Zileuton ameliorates depressive-like behaviors, hippocampal neuroinflammation, apoptosis and synapse dysfunction in mice exposed to chronic mild stress

• Published in: International immunopharmacology Vol. 78; p. 105947
• Main Authors: Liu, Cai-Hong, Tan, Yuan-Zhi, Li, Dan-Dan, Tang, Su-Su, Wen, Xiao-An, Long, Yan, Sun, Hong-Bin, Hong, Hao, Hu, Mei
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.01.2020; Elsevier BV
• Subjects: 5LO; Abnormalities; Apoptosis; Arachidonate 5-lipoxygenase; Bax protein; Bcl-2 protein; Caspase-3; CMS; Depression; Hippocampus; IL-1β; Inflammation; Lipopolysaccharides; Lipoxygenase; Neurogenesis; Neuroinflammation; NF-κB protein; Postsynaptic density proteins; Stress; Tumor necrosis factor-α; DG; SSRIs; FST; CMS; TBST; Depression; Neuroinflammation; SYN; CNS; NF-κB p65; IL-1β; MDD; Neurogenesis; LPS; TUNEL; TST; TNF-α; NSFT; SNRIs; 5LO
• DOI: 10.1016/j.intimp.2019.105947
• ISSN: 1567-5769; 1878-1705

•Zileuton alleviates CMS-induced depressive-like behaviors.•Zileuton represses hippocampal neuroinflammation and apoptosis in the context of depression.•Zileuton promotes hippocampal neurogenesis in the context of depression. Our previous study has found that zileuton, a selective 5-lipoxygenase (5LO) inhibitor, abrogated lipopolysaccharide-induced depressive-like behaviors and hippocampal neuroinflammation. Herein, we further extended our curiosity to investigate effects of zileuton on stress-induced depressive-like behaviors. Our data indicated that zileuton significantly ameliorated depressive-like behaviors in mice subjected to chronic mild stress (CMS), as shown in the tail suspension test, forced swimming test and novelty-suppressed feeding test. The further studies indicated that zileuton suppressed hippocampal neuroinflammation, evidenced by lower levels of TNF-α, IL-1β and nuclear NF-κB p65 as well as decreased number of Iba1-positive cells. It also significantly ameliorated hippocampal apoptosis, indicated by deceased number of TUNEL-positive cells, deceased ratio of cleaved caspase-3/procaspase-3 and increased ratio of Bcl-2/Bax. More importantly, zileuton increased the level of synaptic proteins PSD-95 and SYN and the number of NeuN+/BrdU+ cells in the hippocampus. Over all, zileuton alleviated CMS-induced depressive-like behaviors, neuroinflammatory and apoptotic responses, abnormalities of synapse and neurogenesis in the hippocampus, suggesting that it might has beneficial effects on depression.