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

Abstract

<p>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.</p>