ArticleNeurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics2017
Tonabersat Prevents Inflammatory Damage in the Central Nervous System by Blocking Connexin43 Hemichannels.
Article in Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers.
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Who cites it
43 citing papers in PubMed.
- Gasotransmitters in the regulation of connexins in central and peripheral nervous system injuries.Medical gas research · 2027Review
- Tonabersat Blocks Gap Junctions and Alleviates Thermal Pain Behavior in Mice.International journal of molecular sciences · 2026Article
- Special Issue "Ocular Ischemic Diseases: From Molecular Mechanisms to Therapeutics".International journal of molecular sciences · 2026Article
- Review
- Evaluation of ocular tolerability and bioavailability of tonabersat transfersomes ex vivo.Drug delivery and translational research · 2026Article
- Inhibition of connexin hemichannels protects retinal ganglion cells against ocular nerve injury.Cellular and molecular life sciences : CMLS · 2026Article
- Bridging Hypoxia and Vision Loss: The Emerging Role of Connexins in Local and Systemic Eye Diseases.International journal of molecular sciences · 2026Review
- When the gatekeeper falls: developmental vulnerability of the thalamic reticular nucleus in neonatal and pediatric hypoxic-ischemic brain injury.Frontiers in systems neuroscience · 2026Review
- The Double-Edged Effect of Connexins and Pannexins of Glial Cells in Central and Peripheral Nervous System After Nerve Injury.Molecular neurobiology · 2025Review
- Tonabersat Inhibits Retinal Inflammation After Hypoxia-Ischemia in the Neonatal Rat.International journal of molecular sciences · 2025Article
- Tonabersat enhances temozolomide-mediated cytotoxicity in glioblastoma by disrupting intercellular connectivity through connexin 43 inhibition.Molecular oncology · 2025Article
- Retinal Hyperreflective Foci Are Biomarkers of Ocular Disease: A Scoping Review With Evidence From Humans and Insights From Animal Models.Journal of ophthalmology · 2025Review
- Aberrant CHCHD2-associated mitochondriopathy in Kii ALS/PDC astrocytes.Acta neuropathologica · 2024Article
- Pannexins in the musculoskeletal system: new targets for development and disease progression.Bone research · 2024Review
- Integrating and optimizing tonabersat in standard glioblastoma therapy: A preclinical study.PloS one · 2024Article
- Tonabersat Significantly Reduces Disease Progression in an Experimental Mouse Model of Multiple Sclerosis.International journal of molecular sciences · 2023Article
- Vascular Endothelial Barrier Protection Prevents Atrial Fibrillation by Preserving Cardiac Nanostructure.JACC. Clinical electrophysiology · 2023Article
- Astroglial Connexin 43-Mediated Gap Junctions and Hemichannels: Potential Antidepressant Mechanisms and the Link to Neuroinflammation.Cellular and molecular neurobiology · 2023Review
- The potential roles of stress-induced phosphoprotein 1 and connexin 43 in rats with reperfusion arrhythmia.Immunity, inflammation and disease · 2023Article
- Orally Delivered Connexin43 Hemichannel Blocker, Tonabersat, Inhibits Vascular Breakdown and Inflammasome Activation in a Mouse Model of Diabetic Retinopathy.International journal of molecular sciences · 2023Article
Corrections and comments
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Authors and funding
11 authors.
Funding
Abstract
The cis benzopyran compound tonabersat (SB-220453) has previously been reported to inhibit connexin26 expression in the brain by attenuating the p38-mitogen-activated protein kinase pathway. We show here that tonabersat directly inhibits connexin43 hemichannel opening. Connexin43 hemichannels have been called "pathological pores" based upon their role in secondary lesion spread, edema, inflammation, and neuronal loss following central nervous system injuries, as well as in chronic inflammatory disease. Both connexin43 hemichannels and pannexin channels released adenosine triphosphate (ATP) during ischemia in an in vitro ischemia model, but only connexin43 hemichannels contributed to ATP release during reperfusion. Tonabersat inhibited connexin43 hemichannel-mediated ATP release during both ischemia and reperfusion phases, with direct channel block confirmed using electrophysiology. Tonabersat also reduced connexin43 gap junction coupling in vitro, but only at higher concentrations, with junctional plaques internalized and degraded via the lysosomal pathway. Systemic delivery of tonabersat in a rat bright-light retinal damage model (a model for dry age-related macular degeneration) resulted in significantly improved functional outcomes assessed using electroretinography. Tonabersat also prevented thinning of the retina, especially the outer nuclear layer and choroid, assessed using optical coherence tomography. We conclude that tonabersat, already given orally to over 1000 humans in clinical trials (as a potential treatment for, and prophylactic treatment of, migraine because it was thought to inhibit cortical spreading depression), is a connexin hemichannel inhibitor and may have the potential to be a novel treatment of central nervous system injury and chronic neuroinflammatory disease.
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Registered trials
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