Narcissoside from Bupleurum chinense DC. Alleviates depression by enhancing adult hippocampal neurogenesis via the TREM2/PI3K/Akt pathway.

ETHNOPHARMACOLOGICAL RELEVANCE

Bupleurum chinense DC. (Chaihu) [Apiaceae], a traditional Chinese medicinal herb, is a well-recognized natural remedy known for its antidepressant properties. Narcissoside (NCS), a flavonoid compound primarily extracted from Bupleurum chinense, has been reported to exert neuroprotective effects.

AIM OF THE STUDY

To explore the potential antidepressant effect and mechanism of NCS against neuroinflammation and neurogenesis based on the TREM2/PI3K/Akt pathway.

MATERIALS AND METHODS

Using the chronic unpredictable mild stress (CUMS) mouse chronic stress models, different doses of NCS were administered to intervene. Depression-related behavior was tested in mice treated with NCS using sucrose preference test (SPT), open field test (OFT), tail suspension test (TST), and forced swimming test (FST). Neuroinflammation was observed by ELISA and qRT-PCR. Immunohistochemistry, immunofluorescence, Golgi staining, and electrophysiological methods were used to observe the characteristics of neurogenesis. Analysis of the signaling pathway involving TREM2/PI3K/Akt using western blotting. Pharmacological inhibition of adult neurogenesis by Temozolomide (TMZ) and deletion of TREM2 expression by shRNA lentiviral particles was used to validate the antidepressant-like and neurogenetic effects of microglial TREM2 expression on NCS intervention in CUMS mice. The interaction between NCS and TREM2 was predicted by molecular docking and verified by MST technique.

RESULTS

NCS effectively improved depression-like behavior in mice. NCS reduced the release of pro-inflammatory factors, increased the production of new neurons, alleviated neuron injury, and promoted the dendrite maturation of new neurons in the hippocampus. Temozolomide, which inhibits adult neurogenesis in mice, impaired the antidepressant response of NCS. In addition, TREM2/PI3K/Akt signaling was enhanced after NCS intervention. A murine model subjected to CUMS and treated with NCS, a known flavonoid with novel antidepressant activity, exhibited alleviated depressive symptoms, along with restored neuron injury markers and improved neurogenesis. These effects were observed in depressed mice through modulation of the TREM2/PI3K/Akt signaling pathway. Knocking out TREM2 expression with shRNA lentiviral particles impaired the antidepressant response of NCS.

CONCLUSION

NCS plays an antidepressant role, and its mechanism depends on the inhibition of neuroinflammation, the enhancement of adult hippocampal neurogenesis, and the activation of TREM2/PI3K/Akt pathway.