20(S)-Protopanaxadiol regulating glucocorticoid receptor attenuates ischemic stroke injury by alleviating the...

Glucocorticoids reduce brain edema but are less effective in ischemic stroke (IS), likely due to reduced glucocorticoid receptor (GR) expression. 20(S)-Protopanaxadiol (PPD) activates GR, potentially offering protection, though its role in IS remains unclear.

This study explores PPD's potential to mitigate cerebral ischemic injury via GR activation and its mechanisms.

PPD was formulated into a submicron emulsion, with pharmacokinetics and bioavailability assessed. Neuroprotective effects were evaluated in pMCAO rats and OGD models. GR knockdown examined its role in PPD's regulation of autophagy-lysosomal pathway (ALP) and neuroinflammation.

Molecular docking, molecular dynamics simulation, CETSA, DARTS and ITDR analyses confirmed that PPD binds directly to GR. The PPD submicron emulsion showed high oral bioavailability and blood-brain barrier permeability. PPD treatment reduced infarct volume, improved neurological function, and alleviated brain edema in pMCAO-operated rats, with superior effects compared to other ginsenosides. Additionally, PPD reduced neuronal damage and microglial activation in both pMCAO and OGD models. Notably, PPD reversed the decreased GR expression in the peri‑infarct cortex and promoted GR nuclear translocation. PPD also rescued ALP dysfunction by reducing autophagosome accumulation and restoring lysosomal function in a GR-dependent manner. Moreover, PPD reduced neuroinflammation and NF-κB activity via GR, as GR knockdown or the GR antagonist RU486 abolished PPD's beneficial effects.

This study reveals that PPD submicron emulsion with high bioavailability can alleviate IS-induced brain damage through activating GR, thereby rescuing the ALP dysfunction in neurons and inhibiting microglial activation. Notably, this paper provides the first evidence that PPD not only enhances GR expression but also promotes its nuclear translocation after IS, which offers new scientific insights for the development of PPD as a GR agonist for the treatment of IS.