Abstract
The trefoil factors (TFFs) are a family of three polypeptides, among which TFF1 and TFF3 are widely distributed in the central nervous system. Our previous study indicated that TFF3 was a potential rapid-onset antidepressant as it reversed the depressive-like behaviors induced by acute or chronic mild stress. In order to further identify the antidepressant-like effect of TFF3, we applied an olfactory bulbectomy (OB), a classic animal model of depression, in the present study. To elucidate the mechanism underlying the antidepressant-like activity of TFF3, we tested the role of brain-derived neurotrophic factor (BDNF)-extracellular signal-related kinase (ERK)-cyclic adenosine monophosphate response element binding protein (CREB) signaling in the hippocampus in the process. Chronic systemic administration of TFF3 (0.1 mg/kg, i.p.) for seven days not only produced a significant antidepressant-like efficacy in the OB paradigm, but also restored the expression of BDNF, pERK, and pCREB in the hippocampal CA3. Inhibition of BDNF or extracellular signal-related kinase (ERK) signaling in CA3 blocked the antidepressant-like activity of TFF3 in OB rats. Our findings further confirmed the therapeutic effect of TFF3 against depression and suggested that the normalization of the BDNF-ERK-CREB pathway was involved in the behavioral response of TFF3 for the treatment of depression.
Highlights
Neuropeptides participate in various behavioral and psychiatric processes, such as learning and memory, addiction, depressive, and anxiety disorders [1,2,3,4]
These results indicated that chronic TFF3 treatment reversed the decrease in the expression of BDNTFh, epsheorsepshuoltrsyliantdioicnatoefdERthKa1t /c2h, raonndicCTRFEFB3intrethatemCeAn3t roefvOerBseradtst.hCeodnescirdeearsienginthteheimepxporretasnsitornoloefs BoDf tNheF,BpDhNosFp/EhoRrKy/lCatRioEnBopfaEthRwKa1y/2in, danedprCesRsiEoBn,inthtehteheCrAap3eoufticOeBffreacttss. oCf ToFnFsi3dfeorrindgepthreesismiopnoirntatnhte rOolBespoafrathdeigBmDmNaFy/EcoRnKt/riCbuRtEeBtopaththewreanyeiwnadleopfrtehsesipoant,htwheatyh.erapeutic effects of TFF3 for depression in the olfactory bulbectomy (OB) paradigm may contribute to the renewal of the pathway. 22..11
We found that chronic systemic administration of TFF3 (0.1 mg/kg, i.p.) reversed OB-induced depressive-like behaviors and hyperactivity via decreasing the levels of brain-derived neurotrophic factor (BDNF), pERK1/2, and pCREB in CA3
Summary
Neuropeptides participate in various behavioral and psychiatric processes, such as learning and memory, addiction, depressive, and anxiety disorders [1,2,3,4]. The trefoil factors (TFFs), a family of three small secretory polypeptides (TFF1, 2, and 3) in mammals and amphibians [5] are mainly synthesized and secreted by mucin-producing cells and play a critical role in mucosal defense and repair [6,7] In addition to their prominent expression in epithelia of gastro-intestinal tissues, TFFs are distributed in the central nervous system (CNS) [8]. Chronic antidepressant treatment has been shown to up-regulate the phosphorylation of CREB [28], and the increased CREB activation in rodent models of depression resulted in antidepressant-like effects [32] This evidence suggested that the BDNF-ERK-CREB pathway might be involved in TFF3-mediated antidepressant-like effects. We assessed the alterations of the BDNF-ERK-CREB pathway in the hippocampus, aiming to explain the mechanism underlying the antidepressant-like effects of TFF3 in the rats OB paradigm
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