Total glucosides of paeony ameliorate post-stroke depression-like behaviors by modulating inflammasome activation via inhibition of endoplasmic reticulum stress.

BACKGROUND

Paeonia lactiflora Pall., a medicinal herb with a documented history of over one millennium in traditional Chinese medicine, has been widely employed for its hepatoprotective and antidepressant effects. Total glucosides of paeony (TGP) is a class of bioactive compounds derived from the roots of Paeonia lactiflora Pall., have attracted considerable scientific interest in recent years owing to their demonstrated anti-inflammatory, antidepressant, and neuroprotective properties. However, the exact molecular mechanisms by which TGP regulates inflammatory pathways and its therapeutic benefits on post-stroke depression (PSD)-like behaviors remain incompletely elucidated.

METHODS

This study employed a combination of ultra-high-performance liquid chromatography coupled with quadrupole-Orbitrap mass spectrometry (UHPLC-Q-Orbitrap-MS) and network pharmacology to identify the key active components of TGP and their essential targets. A rat model of PSD was created using middle cerebral artery occlusion (MCAO) in conjunction with social isolation. Subsequent animal experiments were then conducted using this model to investigate the mechanisms underlying the therapeutic effects of TGP on PSD.

RESULTS

UHPLC-Q-Orbitrap-MS and network pharmacology analysis results identified paeoniflorin, albiflorin, galloylpaeoniflorin, and benzoylpaeoniflorin were as the principal bioactive components targeting PSD. These active compounds demonstrated strong affinity for core targets, such as glucose-regulated protein 78 (GRP78), caspase-3, and IL-1β. Animal studies indicated that MCAO coupled with social isolation effectively elicited depressive-like behaviors in the rats. The TGP intervention markedly mitigated the inflammatory response in the ischemic penumbra, diminished neuronal apoptosis, facilitated synaptic remodeling, and effectively suppressed the overactivation of the GRP78/inositol-requiring enzyme 1 α/tumor necrosis factor receptor-associated factor 2/phosphorylated c-Jun N-terminal kinase signaling pathway, alleviating depressive symptoms in the PSD rat model.

CONCLUSIONS

Our findings highlight the beneficial role of TGP in preserving synaptic structural integrity and functionality and suggest a novel mechanism of synaptic dysfunction implicated in the pathophysiology of PSD. The results indicate that the regulation of the ERS signaling pathway by TGP presents therapeutic promise for the treatment of PSD.