Work

Mechanism of Atractylodis Rhizoma in improving cognitive dysfunction in Alzheimer's disease by regulating the cAMP/CREB/BDNF pathway

Year: 2025

Type: article

Abstract: Alzheimer's disease (AD) is a common degenerative neurological disease. As a representative spleen-invigorating Chinese herb, Atractylodis rhizoma belongs to the genus Atractylodes of the Compositae family and possesses the efficacy of invigorating the spleen and resolving phlegm, which aligns with the therapeutic principle of treating AD by invigorating the spleen in traditional Chinese medicine theory. Modern studies have shown that some components of Atractylodis rhizoma exhibit activities such as neuroprotection and anti-inflammation, demonstrating potential in the treatment of neurological diseases. However, its specific pharmacological effects and mechanisms in treating AD remain unclear.In this study, ultra-high performance liquid chromatography-high resolution mass spectrometry (UHPLC-HRMS) was used to analyze the chemical components of the ethanol extract of Atractylodis rhizoma (EEAR). Combined with network pharmacology and molecular docking, the potential targets and action pathways of EEAR against AD were predicted, and RNA-Seq technology was employed to detect the expression of differentially expressed genes for verifying these results. AD rat model was established by injecting Aβ25-35 via bilateral stereotaxic technique. Behavioral tests were conducted to evaluate the effect of EEAR on improving cognitive impairment in AD, and Nissl staining was used to observe pathological changes in the hippocampal tissue of rats. ELISA and RT-qPCR were applied to analyze the impact of EEAR on the expression of IL-6, IL-1β, and TNF-α. An in vitro AD model was constructed by inducing HT22 cells with Aβ25-35; the CREB inhibitor KG-501 was used in combination with Western Blotting and RT-qPCR to detect the expression of proteins and genes related to the cAMP, CREB, and BDNF pathways.Results from component analysis and network pharmacology indicated that the main active components of EEAR include β-Eudesmol, Atractylenolide I, and Atractylon. EEAR exerts its therapeutic effect on AD mainly by regulating key targets such as IL6, TNF, IL1B, and CREB1, as well as the cAMP signaling pathway, a hypothesis verified by transcriptomics. In vivo experimental results showed that EEAR could improve cognitive deficits in rats, enhance their learning and memory abilities, alleviate hippocampal tissue cell damage in AD rats, and reduce the levels of IL-6, IL-1β, and TNF-α. Mechanistic studies revealed that EEAR can promote the expression of cAMP, p-CREB, and BDNF, and this effect vanishes when CREB is inhibited. Therefore, this study is the first to confirm that EEAR can improve cognitive impairment in rats and inhibit neuroinflammation, and its mechanism of treating AD may be closely associated with the cAMP/CREB/BDNF pathway.

Source: International Immunopharmacology

DOI: 10.1016/j.intimp.2025.115923