Cerebral glutamine metabolism under hyperammonemia determined in vivo by localized (1)H and (15)N NMR spectroscopy

Research output: Contribution to journalArticle

Abstract

Brain glutamine synthetase (GS) is an integral part of the glutamate-glutamine cycle and occurs in the glial compartment. In vivo Magnetic Resonance Spectroscopy (MRS) allows noninvasive measurements of the concentrations and synthesis rates of metabolites. (15)N MRS is an alternative approach to (13)C MRS. Incorporation of labeled (15)N from ammonia in cerebral glutamine allows to measure several metabolic reactions related to nitrogen metabolism, including the glutamate-glutamine cycle. To measure (15)N incorporation into the position 5N of glutamine and position 2N of glutamate and glutamine, we developed a novel (15)N pulse sequence to simultaneously detect, for the first time, [5-(15)N]Gln and [2-(15)N]Gln+Glu in vivo in the rat brain. In addition, we also measured for the first time in the same experiment localized (1)H spectra for a direct measurement of the net glutamine accumulation. Mathematical modeling of (1)H and (15)N MRS data allowed to reduce the number of assumptions and provided reliable determination of GS (0.30±0.050 μmol/g per minute), apparent neurotransmission (0.26±0.030 μmol/g per minute), glutamate dehydrogenase (0.029±0.002 μmol/g per minute), and net glutamine accumulation (0.033±0.001 μmol/g per minute). These results showed an increase of GS and net glutamine accumulation under hyperammonemia, supporting the concept of their implication in cerebral ammonia detoxification.

Details

Authors
  • Cristina Cudalbu
  • Bernard Lanz
  • João M N Duarte
  • Florence D Morgenthaler
  • Yves Pilloud
  • Vladimir Mlynárik
  • Rolf Gruetter
External organisations
  • Swiss Federal Institute of Technology
Research areas and keywords

Keywords

  • Ammonia, Animals, Brain, Glutamate-Ammonia Ligase, Glutamic Acid, Glutamine, Hyperammonemia, Magnetic Resonance Spectroscopy, Male, Models, Biological, Nitrogen Isotopes, Rats, Rats, Sprague-Dawley, Journal Article, Research Support, Non-U.S. Gov't
Original languageEnglish
Pages (from-to)696-708
Number of pages13
JournalJournal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism
Volume32
Issue number4
Publication statusPublished - 2012 Apr
Publication categoryResearch
Peer-reviewedYes
Externally publishedYes