Investigating the impact of resveratrol and quercetin on glymphatic function, blood-brain barrier, and neuroglial health: A systematic review.

OBJECTIVE: This systematic review evaluates the therapeutic potential of quercetin (QUE) and resveratrol (RSV) in Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS), focusing on their effects on glymphatic function, cerebrospinal fluid (CSF) dynamics, neuroglial health, and blood-brain barrier (BBB) permeability. METHODS: A systematic search was conducted across PubMed, ScienceDirect, and ProQuest following PRISMA guidelines for studies published between 2019 and 2024. Thirty-six studies, including experimental models and clinical trials, were identified and assessed for outcomes relating to antioxidant, anti-inflammatory, and neuroprotective effects of QUE and RSV. RESULTS: Across 36 studies, both QUE and RSV significantly enhanced antioxidant defences (upregulation of SOD, GSH, GPx, CAT) and downregulated pro-inflammatory cytokines (IL-1β, IL-6, TNF-α, NF-κB). BBB integrity improved via increased claudin‑5/occludin/ZO‑1 expression and reduced Evans blue/sodium fluorescein extravasation; cerebrovascular reactivity and cerebral blood flow (CBF) were frequently restored. Glymphatic outcomes demonstrated enhanced AQP4 polarisation at end feet and accelerated clearance of fluorescent tracers and β-amyloid in vivo, with preserved astrocyte-pericyte coupling. Neuroglial health improved (reduced microglial M1 markers, increased M2/Arg‑1 and astrocytic homeostatic markers), alongside neuronal survival, remyelination markers, and synaptic proteins. Nanoparticle/liposomal formulations of QUE/RSV increased BBB penetration and brain concentrations relative to free compounds. CONCLUSION: QUE and RSV demonstrate significant potential as adjunctive therapies for mitigating neuroinflammation, oxidative stress, and neurodegenerative progression through glymphatic and BBB modulation. However, further high-quality, long-term clinical trials are needed to validate these findings, optimise delivery systems, and establish translational relevance to human neurodegenerative conditions.