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

• Published in: Cell reports. Medicine 2022-06, Vol.3 (6), p.100654-100654, Article 100654
• Main Authors: Irvine, Hannah J., Acharjee, Animesh, Wolcott, Zoe, Ament, Zsuzsanna, Hinson, H.E., Molyneaux, Bradley J., Simard, J. Marc, Sheth, Kevin N., Kimberly, W. Taylor
• Format: Article
• Language: English
• Subjects: Administration, Intravenous; Biomarkers; brain edema; Brain Edema - diagnostic imaging; glibenclamide; Glyburide - administration & dosage; Humans; hypoxanthine; Hypoxanthine - blood; inflammation; Matrix Metalloproteinase 9 - therapeutic use; metabolism; metabolomics; stroke; Stroke - complications
• ISSN: 2666-3791; 2666-3791
• DOI: 10.1016/j.xcrm.2022.100654

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. [Display omitted] •Hypoxanthine is associated with brain edema, including midline shift•Hypoxanthine is reduced by i.v. glibenclamide treatment•Hypoxanthine mediates the association between i.v. glibenclamide and midline shift In this study, Irvine et al. demonstrate that hypoxanthine, a metabolite linked to hypoxia and inflammation, is associated with brain edema and attenuated by i.v. glibenclamide treatment in patients with large ischemic stroke. These findings provide insight into markers of brain edema, which causes secondary neurologic injury after stroke.