Antidepressant-Like Effects of Low- and High-Molecular Weight FGF-2 on Chronic Unpredictable Mild Stress Mice

The occurrence of depressive disorder has long been attributed to changes in monoamines, with the focus of drug treatment strategies being to change the effectiveness of monoamines. However, the success achieved by changing these processes is limited and further stimulates the exploration of alternative mechanisms and treatments. Fibroblast growth factor 2 (FGF-2), which occurs in a high-molecular weight (HMW) and low-molecular weight (LMW) form, is a potent developmental modulator and nervous system regulator that has been suggested to play an important role in various psychiatric disorders. In this study, we investigated the antidepressant effects of HMW and LMW FGF-2 on depression induced by chronic stress. Both peripheral LMW and HMW FGF-2 attenuated the depression-like behaviors in chronic unpredictable mild stress (CUMS) mice to a similar extent, as determined by the forced swimming, tail suspension, and sucrose preference tests. We then showed that CUMS-induced oxidative stresses in mice were inhibited by FGF-2 treatments both in central and peripheral. We also showed that both forms of FGF-2 increased the phosphorylation of ERK and AKT, increased Bcl-2 expression and inhibited caspase-3 activation in CUMS mice. Interestingly, HMW FGF-2 enhanced the activity of the brain-derived neurotrophic factor (BDNF) to a greater extent than did LMW FGF-2 in the hippocampus. Taken together, these results suggest that depressive symptoms can be relieved by administering different forms of FGF-2 peripherally in a CUMS-induced depression model through a similar antidepressant signaling pathway, therefore suggesting a potential clinical use for FGF-2 as a treatment for depression.