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Chronic hyperammonemia impairs the glutamate-nitric oxide-cyclic GMP pathway in cerebellar neurons in culture and in the rat in vivo.
Eur J Neurosci. 1998 Oct; 10(10):3201-9.EJ

Abstract

The aim of this work was to assess whether ammonia concentrations similar to the increase found in the brain of hyperammonemic rats (100 microM), impair N-methyl-D-aspartate (NMDA) receptor-mediated signal transduction. We first measured glutamate neurotoxicity, which in these neurons is mediated by activation of NMDA receptors, as an initial parameter reflecting activation of NMDA receptor-mediated pathways. Long-term treatment of cultured neurons with ammonia prevents glutamate-induced neuronal death. The EC50 was 20 microM, and at 100 microM the protection was complete. The induction of the protective effect was not immediate, but took several hours. Treatment with 100 microM ammonia did not prevent a glutamate- or NMDA-induced rise of intracellular calcium. Ammonia impaired the glutamate-nitric oxide-cGMP (3',5'-cyclic guanosine monophosphate) pathway in a dose- and time-dependent manner. Glutamate-induced formation of cGMP was reduced by 42%, while activation of nitric oxide synthase was not affected. Ammonia reduced by 31% cGMP formation induced by S-nitroso-N-acetyl-penicillamine (SNAP), a NO-generating agent, confirming that the interference occurs at the level of guanylate cyclase activation by nitric oxide. To assess whether chronic moderate hyperammonemia in vivo also impairs the glutamate-nitric oxide-cGMP pathway, we determined by in vivo brain microdialysis in freely moving rats the formation of cGMP induced by NMDA. In hyperammonemic rats, the formation of cGMP induced by NMDA and SNAP was reduced by ca. 60 and 41%, respectively, indicating that chronic hyperammonemia in the animal in vivo also impairs the glutamate-nitric oxide-cGMP pathway. Impairment of this pathway can contribute to the neurological alterations found in hyperammonemia and hepatic encephalopathy.

Authors+Show Affiliations

Laboratory of Neurobiology, Instituto de Investigaciones Citologicas, Fundación Valenciana de Investigaciones Biomédicas, Spain.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

9786213

Citation

Hermenegildo, C, et al. "Chronic Hyperammonemia Impairs the Glutamate-nitric Oxide-cyclic GMP Pathway in Cerebellar Neurons in Culture and in the Rat in Vivo." The European Journal of Neuroscience, vol. 10, no. 10, 1998, pp. 3201-9.
Hermenegildo C, Montoliu C, Llansola M, et al. Chronic hyperammonemia impairs the glutamate-nitric oxide-cyclic GMP pathway in cerebellar neurons in culture and in the rat in vivo. Eur J Neurosci. 1998;10(10):3201-9.
Hermenegildo, C., Montoliu, C., Llansola, M., Muñoz, M. D., Gaztelu, J. M., Miñana, M. D., & Felipo, V. (1998). Chronic hyperammonemia impairs the glutamate-nitric oxide-cyclic GMP pathway in cerebellar neurons in culture and in the rat in vivo. The European Journal of Neuroscience, 10(10), 3201-9.
Hermenegildo C, et al. Chronic Hyperammonemia Impairs the Glutamate-nitric Oxide-cyclic GMP Pathway in Cerebellar Neurons in Culture and in the Rat in Vivo. Eur J Neurosci. 1998;10(10):3201-9. PubMed PMID: 9786213.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Chronic hyperammonemia impairs the glutamate-nitric oxide-cyclic GMP pathway in cerebellar neurons in culture and in the rat in vivo. AU - Hermenegildo,C, AU - Montoliu,C, AU - Llansola,M, AU - Muñoz,M D, AU - Gaztelu,J M, AU - Miñana,M D, AU - Felipo,V, PY - 1998/10/24/pubmed PY - 1998/10/24/medline PY - 1998/10/24/entrez SP - 3201 EP - 9 JF - The European journal of neuroscience JO - Eur J Neurosci VL - 10 IS - 10 N2 - The aim of this work was to assess whether ammonia concentrations similar to the increase found in the brain of hyperammonemic rats (100 microM), impair N-methyl-D-aspartate (NMDA) receptor-mediated signal transduction. We first measured glutamate neurotoxicity, which in these neurons is mediated by activation of NMDA receptors, as an initial parameter reflecting activation of NMDA receptor-mediated pathways. Long-term treatment of cultured neurons with ammonia prevents glutamate-induced neuronal death. The EC50 was 20 microM, and at 100 microM the protection was complete. The induction of the protective effect was not immediate, but took several hours. Treatment with 100 microM ammonia did not prevent a glutamate- or NMDA-induced rise of intracellular calcium. Ammonia impaired the glutamate-nitric oxide-cGMP (3',5'-cyclic guanosine monophosphate) pathway in a dose- and time-dependent manner. Glutamate-induced formation of cGMP was reduced by 42%, while activation of nitric oxide synthase was not affected. Ammonia reduced by 31% cGMP formation induced by S-nitroso-N-acetyl-penicillamine (SNAP), a NO-generating agent, confirming that the interference occurs at the level of guanylate cyclase activation by nitric oxide. To assess whether chronic moderate hyperammonemia in vivo also impairs the glutamate-nitric oxide-cGMP pathway, we determined by in vivo brain microdialysis in freely moving rats the formation of cGMP induced by NMDA. In hyperammonemic rats, the formation of cGMP induced by NMDA and SNAP was reduced by ca. 60 and 41%, respectively, indicating that chronic hyperammonemia in the animal in vivo also impairs the glutamate-nitric oxide-cGMP pathway. Impairment of this pathway can contribute to the neurological alterations found in hyperammonemia and hepatic encephalopathy. SN - 0953-816X UR - https://www.unboundmedicine.com/medline/citation/9786213/Chronic_hyperammonemia_impairs_the_glutamate_nitric_oxide_cyclic_GMP_pathway_in_cerebellar_neurons_in_culture_and_in_the_rat_in_vivo_ L2 - https://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0953-816X&date=1998&volume=10&issue=10&spage=3201 DB - PRIME DP - Unbound Medicine ER -