Abstract
The NMDA type of glutamate receptors modulates learning and memory. Excessive activation of NMDA receptors leads to neuronal degeneration and death. Hyperammonemia and liver failure alter the function of NMDA receptors and of some associated signal transduction pathways. The alterations are different in acute and chronic hyperammonemia and liver failure. Acute intoxication with large doses of ammonia (and probably acute liver failure) leads to excessive NMDA receptors activation, which is responsible for ammonia-induced death. In contrast, chronic hyperammonemia induces adaptive responses resulting in impairment of signal transduction associated to NMDA receptors. The function of the glutamate-nitric oxide-cGMP pathway is impaired in brain in vivo in animal models of chronic liver failure or hyperammonemia and in homogenates from brains of patients died in hepatic encephalopathy. The impairment of this pathway leads to reduced cGMP and contributes to impaired cognitive function in hepatic encephalopathy. Learning ability is reduced in animal models of chronic liver failure and hyperammonemia and is restored by pharmacological manipulation of brain cGMP by administering phosphodiesterase inhibitors (zaprinast or sildenafil) or cGMP itself. NMDA receptors are therefore involved both in death induced by acute ammonia toxicity (and likely by acute liver failure) and in cognitive impairment in hepatic encephalopathy.
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Acknowledgements
This work was supported by grants from the Ministerio de Ciencia y Tecnología (SAF2002-00851 and SAF2005-06089) and from Ministerio de Sanidad (Red G03-155 and PI050253) of Spain and by grants from Consellería de Empresa, Universidad y Ciencia, Generalitat Valenciana (Grupos03/001, GV04B-055, GV04B-012, GVS05/082 and ACOMP06/005).
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Llansola, M., Rodrigo, R., Monfort, P. et al. NMDA receptors in hyperammonemia and hepatic encephalopathy. Metab Brain Dis 22, 321–335 (2007). https://doi.org/10.1007/s11011-007-9067-0
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DOI: https://doi.org/10.1007/s11011-007-9067-0