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外2015 (IF 2.748)在抑郁大鼠模型中给予喹硫平和rTMS治疗,可以通过BDNFERK信号通路缓解抑郁样行为和促进海马源性神经干细胞增殖 Qingrong Tan YIRD
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Quetiapine and repetitive transcranial magnetic stimulation ameliorate depression-like behaviors and up-regulate the proliferation of hippocampal-derived neural stem cells in a rat model of depression: The involvement of the BDNF/ERK signal pathway Yi-huan Chen a,1, Rui-guo Zhang a,1, Fen Xue a,1, Hua-ning Wang a, Yun-chun Chen a, Guang-tao Hu b, Ye Peng c, Zheng-wu Peng a,, Qing-rong Tan a, a Department of Psychiatry, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China b Mental Health Center, 324 Hospital of PLA, Chongqing 400041, China c Air Force General Hospital of PLA, Beijing, China a b s t r a c t a r t i c l e i n f o Article history: Received 25 May 2015 Received in revised form 7 July 2015 Accepted 9 July 2015 Available online 12 July 2015 Keywords: Quetiapine rTMS CUS NSCs BDNF/ERK Quetiapine (QUE) and repetitive transcranial magnetic stimulation (rTMS) have been considered to be possible monotherapies for depression or adjunctive therapies for the treatment of the resistant depression, but the un- derlying mechanisms remain unclear. The present study aimed to assess the effects of combined QUE and rTMS treatment on depressive-like behaviors, hippocampal proliferation, and the in vivo and in vitro expressions of phosphorylated extracellular signal-regulated protein kinase (pERK1/2) and brain-derived neurotrophic factor (BDNF) in male Sprague–Dawley rats. The administration of QUE and rTMS was determined not only to reverse the depressive-like behaviors of rats exposed to chronic unpredictable stress (CUS) but also to restore the protein expressions of pERK1/2 and BDNF and cell proliferation in the hippocampus. Additionally, QUE and rTMS pro- moted the proliferation and increased the expression of pERK1/2 and BDNF in hippocampal-derived neural stem cells (NSCs), and these effects were abolished by U0126. Taken together, these results suggest that the antidepressive-like effects of QUE and rTMS might be related to the activation of the BDNF/ERK signaling path- way and the up-regulation of cell proliferation in the hippocampus. 2015 Elsevier Inc. All rights reserved. 1. Introduction Depression is a major mental health issue worldwide that has a se- vere effect on the life qualities of patients. It is estimated that unipolar depressive disorder will be the leading cause of disability in high- income countries by 2030 (Mathers and Loncar, 2006). The pathogene- sis of depression is still not fully understood, but increasing evidence suggests that hippocampal atrophy is one of the obvious pathologic changes in patients with depression. Hippocampal volumes are reduced in patients with unipolar depression (Videbech and Ravnkilde, 2004), and animal research has also found that neurogenesis is decreased (Jacobs et al., 2000). Moreover, accumulating evidence indicates that antidepressant treatments, including ECT (Scott et al., 2000), antide- pressants (Li et al., 2004) and other (Hurley et al., 2013), appear to in- crease the rate of neurogenesis, Interestingly, the antidepressive-like effects of antidepressants, such as fluoxetine, are blocked when X- irradiation is applied to restrict hippocampal neurogenesis in mice (Santarelli et al., 2003). Thus, the integrity of the hippocampal forma- tion and neurogenesis in the hippocampus plays important roles in the effects of antidepressants. Quetiapine is an atypical antipsychotic that has been approved for the adjunct treatment of major depressive disorder (MDD) and the treatment of acute depressive episodes associated with bipolar disorder by the United States Food and Drug Administration (Pae et al., 2010). A clinical study reported that quetiapine as a monotherapy shows efficacy in the treatment of patients with MDD and with bipolar I and II disor- ders (Endicott et al., 2008). Animal research has also shown that quetiapine reverses the suppression of hippocampal neurogenesis that is induced by repeated restraint stress (Luo et al., 2005), and our previ- ous study found that quetiapine is effective as an augmentation therapy for fluoxetine treatment-resistant depressive-like behaviors in rats in- duced by chronic unpredictable mild stress and that this effect is partial- ly mediated by an increase in the production of new neurons in the Pharmacology, Biochemistry and Behavior 136 (2015) 39–46 Abbreviations: QUE, quetiapine; rTMS, repetitive transcranial magnetic stimulation; pERK1/2, phosphorylated extracellular signal-regulated protein kinase; BDNF, brain- derived neurotrophic factor; CUS, chronic unpredictable stress; NSCs, neural stem cells; MDD, major depressive disorder; SPT, sucrose preference test; FST, forced swimming test; OFT, open-field test. Corresponding authors. E-mail addresses: pengzhengwu1446@163.com (Z. Peng), tanqingr@fmmu.edu.cn (Q. Tan). 1 Contributed equally to this work. http://dx.doi.org/10.1016/j.pbb.2015.07.005 0091-3057/ 2015 Elsevier Inc. All rights reserved. Contents lists available at ScienceDirect Pharmacology, Biochemistry and Behavior journal homepage: www.elsevier.com/locate/pharmbiochembeh

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