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

doi:10.1016/j.xcrm.2022.100654

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

Cell Rep Med. 2022 Jun 21;3(6):100654. doi: 10.1016/j.xcrm.2022.100654. Epub 2022 Jun 13.

Authors

Hannah J Irvine¹, Animesh Acharjee², Zoe Wolcott³, Zsuzsanna Ament³, H E Hinson⁴, Bradley J Molyneaux⁵, J Marc Simard⁶, Kevin N Sheth⁷, W Taylor Kimberly⁸

Affiliations

¹ Division of Neurocritical Care and Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Department of Neurology, NYU Langone Health, New York, NY 10016, USA.
² College of Medical and Dental Sciences, Institute of Cancer and Genomic Sciences, Centre for Computational Biology, University of Birmingham, Birmingham B15 2TT, UK; Institute of Translational Medicine, University Hospitals Birmingham NHS Foundation Trust, Birmingham B15 2TT, UK; NIHR Surgical Reconstruction and Microbiology Research Centre, Birmingham B15 2TT, UK.
³ Division of Neurocritical Care and Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
⁴ Department of Neurology, Oregon Health Sciences University, Portland, OR 97239, USA.
⁵ Division of Neurocritical Care, Department of Neurology, Brigham & Women's Hospital, Boston, MA 02115, USA.
⁶ Department of Neurosurgery, University of Maryland, Baltimore, MD 21201, USA.
⁷ Division of Neurocritical Care, Department of Neurology, Yale University School of Medicine, New Haven, CT 06520, USA.
⁸ Division of Neurocritical Care and Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. Electronic address: wtkimberly@mgh.harvard.edu.

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.

Keywords: brain edema; glibenclamide; hypoxanthine; inflammation; metabolism; metabolomics; stroke.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Administration, Intravenous
Biomarkers
Brain Edema* / diagnostic imaging
Glyburide / administration & dosage
Humans
Hypoxanthine* / blood
Matrix Metalloproteinase 9 / therapeutic use
Stroke* / complications

Substances

Biomarkers
Hypoxanthine
Matrix Metalloproteinase 9
Glyburide

Abstract

Publication types

MeSH terms

Substances

Grants and funding