Hepatic Encephalopathy in Acute Liver Failure: Role of the Glutamate System

Michalak, Adrianna; Knecht, K.; Butterworth, Roger F.

doi:10.1007/978-1-4615-5945-0_2

Cited by 25 publications

(8 citation statements)

References 41 publications

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“…26 It has also been shown recently that both hepatic failure and hyperammonemia alter the content of glutamate transporters. 26,27 Recent reviews of the effects of hyperammonemia and hepatic failure on glutamatergic neurotransmission have been published by Szerb and Butterworth, 28 Michalak et al, 29 Miñ ana et al, 30 and Albrecht. 31 It has been proposed that astrocyte swelling is an important step in the pathogenic mechanisms in acute liver failure and ammonia intoxication.…”

Section: Discussionmentioning

confidence: 99%

Activation of N -methyl-d-aspartate receptors in rat brain in vivo following acute ammonia intoxication: Characterization by in vivo brain microdialysis

2000

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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 ...

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Section: Discussionmentioning

confidence: 99%

Activation of N -methyl-d-aspartate receptors in rat brain in vivo following acute ammonia intoxication: Characterization by in vivo brain microdialysis

2000

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“…Ammonia may impair synaptic glutamate clearance by reducing astrocytic glutamate transporter activity [7,13]. Moreover, ammonia induces glutamate exocytosis from cultured astrocytes in a prostanoid-dependent manner.…”

Section: Introductionmentioning

confidence: 99%

Locomotor impairment and cerebrocortical oxidative stress in portal vein ligated rats in vivo

Bruck

Görg

Bidmon

et al. 2011

Journal of Hepatology

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“…Hepatic encephalopathy may be a consequence of altered glutamatergic neurotransmission (Butterworth 1992; Felipo and Butterworth 2002). Both hyperammonemia and liver failure alter glutamatergic neurotransmission at different steps (reviews; Michalak et al. 1997; Felipo and Butterworth 2002; Monfort et al.…”

mentioning

confidence: 99%

Glutamate‐induced activation of nitric oxide synthase is impaired in cerebral cortexin vivoin rats with chronic liver failure

Rodrigo

Erceg

Rodrı́guez-Dı́az

et al. 2007

Journal of Neurochemistry

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It has been proposed that impairment of the glutamate-nitric oxide-cyclic guanosine monophosphate (cGMP) pathway in brain contributes to cognitive impairment in hepatic encephalopathy. The aims of this work were to assess whether the function of this pathway and of nitric oxide synthase (NOS) are altered in cerebral cortex in vivo in rats with chronic liver failure due to portacaval shunt (PCS) and whether these alterations are due to hyperammonemia. The glutamate-nitric oxide-cGMP pathway function and NOS activation by NMDA was analysed by in vivo microdialysis in cerebral cortex of PCS and control rats and in rats with hyperammonemia without liver failure. Similar studies were done in cortical slices from these rats and in cultured cortical neurons exposed to ammonia. Basal NOS activity, nitrites and cGMP are increased in cortex of rats with hyperammonemia or liver failure. These increases seem due to increased inducible nitric oxide synthase expression. NOS activation by NMDA is impaired in cerebral cortex in both animal models and in neurons exposed to ammonia. Chronic liver failure increases basal NOS activity, nitric oxide and cGMP but reduces activation of NOS induced by NMDA receptors activation. Hyperammonemia is responsible for both effects which will lead, independently, to alterations contributing to neurological alterations in hepatic encephalopathy.

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Hepatic Encephalopathy in Acute Liver Failure: Role of the Glutamate System

Cited by 25 publications

References 41 publications

Activation of N -methyl-d-aspartate receptors in rat brain in vivo following acute ammonia intoxication: Characterization by in vivo brain microdialysis

Activation of N -methyl-d-aspartate receptors in rat brain in vivo following acute ammonia intoxication: Characterization by in vivo brain microdialysis

Locomotor impairment and cerebrocortical oxidative stress in portal vein ligated rats in vivo

Glutamate‐induced activation of nitric oxide synthase is impaired in cerebral cortexin vivoin rats with chronic liver failure

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