Senkyunolide I Improves Septicemia-Induced Brain Dysfunction via Regulating Nrf2 and Astrocyte Activity.

Abstract

Senkyunolide I (Sen I) has a protective effect on the blood-brain barrier (BBB) in rats with sepsis-associated encephalopathy (SAE). This study investigated whether Sen I regulates Nrf2 to ameliorate sepsis-induced brain dysfunction (SIBD). Sixty rats were randomly assigned into Sham group, SAE group (Model group), SAE + Sen I group (72 mg/kg, Sen I group), and SAE+ positive control group (RTA 402, Nrf2 receptor agonist, RTA 402 group), with 15 rats in each group. The cecal ligation and puncture (CLP) method was applied to induce sepsis in rats. SAE modeling was verified 6 h after operation. The drug was administered 24 h after surgery. Six rats in each group were sacrificed 24 h after administration, with brains extracted. The remaining rats would continue to be observed for their survival status until 72 h post-surgery. Brain cell apoptosis was measured using TUNEL. We detected the expression of glial fibrillary acidic protein (GFAP) by immunofluorescence, Nrf2 gene expression by RT-qPCR, and the protein expression of Nrf2, MMP-9, AQP-4, and occludin by Western blot. TNF-α and IL-1β levels were tested by ELISA, and malondialdehyde (MDA) and glutathione peroxidase (GSH-Px) by biochemical tests. Survival rate at 72 h post-surgery, Sham group was 100%. The survival rate of the Sen I group (44.4%) and the RTA 402 group (55.6%) is significantly higher than that of the Model group (11.1%). Both Sen I and RTA 402 can improve the brain tissue damage in rats caused by sepsis, specifically by reducing apoptosis and GFAP expression, reducing TNF-α, IL-1β, and MDA levels, increasing the activity of GSH-Px, downregulating the protein expression of MMP-9 and AQP-4, and upregulating the protein expression of Nrf2 and occludin. Moreover, Sen I significantly increased the expression of Nrf2 in rat brain tissues. Sen I ameliorates SIBD in rats by regulating the expression of Nrf2 and astrocyte activation.