{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T10:46:39Z","timestamp":1789469199773,"version":"build-2803163510"},"reference-count":39,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T00:00:00Z","timestamp":1789430400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Background\/Objectives: A chronic neurological disorder known as epilepsy results in neurodegeneration, oxidative stress, and damage to the retina and the central nervous system\u2019s structure. The main objective of this research was to examine the neuroprotective benefits of Resveratrol (RES) on the retina in a model using Pentylenetetrazol (PTZ) in rats to induce kindling and to investigate the underlying molecular and biochemical mechanisms (SIRT1, GFAP, VEGF, apoptotic pathways, and oxidative stress markers [malondialdehyde (MDA) and reduced glutathione (GSH)] of this protective effect. Methods: A total of thirty-two male Wistar albino rats were randomly assigned to four distinct groups: Sham, RES (5 mg\/kg\/day), PTZ (35 mg\/kg), and PTZ + RES (n = 8 per group). Electrocorticography (ECoG) recordings were used to assess seizure severity. Retinal expression of GFAP, VEGF, SIRT1, Bax, Bcl-2, Caspase-3, and Caspase-9 was evaluated via qPCR and immunofluorescence, while tissue lipid peroxidation (MDA) and reduced glutathione (GSH) levels were quantified spectrophotometrically to directly evaluate retinal redox status. Results: Substantial increases in seizure scores and electrocorticogram spike counts were noted in the PTZ group, whereas RES treatment significantly reduced the total ECoG spike count by 49.6% (from 702.87 \u00b1 145.82 in PTZ to 354.25 \u00b1 31.22 in PTZ + RES, p &lt; 0.0001) and lowered the average seizure stage from 4.25 \u00b1 0.27 to 2.43 \u00b1 0.49 (p &lt; 0.05), while lengthening the initial myoclonic jerk latency (from 162 \u00b1 29.62 s to 219.37 \u00b1 32.12 s, p &lt; 0.01). Molecular and histopathological analyses revealed that RES treatment was associated with enhanced localized retinal cell survival and a significant increase in the nuclear SIRT1 immunofluorescence area fraction in the retina, which more than doubled the nuclear SIRT1 immunofluorescence area fraction in the retina (from 4.2 \u00b1 0.9% in PTZ to 8.4 \u00b1 0.8% in PTZ + RES, p &lt; 0.05) despite a physiological transcription-level feedback reduction in SIRT1 mRNA. Furthermore, RES treatment significantly suppressed PTZ-induced retinal apoptosis (Caspase-3 area fraction decreased from 10.6 \u00b1 0.9% to 5.6 \u00b1 0.8%, p &lt; 0.001) and attenuated reactive gliosis (GFAP area fraction decreased from 14.1 \u00b1 1.2% to 9.1 \u00b1 1.4%, p &lt; 0.01). Biochemically, PTZ kindling induced a profound increase in retinal lipid peroxidation (MDA) and a severe depletion of reduced glutathione (GSH) reserves, both of which were robustly reversed by RES treatment back toward physiological Sham levels (p &lt; 0.01). Conclusions: Chronic epilepsy causes glial activation, oxidative damage, and apoptosis in the retina, with RES-associated retinal protection involving the restoration of redox homeostasis and the upregulation of the SIRT1 signaling pathway. These preclinical findings suggest that RES represents a promising protective strategy against epilepsy-associated retinal damage, though further clinical validation is warranted to establish its therapeutic safety and efficacy in human patients.<\/jats:p>","DOI":"10.3390\/antiox15091168","type":"journal-article","created":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T09:31:57Z","timestamp":1789464717000},"page":"1168","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Resveratrol\u2019s Neuroprotective Effects on the Retina in a Pentylenetetrazol-Induced Epilepsy Model in Rats: Insights into SIRT1 Signaling, Apoptosis, and Gliosis"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4816-830X","authenticated-orcid":false,"given":"Omer","family":"Unal","sequence":"first","affiliation":[{"name":"Department of Physiology, Faculty of Medicine, Samsun University, 55080 Samsun, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7750-482X","authenticated-orcid":false,"given":"Nilufer","family":"Akgun-Unal","sequence":"additional","affiliation":[{"name":"Department of Biophysics, Faculty of Medicine, Ondokuz Mayis University, 55139 Samsun, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elif","family":"Gulbahce-Mutlu","sequence":"additional","affiliation":[{"name":"Department of Medical Biology, Faculty of Medicine, KTO Karatay University, 42020 Konya, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4237-5831","authenticated-orcid":false,"given":"Seda","family":"Simsek","sequence":"additional","affiliation":[{"name":"Department of Histology and Embryology, Faculty of Medicine, Selcuk University, 42130 Konya, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6594-3080","authenticated-orcid":false,"given":"Mustafa","family":"Ayyildiz","sequence":"additional","affiliation":[{"name":"Department of Physiology, Faculty of Medicine, Ondokuz Mayis University, 55139 Samsun, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1111\/epi.13670","article-title":"Operational classification of seizure types by the International League Against Epilepsy: Position Paper of the ILAE Commission for Classification and Terminology","volume":"58","author":"Fisher","year":"2017","journal-title":"Epilepsia"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1016\/j.npep.2014.09.003","article-title":"The interaction between ghrelin and cannabinoid systems in penicillin-induced epileptiform activity in rats","volume":"48","author":"Arslan","year":"2014","journal-title":"Neuropeptides"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1016\/j.seizure.2025.07.010","article-title":"Retinal thinning in epilepsy: A meta-analysis","volume":"131","author":"Chontos","year":"2025","journal-title":"Seizure"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Martinc, B., Grabnar, I., Milosheska, D., Lorber, B., and Vovk, T. (2024). A Cross-Sectional Study Comparing Oxidative Stress in Patients with Epilepsy Treated with Old and New Generation Antiseizure Medications. Medicina, 60.","DOI":"10.3390\/medicina60081299"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Rider, F., Guekht, A., and Shpak, A. (2025). Optical coherence tomography angiography in patients with focal epilepsy. Front. Neurol., 16.","DOI":"10.3389\/fneur.2025.1529409"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"478","DOI":"10.35440\/hutfd.1715741","article-title":"Antiepileptik Kullanan Epilepsi Hastalar\u0131n\u0131n Retina ve Optik Sinir De\u011fi\u015fikliklerinin Optik Koherens Tomografi Anjiografi (OKTA) \u0130le De\u011ferlendirilmesi","volume":"22","year":"2025","journal-title":"Harran \u00dcniversitesi T\u0131p Fak\u00fcltesi Derg."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2235","DOI":"10.1002\/acn3.51473","article-title":"Optical coherence tomography in multiple sclerosis: A 3-year prospective multicenter study","volume":"8","author":"Paul","year":"2021","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1007\/s10072-020-04992-4","article-title":"Retinal nerve fiber layer changes in migraine: A systematic review and meta-analysis","volume":"42","author":"Lin","year":"2021","journal-title":"Neurol. Sci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1186\/s40035-021-00230-9","article-title":"Advances in retina imaging as potential biomarkers for early diagnosis of Alzheimer\u2019s disease","volume":"10","author":"Zhang","year":"2021","journal-title":"Transl. Neurodegener."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Chang, Z., Xie, F., Li, H., Yuan, F., Zeng, L., Shi, L., Zhu, S., Lu, X., Wei, X., and Wang, Q. (2022). Retinal Nerve Fiber Layer Thickness and Associations With Cognitive Impairment in Parkinson\u2019s Disease. Front. Aging Neurosci., 14.","DOI":"10.3389\/fnagi.2022.832768"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1111\/ene.14613","article-title":"Optical coherence tomography measurements as potential imaging biomarkers for Parkinson\u2019s disease: A systematic review and meta-analysis","volume":"28","author":"Zhou","year":"2021","journal-title":"Eur. J. Neurol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"3053","DOI":"10.4103\/IJO.IJO_2802_22","article-title":"Evaluation of ganglion cell complex and retinal nerve fiber layer thinning in epilepsy patients","volume":"71","author":"Duran","year":"2023","journal-title":"Indian J. Ophthalmol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1184","DOI":"10.2174\/1570159X20666221012122855","article-title":"Resveratrol-Mediated Regulation of Mitochondria Biogenesis-associated Pathways in Neurodegenerative Diseases: Molecular Insights and Potential Therapeutic Applications","volume":"21","author":"Shaito","year":"2023","journal-title":"Curr. Neuropharmacol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"604","DOI":"10.30621\/jbachs.1733984","article-title":"Resveratrol Stabilizes Cytosolic \u00df-Catenin Through The Activation of The Thermogenic Cascade","volume":"9","author":"Sercan","year":"2025","journal-title":"J. Basic Clin. Health Sci."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Castro, O.W., Upadhya, D., Kodali, M., and Shetty, A.K. (2017). Resveratrol for Easing Status Epilepticus Induced Brain Injury, Inflammation, Epileptogenesis, and Cognitive and Memory Dysfunction-Are We There Yet?. Front. Neurol., 8.","DOI":"10.3389\/fneur.2017.00603"},{"key":"ref_16","first-page":"36","article-title":"Role of the PGE2 receptor in ischemia-reperfusion injury of the rat retina","volume":"26","author":"Deng","year":"2020","journal-title":"Mol. Vis."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1007\/s10571-019-00781-6","article-title":"Resveratrol Protects Optic Nerve Head Astrocytes from Oxidative Stress-Induced Cell Death by Preventing Caspase-3 Activation, Tau Dephosphorylation at Ser(422) and Formation of Misfolded Protein Aggregates","volume":"40","author":"Means","year":"2020","journal-title":"Cell. Mol. Neurobiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/j.jneumeth.2008.04.019","article-title":"The pilocarpine model of temporal lobe epilepsy","volume":"172","author":"Curia","year":"2008","journal-title":"J. Neurosci. Methods"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2887","DOI":"10.1016\/j.neubiorev.2013.10.011","article-title":"The kainic acid model of temporal lobe epilepsy","volume":"37","author":"Avoli","year":"2013","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"752","DOI":"10.1007\/s12035-026-06054-w","article-title":"Resveratrol Ameliorates PTZ-Induced Seizure Activity and Diaphragm Muscle Dysfunction by Regulating Calcium Handling and Apoptotic Pathways in Rats","volume":"63","author":"Akkoca","year":"2026","journal-title":"Mol. Neurobiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"18365","DOI":"10.1007\/s00210-026-05557-6","article-title":"Epilepsy-induced heart damage and sudep risk: Ion channelopathies, calcium homeostasis, and the therapeutic potential of resveratrol","volume":"399","author":"Unal","year":"2026","journal-title":"Naunyn Schmiedebergs Arch. Pharmacol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1007\/s13311-014-0334-6","article-title":"Diffusion Efficiency and Bioavailability of Resveratrol Administered to Rat Brain by Different Routes: Therapeutic Implications","volume":"12","author":"Shu","year":"2015","journal-title":"Neurotherapeutics"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"134823","DOI":"10.1016\/j.neulet.2020.134823","article-title":"Proconvulsant effect of trans-cinnamaldehyde in pentylenetetrazole-induced kindling model of epilepsy: The role of TRPA1 channels","volume":"721","author":"Arslan","year":"2020","journal-title":"Neurosci. Lett."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1016\/j.freeradbiomed.2016.03.004","article-title":"NADPH oxidase activation is required for pentylenetetrazole kindling-induced hippocampal autophagy","volume":"94","author":"Zhu","year":"2016","journal-title":"Free Radic. Biol. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1129","DOI":"10.1007\/s007020050117","article-title":"Influence of ethanol on the pentylenetetrazol-induced kindling in rats","volume":"105","author":"Fischer","year":"1998","journal-title":"J. Neural Transm."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e00727","DOI":"10.1002\/brb3.727","article-title":"Effect of lamotrigine on seizure development in a rat pentylenetetrazole kindling model","volume":"7","author":"Chen","year":"2017","journal-title":"Brain Behav."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/j.neulet.2016.09.002","article-title":"Resveratrol lacks protective activity against acute seizures in mouse models","volume":"632","author":"Tomaciello","year":"2016","journal-title":"Neurosci. Lett."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"108287","DOI":"10.1016\/j.intimp.2021.108287","article-title":"Resveratrol loaded nanoparticles attenuate cognitive impairment and inflammatory markers in PTZ-induced kindled mice","volume":"101","author":"Siddiqui","year":"2021","journal-title":"Int. Immunopharmacol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"106243","DOI":"10.1016\/j.eplepsyres.2019.106243","article-title":"Micronized resveratrol shows promising effects in a seizure model in zebrafish and signalizes an important advance in epilepsy treatment","volume":"159","author":"Decui","year":"2020","journal-title":"Epilepsy Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"17187","DOI":"10.1074\/jbc.M501250200","article-title":"Mechanism of human SIRT1 activation by resveratrol","volume":"280","author":"Borra","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"151","DOI":"10.18632\/aging.100542","article-title":"Sirt1 activation by resveratrol is substrate sequence-selective","volume":"5","author":"Lakshminarasimhan","year":"2013","journal-title":"Aging"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1002\/ame2.12438","article-title":"Neuroprotective effects of resveratrol on retinal ganglion cells in glaucoma in rodents: A narrative review","volume":"7","author":"Golmohammadi","year":"2024","journal-title":"Anim. Model. Exp. Med."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"D\u2019Angelo, A., Vitiello, L., Lixi, F., Abbinante, G., Coppola, A., Gagliardi, V., Pellegrino, A., and Giannaccare, G. (2024). Optic Nerve Neuroprotection in Glaucoma: A Narrative Review. J. Clin. Med., 13.","DOI":"10.3390\/jcm13082214"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Moshtaghion, S.M., Caballano-Infantes, E., Plaza Reyes, \u00c1., Vald\u00e9s-S\u00e1nchez, L., Fern\u00e1ndez, P.G., de la Cerda, B., Riga, M.S., \u00c1lvarez-Dolado, M., Pe\u00f1alver, P., and Morales, J.C. (2024). Piceid Octanoate Protects Retinal Cells against Oxidative Damage by Regulating the Sirtuin 1\/Poly-ADP-Ribose Polymerase 1 Axis In Vitro and in rd10 Mice. Antioxidants, 13.","DOI":"10.3390\/antiox13020201"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1038\/nrneurol.2012.227","article-title":"The retina as a window to the brain-from eye research to CNS disorders","volume":"9","author":"London","year":"2013","journal-title":"Nat. Rev. Neurol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"652","DOI":"10.1016\/S0002-9343(00)00412-5","article-title":"The evolution of free radicals and oxidative stress","volume":"108","author":"McCord","year":"2000","journal-title":"Am. J. Med."},{"key":"ref_38","first-page":"145","article-title":"In Diabetic Aged Female Rats, Resveratrol Supplementation Prevents Retinal Tissue Damage By Increasing Antioxidant Activity Through SIRT1 Gene Expression","volume":"62","author":"Atacak","year":"2025","journal-title":"Noro Psikiyatr. Ars."},{"key":"ref_39","first-page":"98","article-title":"Effects of S-Methyl Methionine Sulfonium Chloride on Lens Tissue in Pentylenetetrazol-Induced Seizures in Rats","volume":"28","author":"Sinem","year":"2022","journal-title":"Arch. Epilepsy"}],"container-title":["Antioxidants"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3921\/15\/9\/1168\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T09:52:50Z","timestamp":1789465970000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3921\/15\/9\/1168"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,15]]},"references-count":39,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["antiox15091168"],"URL":"https:\/\/doi.org\/10.3390\/antiox15091168","relation":{},"ISSN":["2076-3921"],"issn-type":[{"value":"2076-3921","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,15]]}}}