ArticleJournal of neuroinflammation2022
TNFα-mediated necroptosis in brain endothelial cells as a potential mechanism of increased seizure susceptibility in mice following systemic inflammation.
Article in Journal of neuroinflammation, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 50 citations in OpenAlex.
- GSK'872 mitigates ischemia-reperfusion injury in rat lung transplants by regulating PANoptosis and inflammation in cell type specific manner.Cell communication and signaling : CCS · 2026Article
- Programmed Cell Death of Endothelial Cells in Ischemic Heart Disease: Mechanism and Potential Cell and Gene Therapeutic Prospects.Bioengineering (Basel, Switzerland) · 2026Review
- ISG15 negatively regulates RIPK3-mediated cell death and viral pathogenesis.Cell reports · 2026Article
- The RIPK3 Inhibitor GSK872 Attenuates Inflammation and Necroptosis via Modulation of the JNK Signaling Pathway in LPS-Stimulated Microglia.Biomolecules & therapeutics · 2026Article
- The Biomarkers and Underlying Mechanisms of Mitochondrial and Programmed Cell Death Related Genes in Epilepsy by Combining Transcriptome and Single-Cell Sequencing.Journal of Korean Neurosurgical Society · 2026Article
- Blood-spinal cord barrier disruption after spinal cord injury: a time-dependent mechanistic review.Frontiers in cellular neuroscience · 2026Review
- Cell death signaling and immune regulation: new perspectives on targeted therapy for sepsis.Cellular & molecular biology letters · 2025Review
- THSG counteracts microglial glycolytic reprogramming and neuronal necroptosis both in vivo and in vitro under conditions of neuroinflammation.Scientific reports · 2025Article
- The glycocalyx: a key target for treatment of severe acute pancreatitis-associated multiple organ dysfunction syndrome.Human cell · 2025Review
- Evaluating the impact of Pomalidomide on memory dysfunction induced by neuroinflammation in Pentylenetetrazole-seizure model of male Wistar rats.Metabolic brain disease · 2025Article
- Aging, vascular dysfunction, and the blood-brain barrier: unveiling the pathophysiology of stroke in older adults.Biogerontology · 2025Review
- Mitigating effects of Jiawei Chaihu Shugan decoction on necroptosis and inflammation of hippocampal neurons in epileptic mice.Scientific reports · 2025Article
- Decoding interaction between mitochondria and endoplasmic reticulum in ischemic myocardial injury: targeting natural medicines.Frontiers in pharmacology · 2025Review
- Mechanistic insights into the sleep-glymphopathy-cerebral small vessel disease loop: implications for epilepsy pathophysiology and therapy.Frontiers in neuroscience · 2025Review
- Association between dietary inflammatory index and epilepsy: findings from NHANES.Frontiers in neurology · 2025Article
- MLKL-mediated endothelial necroptosis drives vascular damage and mortality in systemic inflammatory response syndrome.Cellular & molecular immunology · 2024Article
- Causal relationship between immune cells and epilepsy mediated by metabolites analyzed through Mendelian randomization.Scientific reports · 2024Article
- The Neurovascular Unit Dysfunction in the Molecular Mechanisms of Epileptogenesis and Targeted Therapy.Neuroscience bulletin · 2024Review
- Analysis of the role of PANoptosis in seizures via integrated bioinformatics analysis and experimental validation.Heliyon · 2024Article
- Sepsis-Induced Endothelial Dysfunction: Permeability and Regulated Cell Death.Journal of inflammation research · 2024Review
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Authors and funding
8 authors at 4 institutions in 1 country.
Funding
Abstract
backgroundSystemic inflammation is a potent contributor to increased seizure susceptibility. However, information regarding the effects of systemic inflammation on cerebral vascular integrity that influence neuron excitability is scarce. Necroptosis is closely associated with inflammation in various neurological diseases. In this study, necroptosis was hypothesized to be involved in the mechanism underlying sepsis-associated neuronal excitability in the cerebrovascular components (e.g., endothelia cells).
methodsLipopolysaccharide (LPS) was used to induce systemic inflammation. Kainic acid intraperitoneal injection was used to measure the susceptibility of the mice to seizure. The pharmacological inhibitors C87 and GSK872 were used to block the signaling of TNFα receptors and necroptosis. In order to determine the features of the sepsis-associated response in the cerebral vasculature and CNS, brain tissues of mice were obtained for assays of the necroptosis-related protein expression, and for immunofluorescence staining to identify morphological changes in the endothelia and glia. In addition, microdialysis assay was used to assess the changes in extracellular potassium and glutamate levels in the brain.
resultsSome noteworthy findings, such as increased seizure susceptibility and brain endothelial necroptosis, Kir4.1 dysfunction, and microglia activation were observed in mice following LPS injection. C87 treatment, a TNFα receptor inhibitor, showed considerable attenuation of increased kainic acid-induced seizure susceptibility, endothelial cell necroptosis, microglia activation and restoration of Kir4.1 protein expression in LPS-treated mice. Treatment with GSK872, a RIP3 inhibitor, such as C87, showed similar effects on these changes following LPS injection.
conclusionsThe findings of this study showed that TNFα-mediated necroptosis induced cerebrovascular endothelial damage, neuroinflammation and astrocyte Kir4.1 dysregulation, which may coalesce to contribute to the increased seizure susceptibility in LPS-treated mice. Pharmacologic inhibition targeting this necroptosis pathway may provide a promising therapeutic approach to the reduction of sepsis-associated brain endothelia cell injury, astrocyte ion channel dysfunction, and subsequent neuronal excitability.
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