Ammonia is considered the main agent responsible for the neurological alterations in hepatic encephalopathy. It was suggested that ammonia toxicity is mediated by activation of N-methyl-D-aspartate (NMDA) receptors. The aim of this work was to assess, by in vivo brain microdialysis in freely moving rats, whether acute ammonia intoxication leads to activation of NMDA receptors in the cerebellum of the rat in vivo. We measured the effects of ammonia intoxication on the neuronal glutamate-nitric oxide-cyclic guanosine monophosphate (cGMP) pathway, by measuring the ammonia-induced increase of extracellular cGMP. Ammonia intoxication increases extracellular cGMP, and this increase is prevented by (5R,10S)-5-methyl-10,11-dihydro-5H-dibenzo Ammonia is a product of degradation of proteins and of other compounds. However, at high concentrations, ammonia is toxic, leading to functional disturbances of the central nervous system. Ammonia is considered the main agent responsible for the neurological alterations found in patients with liver failure suffering from hepatic encephalopathy. However, the molecular mechanism by which ammonia could lead to this neurological alteration remains unclear. Acute intoxication with large doses of ammonium salts leads to the rapid death of animals. We have proposed that acute ammonia intoxication leads to activation of N-methyl-Daspartate (NMDA) receptors in the brain. In fact, ammoniainduced death of mice and rats can be prevented by previous blocking of NMDA receptors with selective antagonists acting on different sites of the receptor. 1,2 However, a direct demonstration of activation of NMDA receptors following acute intoxication with ammonia is still lacking.The aim of the present work was to assess whether acute ammonia intoxication (by intraperitoneal injection of ammonium acetate) leads to activation of NMDA receptors in the cerebellum of the animal in vivo.Activation of NMDA receptors leads to increased intracellular Ca 2ϩ in the postsynaptic neuron, and Ca 2ϩ binds to calmodulin and activates nitric oxide synthase, leading to increased formation of nitric oxide, which, in turn, activates guanylate cyclase, leading to increased formation of cyclic guanosine monophosphate (cGMP) (Fig. 1). Part of the cGMP formed is released to the extracellular space. To determine whether or not NMDA receptors are activated, we have measured the activation of the glutamate-nitric oxidecGMP pathway in the cerebellum of freely moving rats by in vivo brain microdialysis. Samples from the extracellular space were taken continuously by in vivo brain microdialysis. It has been shown that, under appropriate conditions, activation of NMDA receptors in the rat cerebellum in vivo can be assessed by determining the content of cGMP in samples taken by in vivo microdialysis from the extracellular space of cerebellum in freely moving rats. [3][4][5] We have tested the effect of acute intoxication with different doses of ammonia on activation of NMDA receptors as determined by measuring cGMP in the extracellular ...
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.
Patients with hepatic encephalopathy (HE) may present different neurological alterations including impaired cognitive function and altered motor activity and coordination. HE may lead to coma and death. Many of these neurological alterations are the consequence of altered neurotransmission. Hyperammonemia is a main contributor to the alterations in neurotransmission and in neurological functions in HE. Both glutamatergic and GABAergic neurotransmission are altered in animal models of HE. We review some of these alterations, especially those alterations in glutamatergic neurotransmission responsible for some specific neurological alterations in hyperammonemia and HE: the role 1) of excessive NMDA receptors activation in death induced by acute hyperammonemia; 2) of impaired function of the glutamate-nitric oxide-cGMP pathway, associated to NMDA receptors, in cognitive impairment in chronic HE; 3) of increased extracellular glutamate and activation of metabotropic glutamate receptors in substantia nigra in hypokinesia in chronic HE. The therapeutic implications are discussed. We also review the alterations in the function of the neuronal circuits between basal ganglia-thalamus-cortex modulating motor activity and the role of sequential alterations in glutamatergic and GABAergic neurotransmission in these alterations. HE would be a consequence of altered neuronal communication due to alterations in general neurotransmission involving different neurotransmitter systems in different neurons.
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