Objective:

2

To investigate the therapeutic effect of Xiangshao Granules (XSG) on post-stroke depression (PSD) and explore the underlying mechanisms.

Methods:

2

Forty-three C57BL/6J mice were divided into 3 groups: sham (

n

=15)

PSD+vehicle (

n

=14)

and PSD+XSG (

n

=14) groups according to a random number table. The PSD models were constructed using chronic unpredictable mild stress (CUMS) after middle cerebral artery occlusion (MCAO). The sham group only experienced the same surgical operation

but without MACO and CUMS stimulation. The XSG group received XSG (60 mg/kg per day) by gavage for 4 weeks. The mice in the sham and vehicle groups were given the same volume of 0.9% saline at the same time. The body weight and behavior tests including open field test

sucrose preference test

tail suspension test

and elevated plus-maze test

were used to validate the PSD mouse model. Real-time fluorescence quantitative polymerase chain reaction (RT-qPCR)

enzyme-linked immunosorbent assay (ELISA)

and immunofluorescence staining were used to evaluate the anti-inflammatory effects of XSG. The potential molecular mechanisms were explored and verified through network pharmacology analysis

Nissl staining

Western blot

ELISA

and RT-qPCR

respectively.

Results:

2

The body weight and behavior tests showed that MCAO combined with CUMS successfully established the PSD models. XSG alleviated neuronal damage

reduced the expressions of pro-apoptotic proteins Caspase-3 and B-cell lymphoma-2 (BCL-2)-associated X (BAX)

and increased the expression of anti-apoptotic protein BCL-2 in PSD mice (

P

<

0.05

or

P

<

0.01). XSG inhibited microglial activation and the expressions of pro-inflammatory cytokines including tumor necrosis factor-α

interleukin (IL)-1β

and IL-6 via the toll-like receptor 4/nuclear factor kappa-B signaling pathway in PSD mice (

P

<

0.05 or

P

<

0.01). Furthermore

XSG decreased the expression of indoleamine 2

3-dioxygenase1 (IDO1) and increased the concentration of 5-hydroxytryptamine in PSD mice (

P

<

0.05 or

P

<

0.01).

Conclusion:

2

XSG could reverse the anxiety/depression-like behaviors and reduce the neuronal injury in the hippocampus and prefrontal cortex of PSD mice

which may be a potential therapeutic agent for PSD.