There are many kinds of neurological disorders and neuropsyc

There are many kinds of neurological disorders and neuropsychiatric diseases, like stroke, dementia, schizophrenia and so on. Among these disorders, the most important reason for choosing depression in our study is that FXR has already been demonstrated to regulate the function of CREB, which is closely implicated in depression (Blendy, 2006, Gass and Riva, 2007). More importantly, Yang et al. in 2018 performed a quantitative proteomic study which used CID 2011756 sale samples and implied LXR/RXR and FXR/RXR activation in depression (Yang et al., 2018). However, our study is the first direct evidence showing that FXR is involved in the pathogenesis of depression. We employed CUMS in this study, as it is the most commonly used model of depression and simulates various core symptoms (anhedonia, helplessness, etc.) in human (Qiao et al., 2016). Our western blotting data revealed significantly more level of hippocampal FXR protein in CUMS-stressed rats than the control rats. The qRT-PCR results were consistent with the western blotting data and indicated that the effects of chronic stress on FXR were at transcriptional level. The mPFC-related results were also interesting, meaning that the effects of chronic stress on FXR were region-selective. For this finding, currently we have no persuasive explanations, and more profound molecular studies are required. Besides, in addition to CUMS, there are some other acknowledged models of depression, like the chronic social defeat stress (CSDS) and chronic restraint stress (CRS) models ( Koo et al., 2016; Li et al., 2017a). We wonder that if CSDS and CRS also enhance hippocampal FXR expression, like CUMS, then our conclusion in this study will be further confirmed. Another important significance of this research is showing the correlation between FXR and BDNF biosynthesis. Hippocampal FXR overexpression led to significant reduction in BDNF biosynthesis, while hippocampal FXR knockdown fully reversed the inhibitory effects of chronic stress on BDNF expression. Like CREB, BDNF is very important in brain. BDNF not only regulates many neuronal processes like neurogenesis, neuro-survival and synaptic plasticity, but also is implicated in various neurological disorders including stroke, Alzheimer's disease, Parkinson's disease and so on (Siegel and Chauhan, 2000, Yamada et al., 2002, Pezet and Malcangio, 2004, Schmidt and Duman, 2007). Thus, the role of FXR in brain may be very wide. FXR may indirectly modulates those neuronal processes/neurological disorders through BDNF, and exploring these assumptions will be very interesting and meaningful. Moreover, as the pathophysiology of depression is very complex, involving not only BDNF and CREB, but also a lot of other protein targets (serotonin, mTOR, GSK3β, etc.) (Papazoglou et al., 2015; Ignácio et al., 2016, Boku et al., 2017). Thus we could not determine that the FXR-related depressant/antidepressant responses were mediated through only the CREB-BDNF pathway, other mechanisms may also be involved.
Introduction Farnesoid X receptor (FXR), known as the bile acid receptor, belongs to the nuclear hormone receptor superfamily that is predominantly expressed in mammalian liver, intestine, kidney and adrenal gland, and controls gene networks involved in bile acid homeostasis.1, 2 Additionally, FXR plays a crucial role in regulating lipid and cholesterol homeostasis. Many efforts have been made to unravel physiological and pathological functions of FXR, such as, hepatic cholestasis,4, 5 glucose homeostasis and tolerance6, 7 and diabetic nephropathy. FXR represents an attractive target for the development of novel therapeutic agents and has become regarded as a potential therapy for the treatment of lipid metabolism disorders, hyperlipidemia and cholestatic diseases. The relation between FXR agonists and lipid metabolism disorders has been disclosed by many groups.10, 11 GW4064 and LX335 (WAY-362450) have been reported as synthetic FXR agonists. Some agonists belonging to a different chemical class from GW4064 derivatives have also been disclosed.14, 15 The current research trend on FXR agonists is for the treatment of non-alcoholic fatty liver disease.16, 17, 18