ArticleAnnals of clinical and translational neurology2015
Identification of a neurovascular signaling pathway regulating seizures in mice.
Article in Annals of clinical and translational neurology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed, 44 citations in OpenAlex.
- The Role of Blood-Brain Barrier Disruption in Epilepsy: Mechanisms and Consequences.Neurology international · 2025Review
- The Plasminogen Activation System in the Central Nervous System: Implications for Epilepsy and Neuropsychiatric Disorders.International journal of molecular sciences · 2025Review
- Research progress in glioma-related epilepsy (Review).Biomedical reports · 2025Article
- PA System in the Pathogenesis of Ischemic Stroke.Arteriosclerosis, thrombosis, and vascular biology · 2025Review
- The interaction of tPA with NMDAR1 drives neuroinflammation and neurodegeneration in α-synuclein-mediated neurotoxicity.Journal of neuroinflammation · 2025Article
- Neuroserpin and Extracellular Vesicles in Ischemic Stroke: Partners in Neuroprotection?Aging and disease · 2024Review
- Comparative proteomics of proliferative diabetic retinopathy in people with Type 2 diabetes highlights the role of inflammation, visual transduction, and extracellular matrix pathways.Indian journal of ophthalmology · 2023Article
- Low-density lipoprotein receptor-related protein-1 (LRP1) in the glial lineage modulates neuronal excitability.Frontiers in network physiology · 2023Review
- DNA methylation subclass receptor tyrosine kinase II (RTK II) is predictive for seizure development in glioblastoma patients.Neuro-oncology · 2022Article
- Diabetes and the treatment of ischemic stroke.Journal of diabetes and its complications · 2022Review
- Parvalbumin interneuron-derived tissue-type plasminogen activator shapes perineuronal net structure.BMC biology · 2022Article
- Compartmentalized Actions of the Plasminogen Activator Inhibitors, PAI-1 and Nsp, in Ischemic Stroke.Translational stroke research · 2022Article
- Article
- Historical and current perspectives on blood endothelial cell heterogeneity in the brain.Cellular and molecular life sciences : CMLS · 2022Review
- Tissue Plasminogen Activator in Central Nervous System Physiology and Pathology: From Synaptic Plasticity to Alzheimer's Disease.Seminars in thrombosis and hemostasis · 2022Review
- Neuroserpin, a crucial regulator for axogenesis, synaptic modelling and cell-cell interactions in the pathophysiology of neurological disease.Cellular and molecular life sciences : CMLS · 2022Review
- Neuroserpin: structure, function, physiology and pathology.Cellular and molecular life sciences : CMLS · 2021Review
- Vascular Expression of Permeability-Resistant Occludin Mutant Preserves Visual Function in Diabetes.Diabetes · 2021Article
- Blocking PDGF-CC signaling ameliorates multiple sclerosis-like neuroinflammation by inhibiting disruption of the blood-brain barrier.Scientific reports · 2020Article
- The role of endogenous tissue-type plasminogen activator in neuronal survival after ischemic stroke: friend or foe?Cellular and molecular life sciences : CMLS · 2019Review
Corrections and comments
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Authors and funding
9 authors at 1 institution in 2 countries.
Funding
Abstract
objectiveA growing body of evidence suggests that increased blood-brain barrier (BBB) permeability can contribute to the development of seizures. The protease tissue plasminogen activator (tPA) has been shown to promote BBB permeability and susceptibility to seizures. In this study, we examined the pathway regulated by tPA in seizures.
methodsAn experimental model of kainate-induced seizures was used in genetically modified mice, including mice deficient in tPA (tPA (-/-) ), its inhibitor neuroserpin (Nsp (-/-) ), or both (Nsp:tPA (-/-) ), and in mice conditionally deficient in the platelet-derived growth factor receptor alpha (PDGFRα).
resultsCompared to wild-type (WT) mice, Nsp (-/-) mice have significantly reduced latency to seizure onset and generalization; whereas tPA (-/-) mice have the opposite phenotype, as do Nsp:tPA (-/-) mice. Furthermore, interventions that maintain BBB integrity delay seizure propagation, whereas osmotic disruption of the BBB in seizure-resistant tPA (-/-) mice dramatically reduces the time to seizure onset and accelerates seizure progression. The phenotypic differences in seizure progression between WT, tPA (-/-) , and Nsp (-/-) mice are also observed in electroencephalogram recordings in vivo, but absent in ex vivo electrophysiological recordings where regulation of the BBB is no longer necessary to maintain the extracellular environment. Finally, we demonstrate that these effects on seizure progression are mediated through signaling by PDGFRα on perivascular astrocytes.
interpretationTogether, these data identify a specific molecular pathway involving tPA-mediated PDGFRα signaling in perivascular astrocytes that regulates seizure progression through control of the BBB. Inhibition of PDGFRα signaling and maintenance of BBB integrity might therefore offer a novel clinical approach for managing seizures.
Identifiers
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.