Shenghui decoction inhibits neuronal cell apoptosis to improve Alzheimer's disease through the PDE4B/cAMP/CREB signaling pathway.

Abstract

Background: Shenghui Decoction (SHD) is a frequently utilized traditional Chinese medicine formula in clinical settings for addressing cognitive impairment in elderly individuals. Nevertheless, the precise mechanism by which SHD exerts its effects on the most prevalent form of dementia, Alzheimer's disease (AD), remains to be elucidated.

Methods: Temperature-induced transgenic C. elegans assess Aβ deposition and toxicity. Behavioral experiments are utilized to assess learning and memory capabilities as well as cognitive impairment in APP/PS1 mice. Immunofluorescence and immunohistochemistry are employed to identify Aβ deposits, while UHPLCOE/MS combine network pharmacology is utilized to characterize chemical composition, predict target and analyze the biological processes and signaling pathways modulated by SHD. Molecular biology methodologies confirm the functionality of regulatory pathways. Molecular docking, molecular dynamic simulations (MD) and ultrafiltration-liquid chromatography/mass spectrometry (LC/MS) are employed for the assessment of the binding interactions between active ingredients of SHD and target proteins.

Results: SHD effectively reduced the deposition of Aβ in the head of C. elegans and mitigated its toxicity, as well as improved the learning deficits and cognitive impairment in APP/PS1 mice. Network pharmacology analyses revealed that G protein-coupled receptors (GPCRs) and cell apoptosis are the primary biological processes modulated by SHD, with KEEG results indicating that SHD regulated the cAMP signaling pathway. Subsequent experimental investigations demonstrated that SHD attenuated the loss of neurons in APP/PS1 mice, upregulated the expression of anti-apoptotic protein Bcl-2 and downregulated the expression of pro-apoptotic proteins like cleave-Caspase-3 both in vivo and in vitro. Additionally, SHD decreased intracellular AMP levels while increasing cAMP levels, leading to the phosphorylation of PKA to activate CREB. This process ultimately regulated the expression of Bcl-2, Bdnf, among others, to prevent cell apoptosis and safeguard neurons. Molecular docking, MD, and ultrafiltration-LC/MS revealed that the active constituents of SHD formed stable interactions with the cAMP hydrolysis enzyme phosphodiesterase 4B (PDE4B).

Conclusion: SHD regulated the cAMP/CREB signaling pathway to inhibit neuronal cell apoptosis and improve AD. Furthermore, it is worth noting that this mechanism may be associated with the specific and consistent binding of SHD active ingredients to PDE4B, potentially offering promising candidates for drug development aimed at addressing AD.