Urolithin A mitigates behavioral and synaptic deficits associated with epilepsy through VDAC-1 inhibition: A novel treatment approach

Urolithin A mitigates behavioural and synaptic deficits associated with epilepsy | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Urolithin A mitigates behavioural and synaptic deficits associated with epilepsy SHEFALI MISHRA, Vijaya Verma, Sambit Pradhan, Manish Dwivedi, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4987164/v2 This work is licensed under a CC BY 4.0 License Status: Posted Version 2 posted You are reading this latest preprint version Show more versions Abstract The persistence of drug-resistant epilepsy highlights the need for new therapeutic interventions that target novel mechanisms with homeostatic regulations while minimizing side effects. Slow-acting drugs, particularly small molecules of natural origin with anti-epileptogenic potential, can contribute to this regulation by influencing the processes that drive epileptogenesis and seizure-susceptibility. One promising approach involves modifying the underlying pathophysiological mechanisms of synaptic plasticity leading to a reduced seizure threshold. We show that the administration of Urolithin-A (UA), a small molecule of natural origin, mitigates behavioural and synaptic dysfunctions under chemically and genetically induced epileptic conditions in Drosophila. Additionally, chronic treatment with UA attenuates the altered basal synaptic transmission and single-cell post-synaptic currents, curtailing the deleterious consequences of PTZ-induced chronic kindling of mice. However, UA exerts no seizure-suppressive effects in in-vitro epileptic conditions, implying the absence of acute symptomatic anti-epileptic effects. Here, we identify the direct interactor of UA as the complex of tubulin dimer and VDAC1 through affinity-purification with synthesized UA-attached beads and transcriptomics studies. Finally, neuron specific VDAC1 knockdown in Drosophila mimics UA supplementation effects. VDAC1 inhibition through UA offers new hope as a distinct neuroprotective therapeutic intervention for refractory epilepsy. Biological sciences/Neuroscience/Diseases of the nervous system/Epilepsy Biological sciences/Neuroscience/Molecular neuroscience Epilepsy Urolithin-A synaptic transmission epileptogenesis VDAC-1 behaviour Full Text Additional Declarations The authors declare no competing interests. Supplementary Files SupplementaryNMRandmassofbeadsynthesisreactionproducts.docx RSFinalSupplementaryFile.docx Cite Share Download PDF Status: Posted Version 2 posted You are reading this latest preprint version Show more versions Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4987164","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":367585065,"identity":"79f043a0-dd65-4637-af92-5418aaad7635","order_by":0,"name":"SHEFALI 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