Accumulation of lactate in the rat brain during hyperammonaemia is not associated with impaired mitochondrial respiratory capacity.

Abstract

In acute liver failure (ALF) cerebral oedema and high intracranial pressure (ICP) are potentially deadly complications. Astrocytes cultured in ammonia have shown mitochondrial dysfunction and in rat models of liver failure, de novo lactate production in the brain has been observed and has led to a hypothesis of compromised brain metabolism during ALF. In contrast, normal lactate levels are found in cerebral microdialysate of ALF patients and the oxygen: glucose ratio of cerebral metabolic rates remains normal. To investigate this inconsistency we studied the mitochondrial function in brain tissue with respirometry in animal models of hyperammonaemia. Wistar rats with systemic inflammation induced by lipopolysaccharide or liver insufficiency induced by 90% hepatectomy were given ammonium or sodium acetate for 120 min. A cerebral cortex homogenate was studied with respirometry and substrates of the citric acid cycle, uncouplers and inhibitors of the mitochondrial complexes were successively added to investigate the mitochondrial function in detail. In a separate dose-response experiment cortex from healthy rats was incubated for 120 min in ammonium acetate in concentrations up to 80 mM prior to respirometry. Hyperammonaemia was associated with elevated ICP and increased tissue lactate concentration. No difference between groups was found in total respiratory capacity or the function of individual mitochondrial complexes. Ammonium in concentrations of 40 and 80 mM reduced the respiratory capacity in vitro. In conclusion, acute hyperammonaemia leads to elevated ICP and cerebral lactate accumulation. We found no indications of impaired oxidative metabolism in vivo but only in vitro at extreme concentrations of ammonium.

• Authors: Anne Møller Witt, Fin Stolze Larsen, Peter Nissen Bjerring
• Journal: Metabolic brain disease (Metab Brain Dis) Vol. 32 Issue 2 Pg. 461-470 (04 2017) ISSN: 1573-7365 [Electronic] United States
• PMID: 27928693 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Lipopolysaccharides
• Lactic Acid

Topics

• Animals
• Biosensing Techniques
• Brain Chemistry
• Cerebral Cortex (metabolism)
• Citric Acid Cycle (drug effects)
• Encephalitis (chemically induced, metabolism)
• Hepatectomy
• Hepatic Encephalopathy
• Hyperammonemia (blood)
• Intracranial Hypertension
• Lactic Acid (metabolism)
• Lipopolysaccharides
• Liver Failure, Acute (metabolism)
• Mitochondria (metabolism)
• Oxygen Consumption
• Rats
• Rats, Wistar