Paeonol facilitates the repair of neuronal damage in the mPFC caused by chronic stress via the Rho GTPases-cofilin1 signaling pathway.

BACKGROUND

The Rho GTPases-cofilin1 signalling axis preserves neuronal morphology and synaptic plasticity by modulating actin homeostasis. However, the potential role of paeonol-a bioactive compound derived from Paeonia suffruticosa-in mitigating CUMS-induced neuronal injury via this pathway remains unelucidated.

OBJECTIVE

This study investigates the neuroprotective mechanisms of paeonol against CUMS-associated neuronal injury in the medial prefrontal cortex (mPFC), focusing on the Rho GTPases-cofilin1 signalling axis.

METHODS

60 male Sprague-Dawley rats were divided into five groups: Control, CUMS, Fluoxetine-treated (Flu), low-dose paeonol (LDP, 25 mg/kg), and high-dose paeonol (HDP, 80 mg/kg). Depressive-like phenotypes were induced via a 4-week CUMS paradigm, followed by daily gavage of fluoxetine or paeonol. Behavioral assessments quantified depressive-like phenotypes. Histology used HE and Nissl staining; dendritic morphology was assessed via Golgi impregnation. Protein levels of Rac1, Cdc42, RhoA, Cofilin1, and p-Cofilin1 in mPFC were quantified by Western blot.

RESULTS

CUMS-exposed rats displayed prolonged immobility duration and delayed feeding initiation; paeonol and fluoxetine attenuated these deficits. Golgi analysis showed CUMS reduced total dendritic length, apical dendrite extension, branching complexity and mature dendritic spines (mushroom/branched), while increasing filopodial protrusions in mPFC pyramidal neurons. Both treatments rescued these alterations. Western blot showed CUMS decreased p-cofilin1 levels and downregulated Rac1 and Cdc42 expression, while increasing cofilin1. Paeonol normalized p-cofilin1 phosphorylation, restored Rac1 and Cdc42 expression and reduced cofilin1 levels.

CONCLUSION

Paeonol alleviates CUMS-induced behavioural impairments, potentially through modulating the Rho GTPases-cofilin1 signaling axis.