Cuscuta chinensis Lam. Flavonoids (CCLF) alleviate the symptoms of sepsis-associated encephalopathy via PI3K/Nrf2 pathway

• Published in: Behavioural brain research 2024-05, Vol.465, p.114887, Article 114887
• Main Authors: Boxiang, Qi, Liping, Sheng, Tong, Qian
• Format: Article
• Language: English
• Subjects: Animals; Cuscuta - metabolism; Cuscuta chinensis Lam. Flavonoids; Flavonoids - pharmacology; Flavonoids - therapeutic use; NF-E2-Related Factor 2 - metabolism; Phosphatidylinositol 3-Kinases; PI3K/AKT/Nrf2/ HO-1 signaling pathway; Proto-Oncogene Proteins c-akt - metabolism; Sepsis - complications; Sepsis - drug therapy; Sepsis - pathology; Sepsis-associated encephalopathy; Sepsis-Associated Encephalopathy - drug therapy
• ISSN: 0166-4328; 1872-7549; 1872-7549
• DOI: 10.1016/j.bbr.2024.114887

Sepsis-associated encephalopathy (SAE) frequently encounters patients who are in intensive care units and ∼70% of patients with severe systemic infection. However, due to the unclear pathological mechanisms of SAE, the desease-modifying drug is still lack. Here, we aimed to explore whether the flavonoid components extracted from CCL (CCLF) seeds possess protective effects on SAE animals, and systematically evaluate the transcriptomic alteration (in the hippocampus) after CCLF treatment on SAE animals employing RNA sequencing. We observed that CCLF improved the brain’s learning and memory abilities and the structural integrity of BBB using cecal ligation and puncture (CLP)-induced SAE animal models, evaluated by behavioral test and tissue examination of animals respectively. RNA sequencing results showed that CCLF treatment reverses SAE-induced transcriptomic alteration in the hippocampus. Moreover, CCLF also dramatically relieved inflammatory (such as TNF-α, IL-2, and IL-6) and oxidative (MDA and SOD activity) stresses, and inhibited SAE-induced neuron apoptosis in brain tissues. More importantly, CCLF restored the PI3K/AKT signaling pathway and then induced the Nrf2 nuclear translocation to drive HO-1 expression both in vitro and in vivo. LY294002, an inhibitor of PI3K, obviously blocked CCLF’s functions on anti-apoptosis, anti-inflammation, and anti-oxidation in vivo, demonstrating that CCLF achieves its bioactivities in a PI3K/AKT signaling dependent manner. Altogether, CCLF exhibits remarkable neuro-protective function and may be a promising candidate for further clinical trials for SAE treatment. [Display omitted] •CCLF seed flavonoids (CCLF) improved learning, memory, and BBB integrity in SAE animal models.•RNA sequencing revealed CCLF reversed SAE-induced hippocampal transcriptomic changes.•CCLF showed potent anti-inflammatory and antioxidant effects, reducing cytokines and oxidative markers.•CCLF inhibited SAE-induced neuron apoptosis in brain tissues.•CCLF restored PI3K/AKT signaling, promoting Nrf2 nuclear translocation and HO-1 upregulation.