Role of extracellular cGMP and of hyperammonemia in the impairment of learning in rats with chronic hepatic failure. Therapeutic implications.
Hepatic encephalopathy is a complex neuropsychiatric syndrome present in patients with chronic or acute liver disease. We review here some recent advances in the study, in animal models, of the mechanisms involved in the impairment in intellectual function in hepatic encephalopathy. These studies show that the function of the glutamate-nitric oxide-cGMP pathway is impaired in brain in vivo in rats with chronic hyperammonemia or liver failure and from patients died in hepatic encephalopathy. This impairment leads to a reduced extracellular concentration of cGMP in the cerebellum and is associated with reduced learning ability in these animal models. Moreover, learning ability of hyperammonemic rats was restored by increasing cGMP by: (1) continuous intracerebral administration of zaprinast, an inhibitor of the cGMP-degrading phosphodiesterase, (2) chronic oral administration of sildenafil, an inhibitor of the phosphodiesterase that crosses the blood-brain barrier and (3) continuous intracerebral administration of cGMP. The data summarized indicate that impairment of learning ability in rats with chronic liver failure or hyperammonemia is due to impairment of the glutamate-nitric oxide-cGMP pathway. Moreover, increasing extracellular cGMP by pharmacological means may be a new therapeutic approach to improve cognitive function in patients with hepatic encephalopathy.
Erceg
Slaven
S
Laboratory of Neurobiology, Centro de Investigacion Principe Felipe, Fundación de la C.V., Centro de Investigacion Principe Felipe, Valencia, Spain.
Monfort
Pilar
P
Cauli
Omar
O
Montoliu
Carmina
C
Llansola
Marta
M
Piedrafita
Blanca
B
Felipo
Vicente
V
D000818:Animals; D001921:Brain / Q000378:metabolism / Q000503:physiopathology; D002908:Chronic Disease; D006152:Cyclic GMP / Q000494:pharmacology / Q000502:physiology*; D045604:Extracellular Fluid / Q000378:metabolism; D018698:Glutamic Acid / Q000502:physiology; D006501:Hepatic Encephalopathy / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D022124:Hyperammonemia / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology*; D007858:Learning / Q000187:drug effects; D017093:Liver Failure / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology*; D009569:Nitric Oxide / Q000502:physiology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011687:Purines; D011688:Purinones / Q000494:pharmacology; D051381:Rats; D015398:Signal Transduction; D000068677:Sildenafil Citrate; D013450:Sulfones
D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D011688:Purinones; D013450:Sulfones; D009569:Nitric Oxide; D018698:Glutamic Acid; D000068677:Sildenafil Citrate; C011145:zaprinast; D006152:Cyclic GMP