Xingshen Jieyu Decoction ameliorates post-stroke depression by modulating proBDNF/BDNF signaling via PI3K/Akt pathway

Xingshen Jieyu Decoction (XSJY), a traditional Chinese herbal formula, is well known for alleviating post-stroke depression(PSD) symptoms and exerting neuroprotective effects. It has been clinically applied for PSD treatment. However, the underlying mechanisms remain insufficiently understood.

To investigate the antidepressant effects and molecular mechanisms of XSJY in a PSD rat model, focusing on apoptosis regulation and PI3K/Akt and proBDNF/BDNF signaling pathways.

The chemical profile of XSJY was characterized by HPLC/ESI-MS. A validated PSD model was established by combing middle cerebral artery occlusion(MCAO) with chronic unpredictable mild stress(CUMS). Rats received XSJY at low or high doses(18.72 or 37.44 g/kg/day) or sertraline(5.142 mg/kg/day) for two weeks. Behavior outcomes(body weight, sucrose preference test[SPT], forced swim test[FST], and hippocampal apoptosis(TUNEL staining) were assessed. Western blotting was performed to evaluate PI3K/Akt activity, caspase-3/9,proBDNF, BDNF, p75NTR, TrkB, neurofilament light chain(NF-L) and neurofilament heavy chain(NF-H) expression. To determine pathway specificity, the PI3K inhibitor LY294002 was co-administered.

Forty main compounds were identified in XSJY by HPLC/ESI-MS. XSJY significantly alleviated depressive-like phenotypes, as evidenced by reduced immobility in the FST and increased sucrose preference. It also markedly attenuated hippocampal apoptosis, particularly in the dentate gyrus(DG) region and, with milder or variable effects in the CA1 and CA3 subfields. Molecular analyses showed that XSJY upregulated p-Akt and showed a trend toward increased p-PI3K, suppressed caspase-3 activation and trend to reduce caspase-9, and restored neurotrophin neurotrophin balance by enhancing BDNF/TrkB while reducing proBDNF/p75NTR expression. Co-administration with the PI3K inhibitor LY294002 partially blunted these effects, indicating that XSJY's neuroprotective actions are mediated by both PI3K/Akt-dependent and complementary pathways.

XSJY alleviates depressive-like behaviors in PSD rats by attenuating hippocampal apoptosis(most notably in DG) and restoring neurotrophic balance. Its actions are mediated partly via PI3K/Akt and proBDNF/BDNF signaling, with additional pathways likely contributing to its multi-target neuroprotective effects.