Mechanisms of cognitive alterations in hyperammonemia and hepatic encephalopathy: therapeutical implications.
Patients with liver diseases (e.g. cirrhosis) may present hepatic encephalopathy (HE), an alteration in cerebral function which is a consequence of previous failure of liver function. Patients with minimal or clinical HE present different levels of cognitive impairment. Hyperammonemia is considered a main contributor to the neurological alterations in HE. Animal models of chronic HE (e.g. rats with portacaval shunts) or of "pure" hyperammonemia also show impaired cognitive function. The studies summarized here show that the impairment of some types of cognitive function in chronic HE is due to the impaired function of the glutamate-nitric oxide-cGMP pathway in brain. Both hyperammonemia and neuroinflammation contribute to the impairment of the pathway and of cognitive function. Treatment of rats with chronic HE or hyperammonemia with inhibitors of phosphodiesterase 5 restores the function of the glutamate-nitric oxide-cGMP pathway and cGMP levels in brain as well as the ability to learn a Y maze conditional discrimination task. The same beneficial effects may be obtained by treating the rats chronically with an anti-inflammatory, ibuprofen. As the function of this pathway is also altered in brain of patients died in HE, this alteration would also contribute to cognitive impairment in patients with HE. Increasing cGMP by using inhibitors of phosphodiesterase 5 (PDE-5) or anti-inflammatories (under safe conditions) would be therefore a new therapeutic approach to improve learning and memory performance in individuals with minimal or clinical HE.
Laboratory of Neurobiology, Centro de Investigacion Principe Felipe, Valencia, Spain.
Pilar
P
Monfort
Omar
O
Cauli
Carmina
C
Montoliu
Regina
R
Rodrigo
Marta
M
Llansola
Blanca
B
Piedrafita
Nisrin
N
El Mlili
Jordi
J
Boix
Ana
A
Agustí
Vicente
V
Felipo
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D002531:Cerebellum / Q000502:physiology; D003071:Cognition / Q000502:physiology*; D006152:Cyclic GMP / Q000502:physiology; D006501:Hepatic Encephalopathy / Q000188:drug therapy* / Q000523:psychology*; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D006801:Humans; D022124:Hyperammonemia / Q000188:drug therapy* / Q000523:psychology*; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology; D008568:Memory / Q000502:physiology; D009048:Motor Skills; D009569:Nitric Oxide / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000627:therapeutic use; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects
D000894:Anti-Inflammatory Agents, Non-Steroidal; D010726:Phosphodiesterase Inhibitors; D016194:Receptors, N-Methyl-D-Aspartate; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D006152:Cyclic GMP