Page 80 - JCTR-11-4

Journal of Clinical and

Translational Research

ORIGINAL ARTICLE
Evaluation of the therapeutic effects of

nicotinamide adenine dinucleotide phosphate
oxidase inhibition in a rodent model of

transient ischaemic stroke

Melissa Trotman-Lucas 1 , Melanie Wood 1 , Malcolm J. W. Prior 2 ,
Jingyuan Ya 3 , Claire L. Gibson 1 , and Ulvi Bayraktutan *
3
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

Abstract

Background: Ischaemic stroke, a leading cause of mortality and disability, induces
*Corresponding author: oxidative stress (OS), largely driven by overactive nicotinamide adenine dinucleotide
Ulvi Bayraktutan phosphate (NADPH) oxidase. Targeting this enzyme system may offer therapeutic
(ulvi.bayraktutan@nottingham. benefits by mitigating cerebrovascular damage. Aim: This study investigated whether
ac.uk)
suppressing NADPH oxidase through VAS2870 reduces ischaemic brain injury and
Citation: Trotman-Lucas M, functional deficits in a rodent stroke model. Methods: Male Sprague Dawley rats
Wood M, Prior MJW, Ya J, underwent 45-min middle cerebral artery occlusion (MCAO), followed by intravenous
Gibson CL, Bayraktutan U.
Evaluation of the therapeutic VAS2870 or vehicle administration 30 min post-reperfusion. Infarct volume was
effects of nicotinamide adenine measured at 48 h and day 11 post-MCAO using magnetic resonance imaging or Nissl
dinucleotide phosphate oxidase staining. At day 11 post-MCAO, brains and blood samples were collected to analyse OS,
inhibition in a rodent model of
transient ischaemic stroke. J Clin inflammation and cellular changes. Behavioural tests were used to evaluate cognitive
Transl Res. 2025;11(4):74-97. and functional outcomes. Results: VAS2870 significantly improved survival outcome
doi: 10.36922/jctr.25.00018 following MCAO. However, no significant differences in infarct volume were observed
Received: April 17, 2025 between the control and VAS2870-treated groups. In addition, no significant alterations
were detected in total antioxidant capacity, interleukin-1 beta, tissue inhibitor of
1st revised: May 6, 2025 metalloproteinases-1, or vascular endothelial growth factor levels. Assessment of
2nd revised: June 5, 2025 post-MCAO functional and cognitive deficits revealed a significant worsening of
neurological function following VAS2870 treatment on day 2, whereas no significant
Accepted: July 1, 2025
effect of NADPH oxidase inhibition was found at day 11 post-MCAO. In addition,
Published online: August 18, 2025 cellular analysis showed no effect of NADPH oxidase inhibition on neuronal counts,
Copyright: © 2025 Author(s). neurogenesis, or angiogenesis in MCAO-affected brain regions. Conclusion: Although
This is an open-access article post-MCAO targeting of NADPH oxidase significantly improved acute survival, it did not
distributed under the terms of the significantly reduce ischaemic injury or improve functional outcome. These findings
Creative Commons AttributionNon-
Commercial 4.0 International (CC suggest that although NADPH oxidase inhibition holds promise as a therapeutic
BY-NC 4.0), which permits all strategy, its effectiveness may be limited, particularly when administered during
non-commercial use, distribution, early phases of cerebral reperfusion. Relevance for patients: Although inhibition of
and reproduction in any medium, NADPH oxidase alone did not improve cognition and neurovascular recovery, it may
provided the original work is
properly cited. be beneficial in post-stroke recanalisation therapy.
Publisher’s Note: AccScience
Publishing remains neutral with Keywords: Blood–brain barrier; Ischaemic stroke; Nicotinamide adenine dinucleotide
regard to jurisdictional claims in
published maps and institutional phosphate oxidase; VAS2870; Oxidative stress
affiliations.
Volume 11 Issue 4 (2025) 74 doi: 10.36922/jctr.25.00018