Acute liver failure-induced death of rats is delayed or prevented by blocking NMDA receptors in brain

Abstract

Developing procedures to delay the mechanisms of acute liver failure-induced death would increase patients' survival by allowing time for liver regeneration or to receive a liver for transplantation. Hyperammonemia is a main contributor to brain herniation and mortality in acute liver failure (ALF). Acute ammonia intoxication in rats leads to N-methyl-D-aspartate (NMDA) receptor activation in brain. Blocking these receptors prevents ammonia-induced death. Ammonia-induced activation of NMDA receptors could contribute to ALF-induced death. If this were the case, blocking NMDA receptors could prevent or delay ALF-induced death. The aim of this work was to assess 1) whether ALF leads to NMDA receptors activation in brain in vivo and 2) whether blocking NMDA receptors prevents or delays ALF-induced death of rats. It is shown, by in vivo brain microdialysis, that galactosamine-induced ALF leads to NMDA receptors activation in brain. Blocking NMDA receptors by continuous administration of MK-801 or memantine through miniosmotic pumps affords significant protection against ALF-induced death, increasing the survival time approximately twofold. Also, when liver injury is not 100% lethal (1.5 g/kg galactosamine), blocking NMDA receptors increases the survival rate from 23 to 62%. This supports that blocking NMDA receptors could have therapeutic utility to improve survival of patients with ALF. hyperammonemia; hepatic encephalopathy; galactosamine; MK-801 ACUTE LIVER FAILURE (ALF) may lead to massive liver cell death and severe liver dysfunction. As a consequence, hepatic encephalopathy and multiorgan failure develop rapidly and may lead to rapid death of patients unless they receive a liver transplantation. However, the number of livers available for transplantation is low, leading to long waiting times for transplantation and to death of a relevant percentage of patients before a liver suitable for transplantation becomes available.The liver has a high capacity for regeneration that may allow complete recovery even in patients who have severe liver injury and liver mass loss. It would be therefore of great clinical interest to have procedures to delay ALF-induced death. This would increase survival of patients with ALF either by allowing enough time for regeneration of the liver by itself or to receive a suitable liver for transplantation.The mechanisms by which ALF leads to death are not well understood. The primary event is the death of liver cells by necrosis and apoptosis. This leads to inflammatory responses and decreased functionality of the liver, resulting in decreased elimination of toxic substances, including ammonia, and decreased synthesis and release of substances such as albumin, etc. Progression of ALF leads to multiorgan failure, systemic inflammatory response, hepatic encephalopathy, cerebral edema, and increased intracranial pressure, which seem to be the most important immediate causes of mortality in patients with ALF. Preventing or delaying these processes may help to delay ALF-induced death. One of t...

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