, 1997).…”

“…Clinically, extracellular brain lactate concentrations were found to increase in association with increased ICP in patients with ALF (Tofteng et al, 2002). It has also been demonstrated that alanine is elevated in the hyperammonemic brain (Hilgier et al, 1999;Mans et al, 1994;Swain et al, 1992) and more recently in rats with ALF using nuclear magnetic resonance (NMR) spectroscopy (Chatauret et al, 2003). Increased lactate and alanine production indirectly suggest that anaerobic pathways (increased glycolytic activity) may be stimulated to compensate for a decreased pyruvate oxidation (due to ammonia inhibition on the enzyme alpha-ketoglutarate dehydrogenase in the tricarboxylic acid cycle (Lai and Cooper, 1986)) and maintain ATP production.…”