# Neuroprotective effect of resveratrol on Epac-1/Rap-1 signaling pathway in ischemic stroke rats

## TL;DR

Resveratrol protects the brain from stroke damage by reducing inflammation and neuronal death through a specific signaling pathway.

## Contribution

This study identifies the Epac-1/Rap-1 pathway as a novel mechanism through which resveratrol exerts neuroprotection in ischemic stroke.

## Key findings

- Resveratrol reduced infarct size and neurological deficits in stroke rats.
- Resveratrol modulated microglial polarization and suppressed inflammation via the Epac-1/Rap-1 pathway.
- Resveratrol increased the expression of Epac-1 and Rap-1 proteins in ischemic brain tissue.

## Abstract

To evaluate the neuroprotective effect of resveratrol (Res) and elucidate its underlying mechanism in a rat model of cerebral ischemia–reperfusion injury.

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 h 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.

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).

Res exerts neuroprotective effects against cerebral ischemia–reperfusion injury, potentially by modulating microglial polarization toward the M2 phenotype via the Epac-1/Rap-1 signaling pathway, thereby suppressing inflammation and mitigating neuronal damage.