ArticleMolecular neurobiology2019
Inhibition of Toll-Like Receptor-4 (TLR-4) Improves Neurobehavioral Outcomes After Acute Ischemic Stroke in Diabetic Rats: Possible Role of Vascular Endothelial TLR-4.
Article in Molecular neurobiology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers.
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Who cites it
39 citing papers in PubMed, 52 citations in OpenAlex.
- Neuroprotective Effects of lncRNA EPB41L4A-AS1 Against Ischemic Stroke Injury Through Regulating Microglial State Transition and Ferroptosis via miR-214-3p/GPX4 Axis.Neurochemical research · 2026Article
- Immunotherapies for Ischemic Stroke Patients: Current Status and Future Directions.Medical sciences (Basel, Switzerland) · 2026Review
- TLR4 mediates post-traumatic depression via kynurenine pathway activation in a murine traumatic brain injury model.Frontiers in pharmacology · 2026Article
- Alzheimer's Disease, Obesity, and Type 2 Diabetes: Focus on Common Neuroglial Dysfunctions (Critical Review and New Data on Human Brain and Models).Brain sciences · 2024Review
- Article
- S100A9 deletion in microglia/macrophages ameliorates brain injury through the STAT6/PPARγ pathway in ischemic stroke.CNS neuroscience & therapeutics · 2024Article
- Ischemic stroke and diabetes: a TLR4-mediated neuroinflammatory perspective.Journal of molecular medicine (Berlin, Germany) · 2024Review
- Cerebroprotective Effects of the TLR4-Binding DNA Aptamer ApTOLL in a Rat Model of Ischemic Stroke and Thrombectomy Recanalization.Pharmaceutics · 2024Article
- Toll-like receptors as a missing link in Notch signaling cascade during neurodevelopment.Frontiers in molecular neuroscience · 2024Article
- Liraglutide Improves Diabetic Cardiomyopathy by Downregulation of Cardiac Inflammatory and Apoptosis Markers.Current drug research reviews · 2024Review
- Neuroprotective Effects of Sodium-Glucose Cotransporter-2 (SGLT2) Inhibitors (Gliflozins) on Diabetes-Induced Neurodegeneration and Neurotoxicity: A Graphical Review.International journal of preventive medicine · 2024Review
- Effect and Mechanism of Sodium Butyrate on Neuronal Recovery and Prognosis in Diabetic Stroke.Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology · 2023Article
- Is metformin neuroprotective against diabetes mellitus-induced neurodegeneration? An updated graphical review of molecular basis.Pharmacological reports : PR · 2023Review
- TAK-242 protects against oxygen-glucose deprivation and reoxygenation-induced injury in brain microvascular endothelial cells and alters the expression pattern of lncRNAs.Journal of thoracic disease · 2023Article
- Cerebral microvascular matrix metalloproteinase-3 (MMP3) contributes to vascular injury after stroke in female diabetic rats.Neurochemistry international · 2023Article
- Article
- Stroke: Molecular mechanisms and therapies: Update on recent developments.Neurochemistry international · 2023Review
- Vascular contributions to cognitive impairment/dementia in diabetes: role of endothelial cells and pericytes.American journal of physiology. Cell physiology · 2022Review
- GLP-1 receptor nitration contributes to loss of brain pericyte function in a mouse model of diabetes.Diabetologia · 2022Article
- Signaling pathways involved in ischemic stroke: molecular mechanisms and therapeutic interventions.Signal transduction and targeted therapy · 2022Review
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
Abstract
Diabetes increases the risk of occurrence and poor functional recovery after ischemic stroke injury. Previously, we have demonstrated greater hemorrhagic transformation (HT), edema, and more severe functional deficits after stroke in diabetic animals that also presented with cerebral vasoregression and endothelial cell death in the recovery period. Given that Toll-like receptor 4 (TLR-4) activation in microvascular endothelial cells triggers a robust inflammatory response, we hypothesized that inhibition of TLR-4 signaling prevents endothelial cell death and improves outcomes after stroke. Animals were treated with vehicle or TLR-4 inhibitor TAK242 (3 mg/kg; i.p.) following middle cerebral artery occlusion (MCAO). Neurobehavioral deficits were measured at baseline and day 3 after ischemic stroke. Primary brain microvascular endothelial cells (BMVECs) from diabetic animals were subjected to oxygen glucose deprivation re-oxygenation (OGDR) and treated with 0.1 mM iron(III)sulfate hydrate (iron) (to mimic the post-stroke bleeding) and TLR-4 inhibitors. Ischemic stroke increased the expression of TLR-4 in both hemispheres and in the microvasculature of diabetic animals. Cerebral infarct, edema, HT, and functional deficits were greater in diabetic compared to control animals. Inhibition of TLR-4 significantly reduced the neurovascular injury and improved functional outcomes. OGDR and iron reduced the cell viability and increased the expression of TLR-4 associated proteins (RIP3, MyD88, phospho-NF-kB, and release of IL-6) in BMVECs from diabetic animals. In conclusion, TLR-4 is highly upregulated in the microvasculature and that beneficial effects of TLR-4 inhibition are more profound in diabetes. This suggests that inhibition of vascular TLR-4 may provide therapeutic benefits for stroke recovery in diabetes.
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