Blocking NMDA Receptors Delays Death in Rats with Acute Liver Failure by Dual Protective Mechanisms in Kidney and Brain

Abstract

Treatment of patients with acute liver failure (ALF) is unsatisfactory and mortality remains unacceptably high. Blocking NMDA receptors delays or prevents death of rats with ALF. The underlying mechanisms remain unclear. Clarifying these mechanisms will help to design more efficient treatments to increase patient’s survival. The aim of this work was to shed light on the mechanisms by which blocking NMDA receptors delays rat’s death in ALF. ALF was induced by galactosamine injection. NMDA receptors were blocked by continuous MK-801 administration. Edema and cerebral blood flow were assessed by magnetic resonance. The time course of ammonia levels in brain, muscle, blood, and urine; of glutamine, lactate, and water content in brain; of glomerular filtration rate and kidney damage; and of hepatic encephalopathy (HE) and intracranial pressure was assessed. ALF reduces kidney glomerular filtration rate (GFR) as reflected by reduced inulin clearance. GFR reduction is due to both reduced renal perfusion and kidney tubular damage as reflected by increased Kim-1 in urine and histological analysis. Blocking NMDA receptors delays kidney damage, allowing transient increased GFR and ammonia elimination which delays hyperammonemia and associated changes in brain. Blocking NMDA receptors does not prevent cerebral edema or blood–brain barrier permeability but reduces or prevents changes in cerebral blood flow and brain lactate. The data show that dual protective effects of MK-801 in kidney and brain delay cerebral alterations, HE, intracranial pressure increase and death. NMDA receptors antagonists may increase survival of patients with ALF by providing additional time for liver transplantation or regeneration.

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Acknowledgments

Supported by grants from Ministerio de Ciencia Innovacion Spain (SAF2008-00062, SAF2011-23051; CSD2008-00005; PS09/00806; PI10/01434) and Consellería Educación (PROMETEO-2009-027; ACOMP/2011/053; ACOMP/2012/066) and Conselleria Sanitat (AP-043-10, AP-004/11, AP-087/11) Generalitat Valenciana.

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Correspondence to Vicente Felipo.

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Cauli, O., González-Usano, A., Cabrera-Pastor, A. et al. Blocking NMDA Receptors Delays Death in Rats with Acute Liver Failure by Dual Protective Mechanisms in Kidney and Brain. Neuromol Med 16, 360–375 (2014). https://doi.org/10.1007/s12017-013-8283-5

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Keywords

  • Hyperammonemia
  • Acute liver failure
  • NMDA receptor
  • Intracranial pressure
  • Blood flow
  • Tubular injury
  • Glomerular filtration rate