Hypoxanthine is a pharmacodynamic marker of ischemic brain edema modified by glibenclamide

Hannah J. Irvine, Animesh Acharjee, Zoe Wolcott, Zsuzsanna Ament, H. E. Hinson, Bradley J. Molyneaux, J. Marc Simard, Kevin N. Sheth, W. Taylor Kimberly

Research output: Contribution to journalArticlepeer-review

Abstract

Brain edema after a large stroke causes significant morbidity and mortality. Here, we seek to identify pharmacodynamic markers of edema that are modified by intravenous (i.v.) glibenclamide (glyburide; BIIB093) treatment. Using metabolomic profiling of 399 plasma samples from patients enrolled in the phase 2 Glyburide Advantage in Malignant Edema and Stroke (GAMES)-RP trial, 152 analytes are measured using liquid chromatography-tandem mass spectrometry. Associations with midline shift (MLS) and the matrix metalloproteinase-9 (MMP-9) level that are further modified by glibenclamide treatment are compared with placebo. Hypoxanthine is the only measured metabolite that associates with MLS and MMP-9. In sensitivity analyses, greater hypoxanthine levels also associate with increased net water uptake (NWU), as measured on serial head computed tomography (CT) scans. Finally, we find that treatment with i.v. glibenclamide reduces plasma hypoxanthine levels across all post-treatment time points. Hypoxanthine, which has been previously linked to inflammation, is a biomarker of brain edema and a treatment response marker of i.v. glibenclamide treatment.

Original languageEnglish (US)
Article number100654
JournalCell Reports Medicine
Volume3
Issue number6
DOIs
StatePublished - Jun 21 2022

Keywords

  • brain edema
  • glibenclamide
  • hypoxanthine
  • inflammation
  • metabolism
  • metabolomics
  • stroke

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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