title: Brain regional alterations in the modulation of the glutamate-nitric oxide-cGMP pathway in liver cirrhosis. Role of hyperammonemia and cell types involved.
abstract: Hepatic encephalopathy is a complex neuropsychiatric syndrome present in patients with liver disease that includes impaired intellectual function and alterations in personality and neuromuscular coordination. Hyperammonemia and liver failure result in altered glutamatergic neurotransmission, which contributes to hepatic encephalopathy. Alterations in the function of the glutamate-nitric oxide-cGMP pathway may be responsible for some of the neurological alterations found in hepatic encephalopathy. The function of this pathway is altered in brain from patients died with liver cirrhosis and one altered step of the pathway is the activation of soluble guanylate cyclase by nitric oxide, which is increased in cerebral cortex and reduced in cerebellum from these patients. Portacaval anastomosis and bile duct ligation plus hyperammonemia in rats reproduce the alterations in the activation of soluble guanylate cyclase by NO both in cerebellum and cerebral cortex. We assessed whether hyperammonemia is responsible for the region-selective alterations in guanylate cyclase modulation in liver cirrhosis and whether the alteration occurs in neurons or in astrocytes. Activation of guanylate cyclase by nitric oxide is lower in cerebellar neurons exposed to ammonia (1.5-fold) than in control neurons (3.3-fold). The activation of guanylate cyclase by nitric oxide is higher in cortical neurons exposed to ammonia (8.7-fold) than in control neurons (5.5-fold). The activation is not affected in cerebellar or cortical astrocytes. These findings indicate that hyperammonemia is responsible for the differential alterations in the modulation of soluble guanylate cyclase by nitric oxide in cerebellum and cerebral cortex of cirrhotic patients. Moreover, under the conditions used, the alterations occur selectively in neurons and not in astrocytes.
authors.affiliation: Laboratory of Neurobiology, Centro de Investigacion Principe Felipe, Fundación de la Comunidad Valenciana Centro de Investigacion Principe Felipe, Valencia, Spain.
authors.forename: Regina
authors.initials: R
authors.lastname: Rodrigo
authors.forename: Vicente
authors.initials: V
authors.lastname: Felipo
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000201:enzymology; D001921:Brain / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D002531:Cerebellum / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D002540:Cerebral Cortex / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D002908:Chronic Disease; D006152:Cyclic GMP / Q000502:physiology*; D018698:Glutamic Acid / Q000502:physiology*; D006162:Guanylate Cyclase; D006801:Humans; D022124:Hyperammonemia / Q000150:complications / Q000378:metabolism*; D008103:Liver Cirrhosis / Q000150:complications / Q000378:metabolism*; D017093:Liver Failure / Q000150:complications / Q000378:metabolism; D009474:Neurons / Q000201:enzymology; D009569:Nitric Oxide / Q000502:physiology*; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D015398:Signal Transduction; D000071756:Soluble Guanylyl Cyclase
chemical_list: D018160:Receptors, Cytoplasmic and Nuclear; D009569:Nitric Oxide; D018698:Glutamic Acid; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D006152:Cyclic GMP