Schisandra chinensis lignans regulate immune-neuro crosstalk namely the “CB2R-BDNF” further achieving antidepression dependent on exosomes pathways

• This study reveals that BDNF is the key neurotrophic factor regulated by the activation of the CB2R. • SCL regulated “CB2R-BDNF” crosstalk to stimulate BDNF production further to alleviate neuronal injury. • SCL increased BDNF improve neuronal injury via exosomes-pathway. The current study aims to elucidate the type of neurotrophic factors regulated by SCL-targeted CB2R and to further reveal the mechanisms underlying neurotrophic factors-CB2R crosstalk to achieve neuroprotection. The pharmacological antagonists AM630 and K252a for CB2R and BDNF were administered to mice subjected to CUMS, respectively. Following behavioral analyses, immunofluorescence, hematoxylin-eoxin and Golgi staining were performed to assess depressive-like behavior and neuronal injury in C57BL/6 mice. A PCR-Array assay was employed to identify the neurotrophic factors regulated by SCL-activated CB2R. The components of SCL were identified by UPLC-Q-TOF-MS/MS and the functional analysis between the components in brain with CB2R and TrkB was carried out by molecular docking. Additionally, a siCnr2-induced BV2 cell model was constructed, we employed ultracentrifugation to extract exosomes from microglia. Then, the exosomes were directly used to treat neurons induced by CUMS serum. The western blot was used to validate BDNF-TrkB, PI3K-AKT pathways, apoptosis-related proteins’ expression. The current results showed that SCL alleviated depression-like behaviors and played neuroprotective effects, while the CB2R antagonist AM630 effectively reversed the improvement of SCL. PCR-Array results demonstrated that BDNF was a key factor regulated by CB2R activation, and the further experiment validated AM630 decreased BDNF and its receptor TrkB expressions which were up-regulated by SCL. Additionally, the results also showed that SCL-mediated TrkB activation upregulated CB2R mRNA, alleviated neuron injury. These results revealed SCL regulated “CB2R-BDNF” crosstalk. Subsequently, the 14 lignans were identified in vitro , and the 7 components were pinpointed in the brain. Molecular docking analyses indicated that they all exhibited favorable functional interactions with CB2R and TrkB. In the mechanism, the in vitro results showed the BDNF treated by siCnr2+SCL+LPS was significantly lower than that in the SCL+LPS group. These findings were corroborated in the exosomes secreted by all drugs-treated microglia. Notably, the exosomes of siCnr2+LPS+SCL group treated neurons could effectively reduce neuronal viability and inactivate the BDNF-TrkB and PI3K-AKT pathways compared to the LPS+SCL group. SCL regulated the crosstalk of “CB2R-BDNF” to amplify BDNF production, subsequently mediating exosomes pathways to mitigate neuronal injury and exert antidepressant effects.