ArticleAging and disease2023
Neuronal Zinc Transporter ZnT3 Modulates Cerebral Ischemia-Induced Blood-Brain Barrier Disruption.
Article in Aging and disease, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 6 citations in OpenAlex.
- Zinc homeostasis imbalance: Potential therapeutic value in neurodegenerative diseases.Neural regeneration research · 2026Article
- Zinc dyshomeostasis, mitochondrial dysfunction, and their pathological cycle in ischemic stroke pathophysiology: Mechanisms and potential therapeutic targets.Redox biology · 2026Review
- The zinc-nitric oxide axis in acute brain injury: Convergent oxidative-nitrative stress, peroxynitrite signaling, and therapeutic targets.Redox biology · 2026Review
- Zinc Overload in Microvessels Contributes to Blood-Brain Barrier Disruption by Activating the JAK2 Pathway After Cerebral Ischemia/Reperfusion.CNS neuroscience & therapeutics · 2026Article
- Metal ion dyshomeostasis in neurological disorders: from pathological mechanisms to targeted neuroprotective and regenerative strategies.Frontiers in pharmacology · 2026Review
- Targeting angiogenesis and white matter repair for enhanced functional recovery after acute ischemic stroke: A focus on the roles of glial cells.Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism · 2026Review
- ZIP1-dependent lymphatic adaptations facilitate lymph node metastasis of pancreatic cancer.International journal of biological sciences · 2026Article
- Metallomic Aspects of Stroke and Recovery: ICP-MS Study with Chemometric Analysis.Molecules (Basel, Switzerland) · 2025Article
- A Comprehensive Prediction Model for Futile Recanalization in AIS Patients Post-Endovascular Therapy: Integrating Clinical, Imaging, and No-Reflow Biomarkers.Aging and disease · 2024Article
- Unlocking the brain's zinc code: implications for cognitive function and disease.Frontiers in biophysics · 2024Article
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Authors and funding
10 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Zinc plays important roles in both physiological and pathological processes in the brain. Accumulation of free zinc in ischemic tissue is recognized to contribute to blood-brain barrier (BBB) disruption following cerebral ischemia, but little is known either about the source of free zinc in microvessels or the mechanism by which free zinc mediates ischemia-induced BBB damage. We utilized cellular and animal models of ischemic stroke to determine the source of high levels of free zinc and the mechanism of free zinc-mediated BBB damage after ischemia. We report that cerebral ischemia elevated the level of extracellular fluid (ECF-Zn) of ischemic brain, leading to exacerbated BBB damage in a rat stroke model. Specifically suppressing zinc release from neurons, utilizing neuronal-specific zinc transporter 3 (ZnT3) knockout mice, markedly reduced ECF-Zn and BBB permeability after ischemia. Intriguingly, the activity of zinc-dependent metalloproteinase-2 (MMP-2) was modulated by ECF-Zn levels. Elevated ECF-Zn during ischemia directly bound to MMP-2 in extracellular fluid, increased its zinc content and augmented MMP-2 activity, leading to the degradation of tight junction protein in cerebral microvessels and BBB disruption. These findings suggest the role of neuronal ZnT3 in modulating ischemia-induced BBB disruption and reveal a novel mechanism of MMP-2 activation in BBB disruption after stroke, demonstrating ZnT3 as an effective target for stroke treatment.
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