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.
This is a preview of subscription content, log in to check access.
Buy single article
Instant access to the full article PDF.
Tax calculation will be finalised during checkout.
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
Tax calculation will be finalised during checkout.
Albrecht, J. (2003). Glucose-derived osmolytes and energy impairment in brain edema accompanying liver failure: The role of glutamine reevaluated. Gastroenterology 125:976–978.
Albrecht, J., Bender, A.S., and Norenberg, M.D. (1994). Ammonia stimulates the release of taurine from cultured astrocytes. Brain Res. 660:228–232.
Albrecht, J., and Dolińska, M. (2001). Glutamine as a pathogenic factor in hepatic encephalopathy. J. Neurosci. Res. 65:1–6.
Anderzhanova, E., Oja, S.S., Saransaari, P., and Albrecht, J. (2003). Changes in the striatal extracellular levels of dopamine and dihydroxyphenylacetic acid evoked by ammonia and N-methyl-D-aspartate: Modulation by taurine. Brain Res. 977:290–293.
Banay-Schwartz, M., Palkovits, M., and Lajtha, A. (1993). Heterogeneous distribution of functionally important amino acids in brain areas of adult and aging humans. Neurochem. Res. 18:417–423.
Baran, H., Jellinger, K., and Deecke, L. (1999). Kynurenine metabolism in Alzheimer's disease. J. Neural. Transm. 106:165–181.
Basavappa, S., Mobasheri, A., Errington, R., Huang, C.C., Al-Adawi, S., and Ellory, J.C. (1998). Inhibition of Na+, K+ -ATPase activates swelling-induced taurine efflux in human neuroblastoma cell line. J. Cell. Physiol. 174:145–153.
Bureau, M.H., and Olsen, R.W. (1993). GABAA receptor subtypes: Ligand binding heterogeneity demonstrated by photoaffinity labeling and autoradiography. J. Neurochem. 61:1479–1491.
Chatauret, N., Zwingmann, C., Rose, C., Leibfritz, D., and Butterworth, R.F. (2003). Protective effects of mild hypothermia on brain glucose metabolism in rats with acute liver failure: A 1H/13C-NMR study. Gastroenterology 125:815–824.
Chepkova, A.N., Doreulee, N., Yanovsky, Y., Mukhopadhyay, D., Haas, H.L., and Sergeeva, O.A. (2002). Long-lasting enhancement of cortocostriatal neurotransmission by taurine. Eur. J. Neurosci. 16:1523–1530.
Cordoba, J., Gottstein, J., and Blei, A.T. (1996). Glutamine, myo-inositol, and organic brain osmolytes after portacaval anastomosis in the rat: Implications for ammonia-induced brain edema. Hepatology 24:919–923.
Del Olmo, N., Bustamante, J., Del Rio, R.M., and Solis, J.M. (2000). Taurine activates GABA A but not GABA B receptors in rat hippocampal CA1 area. Brain Res. 864:298–307.
Dringen, R., Pfeiffer, B., and Hamprecht, B. (1999). Synthesis of the antioxidant glutathione in neurons: Supply by astrocytes of CysGly as precursor for neuronal glutathione. J. Neurosci. 19:562–569.
El Idrissi, A., and Trenkner, E. (1999). Growth factors and taurine againts excitotoxicity by stabilizing calcium homeostasis and energy metabolism. J. Neurosci. 19:9459–9468.
Erhardt, S., Oberg, H., and Engberg, G. (2001). Pharmacologically elevated levels of endogenous kynurenic acid prevent nicotine-induced activation of nigral dopamine neurons. Naunyn Schmiedebergs Arch. Pharmacol. 363:21–27.
Faff, L., Reichenbach, A., and Albrecht, J. (1996). Ammonia-induced taurine release from cultured rabbit Muller cells is an osmoresistant process mediated by intracellular accumulation of cyclic AMP. J. Neurosci. Res. 46:231–238.
Faff, L., Reichenbach, A., and Albrecht, J. (1997). Two modes of stimulation by ammonia of taurine release from cultured rabbit Muller cells. Neurochem. Int. 31:301–305.
Faff-Michalak, L., Reichenbach, A., Dettmer, D., Kellner, K., and Albrecht, J. (1994). K+-, hypoosmolarity-, and NH4 +-induced taurine release from cultured rabbit Müller cells: Role of Na+and Cl− ions and relation to cell volume changes. Glia 10:114–120.
Fedele, E., Ansaldo, M.A., Varnier, G., and Raiteri, M. (2000). Benzodiazepine-sensitive GABAA receptors limit the activity of the NMDA/NO/cyclic GMP pathway: A microdialysis study in the cerebellum of freely moving rats. J. Neurochem. 75:782–787.
Fonnum, F., and Lock, E.A. (2004). The contribution of excitotoxicty, glutathione depletion and DNA repair in chemically induced injury to neurons: Exemplified with toxic effects on cerebellar granule cells. J. Neurochem. 88:513–531.
Franco, R., Quesada, O., and Pasantes-Morales, H. (2000). Efflux of osmolyte amino acids during isovolumic regulation in hippocampal slices. J. Neurosci. Res. 61:701–711.
Han, N.L.R., Clements, J.D., and Lynch, J.W. (2004). Comparison of taurine- and glycine-induced conformational changes in the M2-M3 domain of the glycine receptor. J. Biol. Chem. 279:19559–19565.
Häussinger, D., Kircheis, G., Schliess, F., Schliess, R., and Vom Dahl, S. (2000). Hepatic encephalopathy in chronic liver disease: A clinical manifestation of astrocyte swelling and low-grade cerebral edema? J. Hepatol. 32:1035–1038.
Hermenegildo, C., Monfort, P., and Felipo, V. (2000). Activation of N-methyl-D-aspartate receptors in rat brain in vivo following acute ammonia intoxication: Characterization by in vivo brain microdialysis. Hepatology 31:709–715.
Hilgier, W., Anderzhanova, E., Oja, S.S., Saransaari, P., and Albrecht, J. (2003). Taurine reduces ammonia- and N-methyl-D-aspartate-induced accumulation of cyclic GMP and hydroxyl radicals in microdialysates of the rat striatum. Eur. J. Pharmacol. 468:21–25.
Hilgier, W., Oja, S.S., Saransaari, P., and Albrecht, J. (2004). A novel glycine site-specific N-methyl-D-aspartate receptor antagonist prevents activation of the NMDA/NO/CGMP pathway by ammonia. Brain Res. 1015:186–188
Hilgier, W., Oja, S.S., Saransaari, P., and Albrecht, J. (2005). Taurine prevents ammonia-induced accumulation of cyclic GMP in rat striatum by interaction with GABAA and glycine receptors. Brain Res. 1043:242–246.
Hilgier, W., and Olson, J.E. (1994). Brain ion and amino acid contents during edema development in hepatic encephalopathy. J. Neurochem. 62:197–204.
Hilgier, W., Olson, J.E., and Albrecht, J. (1996). Relation of taurine transport and brain edema in rats with simple hyperammonemia or liver failure. J. Neurosci. Res. 45:69–74.
Holopainen, I., Oja, S.S., Marnela, K.M., and Kontro, P. (1986). Free amino acids of rat astrocytes in primary culture: Changes during cell maturation. Int. J. Dev. Neurosci. 4:493–496.
Hussy, N., Deleuze, C., Pantaloni, A., Desarmenien, M.G., and Moos, F. (1997). Agonist action of taurine on glycine receptors in rat supraoptic magnocellular neurones: Possible role in osmoregulation. J. Physiol. 502:609–621.
Jensen, A.A., and Kristiansen, U. (2004). Functional characterization of the human α1 glycine receptor in a fluorescence-based membrane potential assay. Biochem. Pharmacol. 67:1789–1799.
Jiang, Z., Krnjevic, K., Wang, F., and Ye, J.H. (2004). Taurine activates strychnine-sensitive glycine receptors in neurons freshly isolated from nucleus accumbens of young rats. J. Neurophysiol. 91:248–257.
Klejman, A., Węgrzynowicz, M., Mioduszewska, B., Szatmari, E.M., Hetman, M., and Albrecht, J. (2005). Mechanisms of ammonia-induced cell death in rat cortical neurons: Roles of NMDA receptors and glutathione. Neurochem. Int. 47:51–57.
Knyihar-Csillik, E., Csillik, B., Pakaski, M., Krisztin-Peva, B., Dobo, E., Okuno, E., and Vecsei, L. (2004). Decreased expression of kynurenine aminotransferase-I (KAT-I) in the substantia nigra of mice after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment. Neuroscience 126:899–914.
Knyihar-Csillik, E., Okuno, E., and Vecsei, L. (1999). Effects of in vivo sodium azide administration on the immunohistochemical localization of kynurenine aminotransferase in the rat brain. Neuroscience 94:269–277.
Kocki, T., Dolińska, M., Dybel, A., Urbańska, E.M., Turski, W.A., and Albrecht, J. (2002). Regulation of kynurenic acid synthesis in C6 glioma cells. J. Neurosci. Res. 68:622–626.
Kosenko, E., Kaminsky, Y., Grau, E., Miñana, M.D., Grisolia, S., and Felipo, V. (1995). Nitroarginine, an inhibitor of nitric oxide synthetase, attenuates ammonia toxicity and ammonia-induced alterations in brain metabolism. Neurochem. Res. 20:451–456.
Kosenko, E., Kaminsky, Y., Stavroskaya, I.G., and Felipo, V. (2000). Alteration of mitochondrial calcium homeostasis by ammonia-induced activation of NMDA receptors in rat brain in vivo. Brain Res. 880:139– 146.
Lehmann, A., Łslashazarewicz, J.W., and Zeise, M. (1985). N-methylaspartate-evoked liberation of taurine and phosphoethanolamine in vivo:Site of release. J. Neurochem. 45:1172–1177.
Llansola, M., Erceg, S., Hernandez-Viadel, M., and Felipo, V. (2002). Prevention of ammonia and glutamate neurotoxicity by carnitine: Molecular mechanisms. Metab. Brain Dis. 17:389–397.
Master, S., Gottstein, J., and Blei, A. (1999). Cerebral blood flow and the development of ammonia-induced brain edema in rats after portacaval anastomosis. Hepatology 30:876–880.
Monfort, P., Kosenko, E., Erceg, S., Canales, J.J., and Felipo, V. (2002). Molecular mechanism of acute ammonia toxicity: Role of NMDA receptors. Neurochem. Int. 41:95–102.
Mori, M., Gähwiler, B.H., and Gerber, U. (2002). Beta-alanine and taurine as endogenous agonists at glycine receptors in rat hippocampus in vitro. J. Physiol. 539:191–200.
Murthy, C.R., Bender, A.S., Dombro, R.S., Bai, G., and Norenberg, M.D. (2000). Elevation of glutathione levels by ammonium ions in primary cultures of rat astrocytes. Neurochem. Int. 37:255–268.
Norenberg, M.D. (1996). Astrocytic-ammonia interactions in hepatic encephalopathy. Semin. Liver Dis. 16:245–253.
O'Byrne, M.B., and Tipton, K.F. (2000). Taurine-induced attenuation of MPP+ neurotoxicity in vitro: A possible role for the GABA A subclass of GABA receptors. J. Neurochem. 74:2087–2093.
Palkovits, M., Elekes, I., Lang, T., and Patthy, A. (1986). Taurine levels in discrete brain nuclei of rats. J. Neurochem. 47:1333–1335.
Pasantes-Morales, H. (1996). Volume regulation in brain cells: Cellular and molecular mechanisms. Metab. Brain Dis. 11:187–204.
Quinn, M.R., and Harris, C.L. (1995). Taurine allosterically inhibits binding of [35S]-t-butylbicyclophosphorothionate (TBPS) to rat brain synaptic membranes. Neuropharmacology 34:1607–1613.
Quinn, M.R., and Miller, C.L. (1992). Taurine allosterically modulates flunitrazepam binding to synaptic membranes. J. Neurosci. Res. 33:136–141.
Raghavendra Rao, V.L., Audet, R.M., and Butterworth, R.F. (1995). Selective alterations of extracellular brain amino acids in relation to function in experimental portal-systemic encephalopathy: results of an in vivo microdialysis study. J. Neurochem. 65:1221–1228.
Rama Rao, K.V., Jayakumar, A.R., and Norenberg, M.D. (2003). Induction of the mitochondrial permeability transition in cultured astrocytes by glutamine. Neurochem. Int. 43:517–523.
Rzeski, W., Kocki, T., Dybel, A., Wejksza, K., Zdzisińska, B., Kandefer-Szerszeń, M., Turski, W.A., Okuno, E., and Albrecht, J. (2005). Demonstration of kynurenine aminotransferases I and II and characterization of kynurenic acid synthesis in cultured cerebral cortical neurons. J. Neurosci. Res. 80:677–682.
Sagara, J.I., Miura, K., and Bannai, S. (1993). Maintenance of neuronal glutathione by glial cells. J. Neurochem. 61:1672–1676.
Saran, T., Hilgier, W., Kocki, T., Urbańska, E.M., Turski, W.A., and Albrecht, J. (1998). Acute ammonia treatment in vitro and in vivo inhibits the synthesis of a neuroprotectant kynurenic acid in rat cerebral cortical slices. Brain Res. 787:348–350.
Saran, T., Hilgier, W., Urbańska, E.M., Turski, W.A., and Albrecht, J. (2004). Kynurenic acid synthesis in cerebral cortical slices of rats with progressing symptoms of thioacetamide-induced hepatic encephalopathy. J. Neurosci. Res. 75:436–440.
Saransaari, P., and Oja, S.S. (2000). Taurine and neural cell damage. Amino Acid. 19:509–526.
Scharfman, H.E., Goodman, J.H., and Schwarcz, R. (2000). Electrophysiological effects of exogenous and endogenous kynurenic acid in the rat brain: Studies in vivo and in vitro. Amino Acid. 19:283–297.
Scheller, D., Korte, M., Szathmary, S., and Tegtmeier, F. (2000). Cerebral taurine release mechanisms in vivo: Pharmacological investigations in rats using microdialysis for proof of principle. Neurochem. Res. 25:801–807.
Schliess, F., Gorg, B., Fischer, R., Desjardins, P., Bidmon, H.J., Herrmann, A., Butterworth, R.F., Zilles, K., and Häussinger, D. (2002). Ammonia induces MK-801-sensitive nitration and phosphorylation of protein tyrosine residues in rat astrocytes. FASEB J. 16:739–741.
Schwarcz, R., and Pellicciari, R. (2002). Manipulation of brain kynurenines: Glial targets, neuronal effects, and clinical opportunities. J. Pharmacol. Exp. Ther. 303:1–10.
Segovia, G., Del Arco, A., and Mora, F. (1997). Endogenous glutamate increases extracellular concentrations of dopamine, GABA, and taurine through NMDA and AMPA/kainate receptors in striatum of the freely moving rat: A microdialysis study. J. Neurochem. 69:1476–1483.
Shen, W., Mennerick, S., Covey, D.F., and Zorumski, C.F. (2000). Pregnenolone sulfate modulates inhibitory synaptic transmission by enhancing GABA A receptor desensitization. J. Neurosci. 20:3571–3579.
Willard-Mack, C.L., Koehler, R.C., Hirata, T., Cork, L.C., Takahashi, H., Traystman, R.J., and Brusilow, S.W. (1996). Inhibition of glutamine synthetase reduces ammonia-induced astrocyte swelling in the rat. Neuroscience 71:589–599.
Wu, H.Q., Baran, H., Ungerstedt, U., and Schwarcz, R. (1992). Kynurenic acid in the quinolinate-lesioned rat hippocampus: Studies in vitro and in vivo. Eur. J. Neurosci. 4:1264–1270.
Wu, H.Q., Monno, A., Schwarcz, R., and Vezzani, A. (1995) Electrical kindling is associated with a lasting increase in the extracellular levels of kynurenic acid in the rat hippocampus. Neurosci. Lett. 198:91–94.
Wysmyk, U., Oja, S.S., Saransaari, P., and Albrecht, J. (1994). Long-term treatment with ammonia affects the content and release of taurine in cultured cerebellar astrocytes and granule neurons. Neurochem. Int. 24:317–322.
Zielińska, M., Hilgier, W., Law, R.O., Goryński, P., and Albrecht, J. (1999). Effects of ammonia in vitro on endogenous taurine efflux and cell volume in rat cerebrocortical minislices: Influence of inhibitors of volume-sensitive amino acid transport. Neuroscience 91:631–638.
Zielińska, M., Hilgier, W., Law, R.O., Goryński, P., and Albrecht, J. (2002a). Effects of ammonia and hepatic failure on the net efflux of endogenous glutamate, aspartate and taurine from rat cerebrocortical slices: Modulation by elevated K+ concentrations. Neurochem. Int. 41:87–93.
Zielińska, M., Hilgier, W., Borkowska, H.D., Oja, S.S., Saransaari, P., and Albrecht, J. (2002b). Mechanism of ammonia-induced taurine accumulation in the rat striatum in vivo. Neurochem. Res. 27:37–42.
Zielińska, M., Zabł ocka, B., and Albrecht, J. (2003). Effect of ammonia on taurine transport in C6 glioma cells. Adv. Exp. Med. Biol. 526:463–470.
Ziemińska, E., Dolińska, M., Łslashazarewicz, J.W., and Albrecht J. (2000). Induction of permeability transition and swelling of rat brain mitochondria by glutamine. Neurotoxicology 21:295–300.
Zwingmann, C., Flogerl, U., Pfeuffer, J., and Leibfritz, D. (2000). Effects of ammonia exposition on glioma cells: Changes in cell volume and organic osmolytes studied by diffusion-weighted and high-resolution NMR spectroscopy. Dev. Neurosci. 2:2463–2471.
About this article
Cite this article
Albrecht, J., Wegrzynowicz, M. Endogenous Neuroprotectants in Ammonia Toxicity in the Central Nervous System: Facts and Hypotheses. Metab Brain Dis 20, 253–263 (2005). https://doi.org/10.1007/s11011-005-7904-6
- Ammonia neurotoxicity
- kynurenic acid