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A non-purine inhibitor of xanthine oxidoreductase mitigates adenosine triphosphate degradation under hypoxic conditions in mouse brain.
- Source :
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Brain research [Brain Res] 2025 Feb 15; Vol. 1849, pp. 149444. Date of Electronic Publication: 2025 Jan 02. - Publication Year :
- 2025
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Abstract
- The brain is an organ that consumes a substantial amount of oxygen, and a reduction in oxygen concentration can rapidly lead to significant and irreversible brain injury. The progression of brain injury during hypoxia involves the depletion of intracellular adenosine triphosphate (ATP) due to decreased oxidative phosphorylation in the inner mitochondrial membrane. Allopurinol is a purine analog inhibitor of xanthine oxidoreductase that protects against hypoxic/ischemic brain injury; however, its underlying mechanism of action remains unclear. In addition, febuxostat is a non-purine xanthine oxidoreductase inhibitor with a different inhibitory mechanism from allopurinol. The impact of febuxostat on brain injury has not been well investigated. Therefore, this study aimed to examine brain ATP and its catabolite levels in the presence or absence of allopurinol and febuxostat under hypoxic conditions by inactivating brain metabolism using focal microwave irradiation. The hypoxic treatment caused a decrease in the adenylate energy charge and ATP levels and an increase in its catabolic products in mouse brains. The febuxostat group showed higher energy charge and ATP levels and lower ATP catabolites than the control group. Notably, despite the comparable suppression of uric acid production in both inhibitor groups, allopurinol treatment was less effective than febuxostat. These results suggest that febuxostat effectively prevents hypoxia-induced ATP degradation in the brain and that its effect is more potent than allopurinol. This study will contribute to developing therapies for improving hypoxia-induced brain dysfunction.<br />Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.<br /> (Copyright © 2025 The Authors. Published by Elsevier B.V. All rights reserved.)
- Subjects :
- Animals
Mice
Male
Enzyme Inhibitors pharmacology
Hypoxia metabolism
Mice, Inbred C57BL
Uric Acid metabolism
Allopurinol pharmacology
Adenosine Triphosphate metabolism
Brain metabolism
Brain drug effects
Xanthine Dehydrogenase metabolism
Xanthine Dehydrogenase antagonists & inhibitors
Febuxostat pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1872-6240
- Volume :
- 1849
- Database :
- MEDLINE
- Journal :
- Brain research
- Publication Type :
- Academic Journal
- Accession number :
- 39755194
- Full Text :
- https://doi.org/10.1016/j.brainres.2025.149444