Higenamine exerts an antidepressant effect by reducing neuronal damage induced by glutamate excitotoxicity: Based on crosstalk between astrocytes and neuron.

BACKGROUND

Depression is one of the psychiatric disorders with the highest global disability rate. Dysfunction of the glutamatergic system is recognized as a core feature of stress-related psychiatric disorders. Previous studies have demonstrated that Higenamine (Hig) significantly ameliorates depressive-like phenotypes in rats. However, the underlying mechanism of its antidepressant effect, particularly whether it mitigates neuronal injury by modulating astrocyte-neuron crosstalk and inhibiting glutamate (Glu) excitotoxicity, remains unclear.

PURPOSE: This study aimed to investigate whether Hig exerts antidepressant effects by improving neuronal dysfunction via inhibiting excitotoxicity through the regulation of Glu transport between astrocytes and neurons.

STUDY

DESIGN

The effects of Hig on depressive-like behaviors, Glu transport function and neuronal injury were evaluated in chronic unpredictable mild stress (CUMS) mice. Furthermore, a Glu-induced HT22 excitotoxicity model and a primary astrocyte-HT22 Transwell co-culture system were established for further pharmacodynamic validation and mechanistic exploration.

METHODS

Mice were subjected to CUMS for 28 consecutive days. Hig (20 mg/kg) and fluoxetine (Flx, 10 mg/kg) were administered concurrently during the modeling period. Subsequently, sucrose preference test, open field test and forced swimming test were performed to assess depressive-like phenotypes in mice. Multiple assays were applied for in vitro and in vivo detection, including Western blot, immunofluorescence, enzyme-linked immunosorbent assay, quantitative real-time polymerase chain reaction, Nissl staining, CCK-8 assay, viability/cytotoxicity staining and calcium fluorescence probes.

RESULTS

Hig ameliorated Glu transport dysfunction in astrocytes, and alleviated neuroinflammation, neuronal apoptosis and synaptic impairment in CUMS-exposed mice. Consistently, in vitro, Hig preventedGlu-induced functional impairment in HT22 cells and attenuated excitotoxicity by modulating astrocyte-neuron interactions.

CONCLUSION

Hig exerts antidepressant effects by modulating astrocyte-neuron interactions to mitigate neuronal damage induced by Glu excitotoxicity.