TrkB配体对炎症后小鼠抑郁样行为和树突变化的抗抑郁作用。
Antidepressant effects of TrkB ligands on depression-like behavior and dendritic changes in mice after inflammation.
作者信息
Zhang Ji-chun, Wu Jin, Fujita Yuko, Yao Wei, Ren Qian, Yang Chun, Li Su-xia, Shirayama Yukihiko, Hashimoto Kenji
机构信息
Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan (Drs Zhang, Wu, Yao, Ren, Yang, Li, Shirayama, Hashimoto, and Ms Fujita); National Institute of Drug Dependence, Peking University, Beijing, China (Dr Li); Department of Psychiatry, Teikyo University Chiba Medical Center, Chiba, Japan (Dr Shirayama).
出版信息
Int J Neuropsychopharmacol. 2014 Oct 31;18(4):pyu077. doi: 10.1093/ijnp/pyu077.
BACKGROUND
Brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin-related kinase B (TrkB), signaling represent potential therapeutic targets for major depressive disorder. The purpose of this study is to examine whether TrkB ligands show antidepressant effects in an inflammation-induced model of depression.
METHODS
In this study, we examined the effects of TrkB agonist 7,8-dihydroxyflavone (7,8-DHF) and TrkB antagonist ANA-12 on depression-like behavior and morphological changes in mice previously exposed to lipopolysaccharide (LPS). Protein levels of BDNF, phospho-TrkB (p-TrkB), and TrkB in the brain regions were also examined.
RESULTS
LPS caused a reduction of BDNF in the CA3 and dentate gyrus (DG) of the hippocampus and prefrontal cortex (PFC), whereas LPS increased BDNF in the nucleus accumbens (NAc). Dexamethason suppression tests showed hyperactivity of the hypothalamic-pituitary-adrenal axis in LPS-treated mice. Intraperitoneal (i.p.) administration of 7,8-DHF showed antidepressant effects on LPS-induced depression-like behavior, and i.p. pretreatment with ANA-12 blocked its antidepressant effects. Surprisingly, ANA-12 alone showed antidepressant-like effects on LPS-induced depression-like behavior. Furthermore, bilateral infusion of ANA-12 into the NAc showed antidepressant effects. Moreover, LPS caused a reduction of spine density in the CA3, DG, and PFC, whereas LPS increased spine density in the NAc. Interestingly, 7,8-DHF significantly attenuated LPS-induced reduction of p-TrkB and spine densities in the CA3, DG, and PFC, whereas ANA-12 significantly attenuated LPS-induced increases of p-TrkB and spine density in the NAc.
CONCLUSIONS
The results suggest that LPS-induced inflammation may cause depression-like behavior by altering BDNF and spine density in the CA3, DG, PFC, and NAc, which may be involved in the antidepressant effects of 7,8-DHF and ANA-12, respectively.
背景
脑源性神经营养因子（BDNF）及其受体原肌球蛋白相关激酶B（TrkB）信号通路是重度抑郁症潜在的治疗靶点。本研究旨在探讨TrkB配体在炎症诱导的抑郁症模型中是否具有抗抑郁作用。
方法
在本研究中，我们检测了TrkB激动剂7,8-二羟基黄酮（7,8-DHF）和TrkB拮抗剂ANA-12对先前暴露于脂多糖（LPS）的小鼠抑郁样行为和形态学变化的影响。还检测了脑区中BDNF、磷酸化TrkB（p-TrkB）和TrkB的蛋白水平。
结果
LPS导致海马体的CA3区和齿状回（DG）以及前额叶皮质（PFC）中BDNF减少，而LPS使伏隔核（NAc）中的BDNF增加。地塞米松抑制试验显示LPS处理的小鼠下丘脑-垂体-肾上腺轴功能亢进。腹腔注射（i.p.）7,8-DHF对LPS诱导的抑郁样行为具有抗抑郁作用，而ANA-12的腹腔预处理可阻断其抗抑郁作用。令人惊讶的是，单独使用ANA-12对LPS诱导的抑郁样行为具有抗抑郁样作用。此外，双侧向NAc注射ANA-12显示出抗抑郁作用。此外，LPS导致CA3区、DG区和PFC区的树突棘密度降低，而LPS使NAc中的树突棘密度增加。有趣的是，7,8-DHF显著减弱了LPS诱导的CA3区、DG区和PFC区p-TrkB和树突棘密度的降低，而ANA-12显著减弱了LPS诱导的NAc区p-TrkB和树突棘密度的增加。
结论
结果表明，LPS诱导的炎症可能通过改变CA3区、DG区、PFC区和NAc区的BDNF和树突棘密度而导致抑郁样行为，这可能分别与7,8-DHF和ANA-12的抗抑郁作用有关。
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