Paeoniflorin inhibits pyruvate dehydrogenase kinase 3 and promotes BDNF activity by modulating neuronal activity and TNF-α

Abstract

Metabolic dysregulation causes diseases like diabetes and cancer, making PDKs attractive targets. However, a thorough investigation into the unique roles played by the different members of the PDK family, especially PDK3, about memory loss and related diseases like Alzheimer’s disease (AD) is still lacking. The current study investigates PF’s potential to reduce PDK3-associated toxicity in neurodegenerative illnesses, including AD. The association between PF and PDK3 presents a significant opportunity for medication development and AD therapy approaches. PF efficiently suppresses PDK3 activity, as demonstrated by molecular docking and biophysical characterization, providing an in-depth understanding of their molecular interactions. PF significantly inhibited PDK3 in a concentration-dependent manner with an IC50 value of 4.88 µM. Considering this, the current investigation also explores the biological component of PF, which exhibits potential in treating AD and is primarily associated with neuroprotection. In the present study, a 3-hour pre-treatment of PF was administered at varying concentrations (4, 6, and 8 µM) in response to the 24-hour SCP (2 mM)-mediated toxicity. Based on the results of in silico and biophysical characterization, it is concluded that PF inhibits the PDK3 activity. Additionally, it can enhance cell viability, suppress ROS expression, impede apoptosis, and downregulate TNF-α expression. When combined, these actions help to prevent neuronal death in an in vitro model of SCP. PF strengthens the memory marker, which is confirmed through BDNF expression. This study found that all results were more effective at lower and moderate doses of PF. Our research indicates that PF boosts memory, decelerates the progression of oxidative stress, and could potentially serve as a dose-dependent treatment for AD.