Paeonol mitigates chronic stress-induced amygdalar neuronal damage through glycogen synthase kinase-3β/calcineurin axis regulation of synaptic plasticity.

Objective: This study aimed to elucidate the neuroprotective mechanisms of paeonol in ameliorating chronic stress-induced amygdala neuronal injury via modulation of the glycogen synthase kinase-3β (GSK3β)/calcineurin signaling pathway. Paeonol, a polyphenolic compound from Moutan Cortex, exhibits therapeutic effects. Studies show it alleviates lipopolysaccharide-induced depression-like behaviors in mice, though its mechanisms remain unclear.

Methods: Forty-eight Sprague-Dawley rats were divided into four groups: control, chronic unpredictable mild stress (CUMS) model, low-dose paeonol (25 mg/kg), and high-dose paeonol (80 mg/kg). Paeonol was administered intragastrically 1-week post-CUMS induction for 4 weeks. Behavioral tests assessed depression-like behaviors. Neuronal morphology was evaluated via hematoxylin and eosin, Nissl, and Golgi staining, while western blot quantified cofilin1, p-cofilin1, GSK3β, and calcineurin expression.

Results: CUMS rats exhibited depressive-like behaviors, neuronal nuclear pyknosis, interstitial edema, hyperchromatic cytoplasm, and reduced Nissl body integrity. Golgi staining revealed increased dendritic complexity and spine density. CUMS upregulated p-cofilin1 and GSK3β while downregulating total cofilin1 and calcineurin. Paeonol treatment alleviated depressive behaviors, reduced neuronal damage, and normalized dendritic complexity and spine density. Molecularly, paeonol suppressed p-cofilin1 and GSK3β expression while restoring cofilin1 and calcineurin levels.

Conclusion: Chronic stress induces dendritic hypertrophy and spine hyperplasticity, contributing to depressive phenotypes. Paeonol counteracts these effects, likely by modulating the GSK3β/calcineurin pathway, highlighting its therapeutic potential for stress-related neuronal injury.