CREB-mediated generation and neuronal growth regulates the behavioral improvement of geniposide in diabetes-associated depression mouse model.

Metabolic disorder particularly diabetes is one of the leading causes of psychiatric or other neurodegenerative diseases. Previous clinical and pre-clinical studies indicate anti-diabetic drugs such as GLP-1 analogs or GLP-1 receptor (GLP-1R) agonists could perform the neuroprotective effects with multiple molecular mechanisms. As one of natural compound to stimulate GLP-1R, geniposide was reported could improve cognitive behaviors in diabetes associated Alzheimer's disease rat model. Stimulating of GLP-1R could act the crosstalk downstream like neurotrophic factor mediated cAMP-response element binding protein (CREB) would be activated and exert cellular events including promotion of adult neurogenesis, which is one of important treatment targets in antidepressant. Here in this study, we employed HDF in combined with corticosterone (CORT) treatment to create diabetes associated depression model. Geniposide treatment could not only correct the metabolic pattern but could also improve the cognitive dysfunctions and depressive/anxiety symptoms. In consistent with its pro-neurogenic effects, geniposide also enhanced the activity of CREB in hippocampal tissue. Moreover, blocking CREB activity with 666-15 significantly compromised the effects of geniposide in promotion of neurogenesis and behavioral protective effects. In conclusion, this study expands the application of geniposide to treat diabetes associated depression subject and identified the underlying molecular mechanism for such effects.