FIGURE 14.

The antidepressant mechanism of Honokiol. Honokiol activates HIF-1α and translocates HIF-1α into the nucleus. Target genes, such as vascular endothelial growth factor (VEGF) and erythropoietin (EPO), are regulated by hypoxia-inducible factor-1α (HIF-1α). HIF-1α can bind to the hypoxia response elements of many target genes to mediate protein synthesis. Ultimately, these growth factors are secreted into the extracellular space between cells. VEGF binds to and activates its receptor VEGFR-2 on adjacent cells. Activation of the VEGFR-2 receptor leads to activation of the PI3K-AKT-mTOR signaling pathway in adjacent cells. The PI3K-AKT-mTOR signaling pathway plays an important role in nerve cell proliferation, survival, and synaptic plasticity, and finally improves depression. 2-ME and SU5416 were applied to investigate whether synaptic plasticity in neurons is dependent on the HIF-1α-VEGF pathway.