20(S)‐Protopanaxadiol‐Loaded Nanomicelles Prevent Depressive Behaviors in a Mouse Model of Depression via Activating the BDNF/ERK Signaling Pathway

Abstract The existing antidepressant therapies are limited by efficacy gaps and adverse effects. Naturally derived ginsenosides including 20(S)‐protopanaxadiol (PPD), exhibit promising antidepressant properties although issues like poor aqueous solubility and low oral bioavailability exist. This study developed and evaluated PPD‐loaded PEG‐PCL nanomicelles (Nano‐PPD) in a murine model of corticosterone (CORT)‐induced depression. Nano‐PPD yields spherical nanoparticles with a uniform diameter of 165 nm. Pharmacokinetic studies revealed that Nano‐PPD increased PPD bioavailability by ~3‐fold and prolonged circulation time by 1.5‐fold increase of Tmax compared with free PPD. In 21‐day intervention of CORT‐challenged C57BL/6J male mice, both PPD and Nano‐PPD effectively alleviated depressive‐like behaviors according to increased locomotor activity in the open field test and reduce immobility duration in forced swim and tail suspension tests. Nano‐PPD outperformed free PPD at equivalent doses (p < 0.05). Mechanistically, Nano‐PPD activated the ERK1/2 signaling pathway and upregulated BDNF expression in the prefrontal cortex with implications in mood regulation. Safety assessments confirmed that Nano‐PPD did not alter the serum biomarker levels nor the histopathology in the liver and kidney. Collectively, these findings demonstrate that Nano‐PPD possesses favorable pharmacokinetics and potent activity for modulating the neurotrophic pathways, representing a promising translational strategy for the prevention and treatment of depression.