Carnosic acid alleviates depression-like behaviors on chronic mild stressed mice via PPAR-γ-dependent regulation of ADPN/FGF9 pathway

Rationale The pathway of adiponectin (ADPN)/fibroblast growth factor 9 (FGF9) was recently thought as a key role in the development of depression. ADPN is crucially regulated by peroxisome proliferator-activated receptor-gamma (PPAR-gamma). Natural material carnosic acid (CA) has been applied for therapeutics of mental disorders. Objectives To evaluate the antidepressive effect of CA in stress-treated mice and define whether its effects is involved in the regulation of ADPN/FGF9 pathway. Methods In vivo study, the levels of ADPN and FGF9 in both serum and hippocampus tissues, the expressions of ADPN receptor 2 (AdipoR2) in hippocampus and PPAR-gamma in abdominal adipose, as well as the pathological changes of hippocampus were determined in 28-day period of chronic unpredictable mild stress (CUMS)-induced depression model of male ICR (Institute of Cancer Research) mice or adipo(-/-) mice. In vitro study, the level of ADPN and the mRNA expressions of both ADPN and PPAR-gamma were determined in mouse 3T3-L1 preadipocytes. Results In vivo study, treatment with CA (50 or 100 mg/kg per day) for 21 days markedly suppressed depressive-like behaviors, the elevating levels of FGF9 and decreasing levels of ADPN in both serum and hippocampus tissues, the downregulating protein and mRNA expressions of AdipoR2 in hippocampus and PPAR-gamma in abdominal adipose, as well as the pathological injury of hippocampus induced by CUMS in male ICR mice. The antidepressive effects of CA were markedly attenuated in male CUMS-treated adipo(-/-) mice. In vitro study, incubation with CA (3-30 mu mol/L) for 24 h could concentration-dependently upregulate the mRNA expressions of both PPAR-gamma and ADPN as well as increase the level of ADPN. The experiments using PPAR-gamma-specific inhibitor GW9662 and transient transfection with mutated PPAR-gamma-binding site promotor constructs showed that the activation of PPAR-gamma mediated CA-induced ADPN expression in adipocytes. Conclusions CA could significantly improve stress-induced depressive disorder, which may be related to regulating the dysfunction of ADPN-FGF9 pathway via activating PPAR-gamma in adipocytes.

Automated summary

The study evaluated the antidepressive effect of CA in stress-treated mice and investigated whether its effects are related to the regulation of the ADPN/FGF9 pathway.