Identification of Salvianolic acid A as a potent inhibitor of PDEs to enhance proliferation of human neural stem cells

Abstract

The inhibition of phosphodiesterases (PDEs) is a promising therapeutic strategy for treating central nervous system (CNS) disorders due to its capacity to facilitate neuroplasticity. Salvianolic acid A (SAA) shows promise in treating CNS disorders, but its specific targets are still unclear. This study has discovered that SAA directly targets PDEs to promote the proliferation of neural stem cells (NSCs). A pharmacophore model for PDE9 inhibitors was developed and validated to screen a compound database, leading to the discovery of SAA as an active agent. Further investigation into the anti-PDEs activity of SAA has revealed that it is a broad-spectrum PDEs inhibitor, with IC₅₀ values of 28.26, 34.18, and 31.68 µM for PDE4, PDE5, and PDE9, respectively. Furthermore, the proliferation of human NSCs (H9) was significantly enhanced by 30–90 µM SAA. This study also provides comprehensive elucidations of signaling pathways associated with direct targeting of PDEs for neuroplasticity in stroke. Furthermore, molecular dynamics (MD) simulations revealed that SAA effectively interacts with the crucial amino acid residues of PDE9. The decomposition of binding free energy for acid residues offers further insight into the interactions between SAA and these key amino acids, thus providing more information for understanding the mechanism of SAA bound to PDE9.