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Metabolic Brain Disease

, Volume 28, Issue 2, pp 151–154 | Cite as

Chronic hyperammonemia, glutamatergic neurotransmission and neurological alterations

  • Marta Llansola
  • Carmina Montoliu
  • Omar Cauli
  • Vicente Hernández-Rabaza
  • Ana Agustí
  • Andrea Cabrera-Pastor
  • Carla Giménez-Garzó
  • Alba González-Usano
  • Vicente FelipoEmail author
Original Paper

Abstract

This mini-review focus on our studies on alterations in glutamatergic neurotransmission and their role in neurological alterations in rat models of chronic hyperammonemia and hepatic encephalopathy (HE). Hyperammonemia impairs the glutamate-nitric oxide (NO)-cGMP pathway in cerebellum, which is responsible for reduced learning ability. We studied the underlying mechanisms and designed treatments to restore the pathway and learning. This was achieved by treatment with: phosphodiesterase 5 inhibitors, cGMP, anti-inflammatories (ibuprofen), p38 inhibitors or GABAA receptor antagonists (bicuculline). Hyperammonemia alters signal transduction associated to metabotropic glutamate receptors (mGluRs). Hypokinesia in hyperammonemia and HE is due to increased extracellular glutamate and mGluR1 activation in substantia nigra; blocking this receptor restores motor activity. The motor responses to mGluRs activation in nucleus accumbens (NAcc) are altered in hyperammonemia and HE, with reduced dopamine and increased glutamate release. This leads to activation of different neuronal circuits and enhanced motor responses. These studies show that altered responses to activation of NMDA receptors and mGluRs play essential roles in cognitive and motor alterations in hyperammonemia and HE and provide new treatments restoring cognitive and motor function.

Keywords

Hyperammonemia Hepatic encephalopathy NMDA receptor mGluRs Learning Motor function 

Notes

Acknowledgments

Supported in part by grants from Ministerio de Ciencia Innovacion Spain (SAF2011-23051; CSD2008-00005); Consellería Educación, (PROMETEO-2009-027; ACOMP/2011/053; ACOMP/2012/066) and Sanitat (AP-004/11) Generalitat Valenciana.

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Copyright information

© Springer Science+Business Media New York 2012

Authors and Affiliations

  • Marta Llansola
    • 1
  • Carmina Montoliu
    • 2
  • Omar Cauli
    • 1
  • Vicente Hernández-Rabaza
    • 1
  • Ana Agustí
    • 1
  • Andrea Cabrera-Pastor
    • 1
  • Carla Giménez-Garzó
    • 1
  • Alba González-Usano
    • 1
  • Vicente Felipo
    • 1
    Email author
  1. 1.Laboratory of NeurobiologyCentro de Investigación Principe FelipeValenciaSpain
  2. 2.Fundación Investigacion Hospital Clínico Universitario de Valencia. INCLIVAValenciaSpain

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