Caesalpinia sappan L. Wood is a Potential Source of Natural Phosphodiesterase-1 Inhibitors

Abstract

Introduction: A decrease in cAMP and cGMP levels in the brain is linked to human cognitive problems. The degradation of cellular cAMP and cGMP is attributed to phosphodiesterases (PDEs), which constitute a superfamily of enzymes. The inhibition of PDE1 is a promising mechanism to increase cAMP and cGMP levels associated with cognitive disorders. Caesalpinia sappan L. (CS) wood is a natural coloring agent usually consumed as a traditional refreshment or drink by people in Yogyakarta, Indonesia. However, scientific evidence regarding the inhibitory activity of CS wood against PDE1 has yet to be obtained. This study aimed to investigate the potency of CS wood as a PDE1 inhibitor. Methods: The ethanol extract of CS wood and its fractions were evaluated in vitro by using a cyclic nucleotide phosphodiesterase assay kit. The presence of brazilin in the extract and fractions was analyzed by thin-layer chromatography. In silico assay was performed using MOE software to obtain insights into the interaction between compounds in the CS wood and the enzyme. Results: Ethanol extract and ethyl acetate soluble fraction effectively inhibited the PDE1 activity. Interestingly, brazilin, the major compound in CS wood, also exhibited a potent inhibitory effect on the enzyme. The in silico assay revealed that the interaction between tetraacetylbrazilin and brazilin with the PDE1B active site involved hydrogen bonding and π-π interactions. Conclusion: Ethanol extract, ethyl acetate soluble fraction, and brazilin inhibited the PDE1 activity. CS wood and its chemical constituent could be developed as natural cognitive enhancers.

Development of White Cabbage, Coffee, and Red Onion Extracts as Natural Phosphodiesterase-4B (PDE4B) Inhibitors for Cognitive Dysfunction: In Vitro and In Silico Studies

“…RMSD is a distinctive characteristic that demonstrates the capacity of both native ligand complexes and proteins to duplicate themselves in the development of an appropriate configuration. The preferred RMSD value is 1 Å, though 2 Å is also appropriate [ 215 ]. Sixty-three compounds were tested against PDB4B (PDB ID: 4KP6) by performing their molecular docking with MOE.…”

The role of Phosphodiesterase-1 and its natural product inhibitors in Alzheimer’s disease: A review

“…Numerous plants in the literature specifically target PDE1 in the brain ( Helmi et al, 2020a ). Certain plants have been found to be successful candidates for inhibiting the activity of PDE1 ( Helmi et al, 2020b ). Active compounds from plants that inhibit PDE1 are shown in Figure 7 , and their details are given in Table 2 .…”

“…Numerous reports have shown that C. sappan has antioxidant, antibacterial, antidiarrheal, antiinflammatory, anticancer, hepatoprotector, and antidiabetic activities. C. sappan has been scientifically documented to enhance cognition via PDE1 inhibition ( Table 2 ) ( Helmi et al, 2020a ; Helmi et al, 2020b ).…”

“…We found some study gaps. For example, the synergy between Cesalpinea shuppan and PDE1 inhibition requires further studies ( Helmi et al, 2020b ). Nimodipine is inadequate for use as a long-term memory booster despite its short-term advantages in vascular dementia.…”

“…Supplementary well-planned clinical studies are needed to ascertain the efficacy and safety of PDE inhibitors in individuals with AD ( Nabavi et al, 2019 ). Among all members of the PDE superfamily of enzymes, PDE1 has been found to be highly expressed in the brain ( Helmi et al, 2020b ) and is considered to be responsible for AD development via the mechanism of cAMP/cGMP downregulation in neuronal cells ( Ribaudo et al, 2021 ).…”