AccScience Publishing / JCTR / Volume 11 / Issue 4 / DOI: 10.36922/jctr.25.00018
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ORIGINAL ARTICLE

Evaluation of the therapeutic effects of nicotinamide adenine dinucleotide phosphate oxidase inhibition in a rodent model of transient ischaemic stroke

Melissa Trotman-Lucas1 ,  Melanie Wood1 ,  Malcolm J. W. Prior2 ,  Jingyuan Ya3 ,  Claire L. Gibson1 ,  Ulvi Bayraktutan3*
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1 School of Psychology, Faculty of Science, University of Nottingham, Nottingham, United Kingdom
2 Pre-clinical Imaging Facility, School of Medicine, Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham, United Kingdom
3 Academic Unit of Mental Health and Clinical Neuroscience, School of Medicine, Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham, United Kingdom
JCTR 2025, 11(4), 74–97; https://doi.org/10.36922/jctr.25.00018
Received: 17 April 2025 | Revised: 5 June 2025 | Accepted: 1 July 2025 | Published online: 18 August 2025
© 2025 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution -Noncommercial 4.0 International License (CC-by the license) ( https://creativecommons.org/licenses/by-nc/4.0/ )
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Abstract

Background: Ischaemic stroke, a leading cause of mortality and disability, induces oxidative stress (OS), largely driven by overactive nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. Targeting this enzyme system may offer therapeutic benefits by mitigating cerebrovascular damage. Aim: This study investigated whether suppressing NADPH oxidase through VAS2870 reduces ischaemic brain injury and functional deficits in a rodent stroke model. Methods: Male Sprague Dawley rats underwent 45-min middle cerebral artery occlusion (MCAO), followed by intravenous VAS2870 or vehicle administration 30 min post-reperfusion. Infarct volume was measured at 48 h and day 11 post-MCAO using magnetic resonance imaging or Nissl staining. At day 11 post-MCAO, brains and blood samples were collected to analyse OS, inflammation and cellular changes. Behavioural tests were used to evaluate cognitive and functional outcomes. Results: VAS2870 significantly improved survival outcome following MCAO. However, no significant differences in infarct volume were observed between the control and VAS2870-treated groups. In addition, no significant alterations were detected in total antioxidant capacity, interleukin-1 beta, tissue inhibitor of metalloproteinases-1, or vascular endothelial growth factor levels. Assessment of post-MCAO functional and cognitive deficits revealed a significant worsening of neurological function following VAS2870 treatment on day 2, whereas no significant effect of NADPH oxidase inhibition was found at day 11 post-MCAO. In addition, cellular analysis showed no effect of NADPH oxidase inhibition on neuronal counts, neurogenesis, or angiogenesis in MCAO-affected brain regions. Conclusion: Although post-MCAO targeting of NADPH oxidase significantly improved acute survival, it did not significantly reduce ischaemic injury or improve functional outcome. These findings suggest that although NADPH oxidase inhibition holds promise as a therapeutic strategy, its effectiveness may be limited, particularly when administered during early phases of cerebral reperfusion. Relevance for patients: Although inhibition of NADPH oxidase alone did not improve cognition and neurovascular recovery, it may be beneficial in post-stroke recanalisation therapy.

Graphical abstract
Keywords
Blood–brain barrier
Ischaemic stroke
Nicotinamide adenine dinucleotide phosphate oxidase
VAS2870
Oxidative stress
Funding
This research was funded by the University of Nottingham’s Faculty of Science Pump Priming Award (Grant number: A929A2).
Conflict of interest
The authors declare that they have no competing interests.
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Journal of Clinical and Translational Research, Electronic ISSN: 2424-810X Print ISSN: 2382-6533, Published by AccScience Publishing
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