Original Paper

Neurochemical Research

, Volume 36, Issue 3, pp 443-451

First online:

Non-invasive Monitoring of L-2-Oxothiazolidine-4-Carboxylate Metabolism in the Rat Brain by In vivo 13C Magnetic Resonance Spectroscopy

  • Michael P. GamcsikAffiliated withUNC/NCSU Joint Department of Biomedical Engineering Email author 
  • , M. Daniel ClarkAffiliated withDepartment of Neuroscience, McKnight Brain Institute, University of Florida
  • , Susan M. LudemanAffiliated withDepartments of Arts and Sciences and Pharmaceutical Sciences, Albany College of Pharmacy and Health Sciences
  • , James B. SpringerAffiliated withDepartment of Medicine, Duke University Medical Center
  • , Michael A. D’AlessandroAffiliated withDepartments of Arts and Sciences and Pharmaceutical Sciences, Albany College of Pharmacy and Health Sciences
  • , Nicholas E. SimpsonAffiliated withDepartment of Medicine, University of Florida
  • , Roxana PourdeyhimiAffiliated withUNC/NCSU Joint Department of Biomedical Engineering
  • , C. Bryce JohnsonAffiliated withUNC/NCSU Joint Department of Biomedical Engineering
  • , Stephanie D. TeeterAffiliated withUNC/NCSU Joint Department of Biomedical Engineering
    • , Stephen J. BlackbandAffiliated withDepartment of Neuroscience, McKnight Brain Institute, University of Florida
    • , Peter E. ThelwallAffiliated withNewcastle Magnetic Resonance Centre, Campus for Ageing and Vitality, Newcastle University

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Abstract

The cysteine precursor L-2-oxothiazolidine-4-carboxylate (OTZ, procysteine) can raise cysteine concentration, and thus glutathione levels, in some tissues. OTZ has therefore been proposed as a prodrug for combating oxidative stress. We have synthesized stable isotope labeled OTZ (i.e. L-2-oxo-[5-13C]-thiazolidine-4-carboxylate, 13C-OTZ) and tracked its uptake and metabolism in vivo in rat brain by 13C magnetic resonance spectroscopy. Although uptake and clearance of 13C-OTZ was detectable in rat brain following a bolus dose by in vivo spectroscopy, no incorporation of isotope label into brain glutathione was detectable. Continuous infusion of 13C-OTZ over 20 h, however, resulted in 13C-label incorporation into glutathione, taurine, hypotaurine and lactate at levels sufficient for detection by in vivo magnetic resonance spectroscopy. Examination of brain tissue extracts by mass spectrometry confirmed only low levels of isotope incorporation into glutathione in rats treated with a bolus dose and much higher levels after 20 h of continuous infusion. In contrast to some previous studies, bolus administration of OTZ did not alter brain glutathione levels. Even a continuous infusion of OTZ over 20 h failed to raise brain glutathione levels. These studies demonstrate the utility of in vivo magnetic resonance for non-invasive monitoring of antioxidant uptake and metabolism in intact brain. These types of experiments can be used to evaluate the efficacy of various interventions for maintenance of brain glutathione.

Keywords

Magnetic resonance Metabolism Cysteine Glutathione Taurine