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Cyclic GMP pathways in hepatic encephalopathy. Neurological and therapeutic implications

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Abstract

Cyclic GMP (cGMP) modulates important cerebral processes including some forms of learning and memory. cGMP pathways are strongly altered in hyperammonemia and hepatic encephalopathy (HE). Patients with liver cirrhosis show reduced intracellular cGMP in lymphocytes, increased cGMP in plasma and increased activation of soluble guanylate cyclase by nitric oxide (NO) in lymphocytes, which correlates with minimal HE assessed by psychometric tests. Activation of soluble guanylate cyclase by NO is also increased in cerebral cortex, but reduced in cerebellum, from patients who died with HE. This opposite alteration is reproduced in vivo in rats with chronic hyperammonemia or HE. A main pathway modulating cGMP levels in brain is the glutamate-NO-cGMP pathway. The function of this pathway is impaired both in cerebellum and cortex of rats with hyperammonemia or HE. Impairment of this pathway is responsible for reduced ability to learn some types of tasks. Restoring the pathway and cGMP levels in brain restores learning ability. This may be achieved by administering phosphodiesterase inhibitors (zaprinast, sildenafil), cGMP, anti-inflammatories (ibuprofen) or antagonists of GABAA receptors (bicuculline). These data support that increasing cGMP by safe pharmacological means may be a new therapeutic approach to improve cognitive function in patients with minimal or clinical HE.

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Acknowledgements

Supported by grants from Ministerio de Ciencia e Innovacion (SAF2005-06089, SAF2008-00062, CSD2008-00005) and from Ministerio de Sanidad (FIS 06/0065) of Spain and from Conselleria de Educacion de la Generalitat Valenciana (ACOMP/2009/191; ACOMP06/005, ACOMP-2009-025; PROMETEO/2009/027) and AP005/06, EVES 034/2007, AP-024/08 and A-01/08 from Conselleria de Sanitat of Generalitat Valenciana.

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  1. Fundación Investigación Hospital Clínico de Valencia, Valencia, Spain

    Carmina Montoliu

  2. Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, Avda Autopista del Saler 16, 46012, Valencia, Spain

    Regina Rodrigo, Pilar Monfort, Marta Llansola, Omar Cauli, Jordi Boix, Nisrin ElMlili, Ana Agusti & Vicente Felipo

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  1. Carmina Montoliu
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Montoliu, C., Rodrigo, R., Monfort, P. et al. Cyclic GMP pathways in hepatic encephalopathy. Neurological and therapeutic implications. Metab Brain Dis 25, 39–48 (2010). https://doi.org/10.1007/s11011-010-9184-z

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