NADPH-DEPENDENT REDOX HOMEOSTASIS OF THE BRAIN IN METABOLIC SYNDROME: MECHANISMS OF DYSREGULATION AND THERAPEUTIC DIRECTIONS
DOI:
https://doi.org/10.11603/mcch.2410-681X.2026.i1.15998Keywords:
metabolic syndrome; blood-brain barrier; brain; NADPH; oxidative stress.Abstract
Introduction. Metabolic syndrome is associated not only with cardiometabolic complications but also with cerebrovascular disorders, in which endothelial dysfunction, microcirculatory impairment, and increased blood– brain barrier permeability play a central pathogenetic role. For a mechanistic explanation of the resistance or vulnerability of barrier structures, it is reasonable to analyze not the general concept of oxidative stress, but specific biochemical links that determine the restorative capacity of neurovascular unit cells. The Aim of the Study. To summarize current evidence on the role of reduced nicotinamide adenine dinucleotide phosphate (NADPH) in maintaining redox homeostasis of the brain in metabolic syndrome. Research methods. A review of publications from 2020–2025 was conducted. The search was performed in the international databases PubMed/MEDLINE, ScienceDirect, Scopus, Wiley Online Library, Web of Science, PubMed Central, Google Scholar, and ResearchGate. The following key terms were used: “metabolic syndrome”, “blood-brain barrier”, “brain”, “NADPH”, and “oxidative stress”. The analysis included systematic reviews, clinical studies, and meta-analyses addressing the relationship between cerebrovascular disorders, mechanisms of blood–brain barrier injury, and the development of metabolic syndrome. Results and Discussion. NADPH is a key resource for the glutathione and thioredoxin systems, which ensure neutralization of peroxide load and stability of tight-junction proteins. In metabolic syndrome, NADPH consumption increases due to activation of the polyol pathway, enhanced NADPH oxidase (NOX) activity, and glycotoxic cascades associated with advanced glycation end-products and inflammatory endothelial activation. These changes contribute to endothelial dysfunction, extracellular matrix degradation, increased blood–brain barrier permeability, and impaired neurovascular coupling. Potential approaches that may support barrier structures are discussed, including metabolic correction agents with vascular effects, modulation of the renin–angiotensin system, statins, and activation of NRF2-dependent cytoprotective programs. Conclusions. An NADPH-centered concept provides a consistent link between metabolic disturbances in metabolic syndrome and barrier dysfunction with cerebrovascular consequences via depletion of the restorative capacity of the neurovascular unit.
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Accepted 2026-03-13
Published 2026-04-28
