Li Jiali, Luo Yixiao, Zhang Ruoxi, Shi Haishui, Zhu Weili, Shi Jie
National Institute on Drug Dependence, Peking University, Beijing 100191, China.
Department of Pharmacology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.
Int J Mol Sci. 2015 Nov 30;16(12):28386-400. doi: 10.3390/ijms161226105.
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.
三叶因子（TFFs）是由三种多肽组成的一个家族，其中TFF1和TFF3广泛分布于中枢神经系统。我们之前的研究表明，TFF3是一种潜在的速效抗抑郁药，因为它能逆转急性或慢性轻度应激诱导的抑郁样行为。为了进一步确定TFF3的抗抑郁样作用，在本研究中我们采用了嗅球切除术（OB），这是一种经典的抑郁症动物模型。为了阐明TFF3抗抑郁样活性的潜在机制，我们在此过程中测试了脑源性神经营养因子（BDNF）-细胞外信号调节激酶（ERK）-环磷酸腺苷反应元件结合蛋白（CREB）信号通路在海马体中的作用。连续7天腹腔注射TFF3（0.1mg/kg）不仅在OB模型中产生了显著的抗抑郁样效果，还恢复了海马CA3区BDNF、pERK和pCREB的表达。抑制CA3区的BDNF或细胞外信号调节激酶（ERK）信号通路可阻断TFF3在OB大鼠中的抗抑郁样活性。我们的研究结果进一步证实了TFF3对抑郁症的治疗作用，并表明BDNF-ERK-CREB通路的正常化参与了TFF3治疗抑郁症的行为反应。
