Ketamine Alleviates Depressive-Like Behaviors via Down-Regulating Inflammatory Cytokines Induced by Chronic Restraint Stress in Mice

• Published in: Biological & pharmaceutical bulletin Vol. 40; no. 8; pp. 1260 - 1267
• Main Authors: Tan, Sijie, Wang, Yan, Chen, Ke, Long, Zhifeng, Zou, Ju
• Format: Journal Article
• Language: English
• Published: Japan The Pharmaceutical Society of Japan 2017; Japan Science and Technology Agency
• Subjects: Animals; Antidepressive Agents - pharmacology; Behavior, Animal - drug effects; Brain; Corticosterone - blood; Cytokines; Cytokines - metabolism; depression; Down-regulation; Down-Regulation - drug effects; Excitatory Amino Acid Antagonists - pharmacology; Food Preferences; Hippocampus; Hippocampus - drug effects; Hippocampus - metabolism; Inflammation; Inflammatory response; Interleukin 6; Ketamine; Ketamine - pharmacology; Kinases; MAP kinase; Mental depression; Mice; Microglia; P2X7; p38 Mitogen-Activated Protein Kinases - metabolism; Protein kinase; Receptors, Purinergic P2X7 - metabolism; Restraint, Physical - adverse effects; Stress, Psychological - blood; Stress, Psychological - metabolism; Studies; Sucrose; Sugar; Swimming; TLR4 protein; Toll-Like Receptor 4 - metabolism; toll-like receptor type 4 (TLR4); Toll-like receptors; Tumor necrosis factor; Tumor necrosis factor-TNF; depression; P2X7; inflammation; ketamine; toll-like receptor type 4 (TLR4)
• ISSN: 0918-6158; 1347-5215
• DOI: 10.1248/bpb.b17-00131

The purpose of the present study was to investigate whether ketamine’s rapid antidepressant effects were associated with its anti-inflammatory actions and to explore the underlying molecular mechanism. Depressive-like behaviors was induced in mice using chronic restraint stress (CRS) method. Anti-depressive effects of ketamine were evaluated by forced swimming tests (FST) and sucrose preference test (SPT). Subsequently, brain tissue was harvested to investigate inflammatory response in the hippocampus via investigating reactive microglia numbers, serum cytokines levels and the toll-like receptor type 4 (TLR4)/p38 mitogen-activated protein kinase (MAPK) pathway. CRS exposure caused depressive-like behaviors in mice, which was associated with increased pre-inflammatory cytokines (interleukin (IL)-1β, tumor necrosis factor (TNF)-α and IL-6) levels, reactive microglia numbers and up-regulated regulatory molecules such as TLR4/p38 and P2X7 receptor in hippocampus. Such neurobehavioral and biochemical abnormalities were normalized by ketamine treatment. CRS-induced depression-like behaviours are associated with activation of hippocampal inflammatory response, whereas down-regulation of pro-inflammatory cytokines may contribute to ketamine’s antidepressant effects in mice.