Patients with liver disease with overt or minimal hepatic encephalopathy show impaired intellectual capacity. The underlying molecular mechanism remains unknown. Rats with portacaval anastomosis or with hyperammonemia without liver failure also show impaired learning ability and impaired function of the glutamate-nitric oxide-cyclic guanine monophosphate (glutamate-NO-cGMP) pathway in brain. We hypothesized that pharmacological manipulation of the pathway in order to increase cGMP content could restore learning ability. We show by in vivo brain microdialysis that chronic oral administration of sildenafil, an inhibitor of the phosphodiesterase that degrades cGMP, normalizes the function of the glutamate-NO-cGMP pathway and extracellular cGMP in brain in vivo in rats with portacaval anastomosis or with hyperammonemia. Moreover, sildenafil restored the ability of rats with hyperammonemia or with portacaval shunts to learn a conditional discrimination task. In conclusion, impairment of learning ability in rats with chronic liver failure or with hyperammonemia is the result of impairment of the glutamate-NO-cGMP pathway. Moreover, chronic treatment with sildenafil normalizes the function of the pathway and restores learning ability in rats with portacaval shunts or with hyperammonemia. Pharmacological manipulation of the pathway may be useful for the clinical treatment of patients with overt or minimal hepatic encephalopathy. (HEPATOLOGY 2005;41:299-306.) H epatic encephalopathy is a neuropsychiatric syndrome covering a wide range of neuropsychiatric disturbances ranging from minimal changes in personality or altered sleep-and-waking cycle to deep coma and death. Patients with liver cirrhosis with normal neurological or mental status examination results may have minimal forms of hepatic encephalopa-thy showing intellectual function impairment as revealed by neuropsychological testing. 1,2 Hyperammonemia is considered one of the main factors responsible for the neurological alterations in hepatic encephalopathy, 3 and the classical clinical treatments are directed toward reducing blood ammonia levels. However, the molecular mechanisms by which hyperammonemia and liver failure lead to neurological alterations and to impairment of intellectual function remain unclear.
The molecular mechanisms involved in different types of learning are not well known. N-methyl-D-aspartate (NMDA) receptors are involved in some types of learning. Activation of NMDA receptors increases calcium in postsynaptic neurons. Calcium binds to calmodulin and activates neuronal nitric oxide (NO) synthase, increasing NO, which activates guanylate cyclase, increasing cyclic guanine monophosphate (cGMP), part of which is released to the extracellular space. Activation of this glutamate-NO-cGMP pathway may be involved in some forms of learning. Some recent reports indicate that guanylate cyclase and cGMP are important in learning and memory. Administration of a membrane permeant analog of cGMP facilitated memory consolidation, 4 whereas bilateral intrahippocampal administration of an inhibitor Abbreviations: NMDA, N-methyl-D-aspartate; NO, nitric oxide; cGMP, cyclic guanine monophosphate.