ORIGINAL RESEARCH article
Front. Neurosci.
Sec. Neuropharmacology
Neuroprotective effect of resveratrol on Epac-1/Rap-1 signaling pathway in ischemic stroke rats
Provisionally accepted
- 1the Fourth Affiliated Hospital of Southwest Medical University, Meishan, China
- 2Affiliated Hospital of Traditional Chinese Medicine of Southwest Medical University, Luzhou, China
- 3Affiliated Hospital of Southwest Medical University, Sichuan, China
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Objective: To evaluate the neuroprotective effect of resveratrol (Res) and elucidate its underlying mechanism in a rat model of cerebral ischemia-reperfusion injury. Methods: Adult male Sprague–Dawley rats received intraperitoneal Res (40 mg/kg/day) for three consecutive days, followed by transient middle cerebral artery occlusion/reperfusion (MCAO/R). Animals were randomly divided into Sham, MCAO/R, and Res groups. Neurological function was evaluated 24 hours after reperfusion. Cerebral infarct volume was assessed by 2,3,5-triphenyltetrazolium chloride (TTC) staining. The serum levels of M1/M2 polarization markers, including the enzymes inducible nitric oxide synthase (iNOS) and arginase-1 (Arg-1), as well as the cytokines interleukin-12 (IL-12) and interleukin-10 (IL-10), were measured by enzyme-linked immunosorbent assay (ELISA). Apoptosis (non-specific neuronal apoptosis) was detected by the terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining method. To investigate the underlying mechanism, we focused on the exchange protein directly activated by cAMP-1 (Epac-1) and its downstream effector Ras-related protein 1 (Rap-1), which are known regulators of neuroinflammation. The expression levels of the exchange proteins directly activated by Epac-1 and Rap-1 in ischemic brain tissue were detected using Western blotting. Results: Relative to the Sham group, the MCAO/R group exhibited significantly larger infarct volumes and higher neurological deficit scores, together with increased serum iNOS and IL-12 and decreased IL-10 and Arg-1 (all P < 0.05). The apoptosis of neuronal cells increases while the expressions of Epac-1 and Rap-1 proteins decrease. (P < 0.05). Res treatment significantly reduced infarct size and neurological deficits; lowered serum iNOS and IL-12; raised IL-10 and Arg-1; and improved Epac-1 and Rap-1 expression compared with the MCAO/R group (all P < 0.05). Conclusion: Res exerts neuroprotective effects against cerebral ischemia-reperfusion injury, potentially by modulating microglial polarization toward the M2 phenotype via the Epac-1/Rap-1 signalling pathway, thereby suppressing inflammation and mitigating neuronal damage.
Keywords: Cerebral Infarction, Epac-1/Rap-1 signaling pathway, ischemia-reperfusioninjury, Neuroprotection, resveratrol
Received: 12 Sep 2025; Accepted: 15 Dec 2025.
Copyright: © 2025 Li, He, Gao and Zou. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Yue Zou
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