Therapeutic Targeting of the Neurovascular Unit in Vascular Cognitive Impairment and Dementia

Vascular dementia (VaD) is the second most common form of dementia globally, yet it remains significantly underserved by disease-modifying therapeutics. Unlike Alzheimer’s disease, VaD is fundamentally rooted in cerebrovascular pathology: chronic cerebral hypoperfusion, blood-brain barrier (BBB) disruption, white matter injury, and neuroinflammation, making the neurovascular unit (NVU) a compelling but underexplored therapeutic target. Despite growing recognition of the vascular contribution to cognitive impairment and dementia (VCID), the translational pipeline from pharmacological and mechanistic insight to drug candidate remains sparse. Central to VaD pathophysiology is the dysregulation of interconnected signalling cascades, including PI3K/AKT/GSK3β, Nrf2-mediated antioxidant defence, and inflammatory cytokine networks, that collectively govern neuronal survival, endothelial integrity, and microglial activation, representing high-value targets for phytochemical, small-molecule, peptide, and biological therapies. Despite substantial preclinical progress, a critical gap persists between mechanistic discovery and clinically actionable drug candidates, compounded by VaD heterogeneity and limited translational biomarker use.This Research Topic aims to consolidate and advance the field by bringing together original research, systematic reviews, and perspective articles that address the broader drug discovery pipeline for vascular dementia and related cerebrovascular diseases. Specifically, it seeks to establish a clearer mechanistic framework for druggable target identification within the NVU, with emphasis on the interconnected roles of oxidative stress, mitochondrial dysfunction, and neuroinflammation in VaD pathophysiology. It aims to evaluate the translational potential of plant-derived and natural compound candidates, small molecules, peptides, glycopeptides, and biologics, linking preclinical pharmacological findings from rodent models of cerebral hypoperfusion, MCAo, and 4VO to clinically actionable lead compounds. Finally, it seeks to promote rational multi-target drug design and combination pharmacotherapy strategies that address the multi-factorial nature of VaD, and to identify key gaps in the translational pipeline where phytochemical, small-molecule, peptide, and biological approaches show the greatest unmet need.To gather further insights into the discovery, development, and translational evaluation of pharmacological strategies targeting the neurovascular unit in vascular cognitive impairment and dementia, we welcome articles addressing, but not limited to, the following themes:- Phytochemical, natural product-derived, and small-molecule drug discovery: lead identification, optimisation, and - ADMET profiling for cerebrovascular therapeutics- Peptide, glycopeptide, and biologic therapies for vascular dementia and VCID- Druggable targets within the neurovascular unit in cerebrovascular disease and vascular dementia- Nrf2 activators and antioxidant drug candidates targeting oxidative stress in VaD and related cerebrovascular conditions, including phytochemical and non-phytochemical modulators- Pharmacological modulation of neuroinflammation: CSF-1R/IL-34 inhibitors, microglial-targeted agents, and anti-synaptic pruning strategies in cognitive decline- Drug strategies targeting BBB restoration: tight junction stabilisers, pericyte-directed therapies, endothelial pharmacology, and BBB-modulating peptides or biologics for cerebrovascular protection- GSK3β inhibitors and PI3K/AKT pathway-directed drug candidates for neuroprotection and synaptic preservation in VaD- Preclinical pharmacology and model refinement for translational validity in VaD research, including natural compound, peptide, biologic, and small-molecule testing paradigms- Pharmacodynamic and prognostic biomarkers for patient stratification, target engagement, and clinical trial design in VCIDBoth basic science and translational original research contributions and reviews are welcome. We particularly encourage submissions that integrate pharmacological mechanistic insight with drug discovery potential and span multiple model systems to strengthen translational inference. Topic editors: Yogesh Kanna Sathyamoorthy, Kishore Kumar S. Narasimhan Source: https://www.frontiersin.org/research-topics/82663/therapeutic-targeting-of-the-neurovascular-unit-in-vascular-cognitive-impairment-and-dementia