TNFα, disrupts blood brain barrier integrity to maintain prolonged depressive-like behavior in mice

被引:192
作者
Cheng, Yuyan [1 ,2 ]
Desse, Sachi [3 ]
Martinez, Ana [4 ]
Worthen, Ryan J. [1 ,2 ]
Jope, Richard S. [1 ,2 ]
Beurel, Eleonore [1 ,2 ]
机构
[1] Univ Miami, Miller Sch Med, Dept Psychiat & Behav Sci, Miami, FL 33136 USA
[2] Univ Miami, Miller Sch Med, Dept Biochem & Mol Biol, Miami, FL 33136 USA
[3] Univ Miami, Dept Biol, Coral Gables, FL 33146 USA
[4] CSIC, Ctr Invest Biol, E-28014 Madrid, Spain
关键词
Blood brain barrier; Depression recovery; GSK3; Learned helplessness; Neuroinflammation; TNF alpha; GLYCOGEN-SYNTHASE KINASE-3; SPHINGOSINE; 1-PHOSPHATE; LEARNED HELPLESSNESS; MAJOR DEPRESSION; ANIMAL-MODELS; RAT MODEL; PERMEABILITY; RECEPTOR; FTY720; CELLS;
D O I
10.1016/j.bbi.2018.02.003
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Recovery from major depressive disorder is difficult, particularly in patients who are refractory to antidepressant treatments. To examine factors that regulate recovery, we developed a prolonged learned helplessness depression model in mice. After the induction of learned helplessness, mice were separated into groups that recovered or did not recover within 4 weeks. Comparisons were made between groups in hippocampal proteins, inflammatory cytokines, and blood brain barrier (BBB) permeability. Compared with mice that recovered and control mice, non-recovered mice displaying prolonged learned helplessness had greater hippocampal activation of glycogen synthase kinase-3 (GSK3), higher levels of tumor necrosis factor-a (TNF alpha), interleukin-17A, and interleukin-23, increased permeability of the blood brain barrier (BBB), and lower levels of the BBB tight junction proteins occludin, ZO1, and claudin-5. Treatment with the GSK3 inhibitor TDZD-8 reduced inflammatory cytokine levels, increased tight junction protein levels, and reversed impaired recovery from learned helplessness, demonstrating that prolonged learned helplessness is reversible and is maintained by abnormally active GSK3. In non-recovered mice with prolonged learned helpless, stimulation of sphingosine 1-phosphate receptors by Fingolimod or administration of the TNFa inhibitor etanercept repaired the BBB and reversed impaired recovery from prolonged learned helplessness. Thus, disrupted BBB integrity mediated in part by TNF alpha contributes to blocking recovery from prolonged learned helplessness depression-like behavior. Overall, this report describes a new model of prolonged depression-like behavior and demonstrates that stress-induced GSK3 activation contributes to disruption of BBB integrity mediated by inflammation, particularly TNF alpha, which contributes to impaired recovery from prolonged learned helplessness. (C) 2018 Elsevier Inc. All rights reserved.
引用
收藏
页码:556 / 567
页数:12
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