Resveratrol’s Neuroprotective Effects on the Retina in a Pentylenetetrazol-Induced Epilepsy Model in Rats: Insights into SIRT1 Signaling, Apoptosis, and Gliosis

Background/Objectives: A chronic neurological disorder known as epilepsy results in neurodegeneration, oxidative stress, and damage to the retina and the central nervous system’s 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 ± 145.82 in PTZ to 354.25 ± 31.22 in PTZ + RES, p < 0.0001) and lowered the average seizure stage from 4.25 ± 0.27 to 2.43 ± 0.49 (p < 0.05), while lengthening the initial myoclonic jerk latency (from 162 ± 29.62 s to 219.37 ± 32.12 s, p < 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 ± 0.9% in PTZ to 8.4 ± 0.8% in PTZ + RES, p < 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 ± 0.9% to 5.6 ± 0.8%, p < 0.001) and attenuated reactive gliosis (GFAP area fraction decreased from 14.1 ± 1.2% to 9.1 ± 1.4%, p < 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 < 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.