Endogenous Neuroprotectants in Ammonia Toxicity in the Central Nervous System: Facts and Hypotheses
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The paper overviews experimental evidence suggestive of the engagement of three endogenous metabolites: taurine, kynurenic acid, and glutathione (GSH) in the protection of central nervous system (CNS) cells against ammonia toxicity. Intrastriatal administrationof taurine via microdialysis probe attenuates ammonia-induced accumulation of extracellular cyclic guanosine monophosphate (cGMP) resulting from overactivation of the N-methyl-D-aspartate/nitric oxide (NMDA/NO) pathway, and this effect involves agonistic effect of taurine on the GABA-A and glycine receptors. Taurine also counteracts generation of free radicals, increased release of dopamine, and its metabolism to dihydroxyphenylacetic acid (DOPAC). Taurine reduces ammonia-induced increase of cell volume (edema) in cerebrocortical slices by a mechanism involving GABA-A receptors. Massive release of radiolabeled or endogenous taurine from CNS tissues by ammonia in vivo and in vitro is thoughtto promote its neuroprotective action, by making the amino acid available for interactionwith cell membranes and/or by driving excess water out of the CNS cells (astrocytes) thatunderwent ammonia-induced swelling. Ammonia in vivo and in vitro affects in variable waysthe synthesis of kynurenic acid (KYNA). Since KYNA is an endogenous NMDA receptor antagonist with a high affinity towards its glycine site, changes in its content may counter overactivation or depression of glutaminergic transmission observed at the different stages of hyperammonemia. GSH is a major antioxidant in the CNS whose synthesis is partly compartmented between neurons and astrocytes: astrocytic GSH is a source of precursors for the synthesis of neuronal GSH. Ammonia in vitro stimulates GSH synthesis in cultured astrocytes, which may compensate for increased GSH consumption (decreased GSH/GSSG ratio) in neurons.
KeywordsAmmonia neurotoxicity taurine kynurenic acid glutathione
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