Icariin and icaritin ameliorated hippocampus neuroinflammation via mediating HMGB1 expression in social defeat model in mice

• Published in: International immunopharmacology Vol. 75; p. 105799
• Main Authors: Liu, Lumei, Zhao, Zhengxiao, Lu, Linwei, Liu, Jiaqi, Sun, Jing, Dong, Jingcheng
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.10.2019; Elsevier BV
• Subjects: Activation; Animals; Anti-Inflammatory Agents - pharmacology; Anti-Inflammatory Agents - therapeutic use; Behavior, Animal - drug effects; Cytokines - blood; Cytokines - genetics; Cytoplasm; Depression; Disease Models, Animal; Flavonoids - pharmacology; Flavonoids - therapeutic use; High mobility group proteins; Hippocampus; Hippocampus - drug effects; Hippocampus - metabolism; HMGB1; HMGB1 protein; HMGB1 Protein - blood; HMGB1 Protein - genetics; HMGB1 Protein - metabolism; Icariin; Icaritin; Inflammation; Inflammatory response; Male; Mice, Inbred C57BL; Microglia; Neurogenesis; Neuroinflammation; Neuroprotection; Neuroprotective Agents - pharmacology; Neuroprotective Agents - therapeutic use; NF-kappa B - metabolism; NF-κB protein; Proteins; Receptor for Advanced Glycation End Products - metabolism; Signal Transduction - drug effects; Signaling; Social interactions; Stress; Stress, Psychological - drug therapy; Stress, Psychological - metabolism; TLR4 protein; Toll-like receptors; Translocation; Icariin; Depression; Neuroinflammation; HMGB1; Neurogenesis; Icaritin
• ISSN: 1567-5769; 1878-1705
• DOI: 10.1016/j.intimp.2019.105799

Depression is a chronic, severe, and often life-threatening disease accompanied with impaired neurogenesis. Evidence showed that neuroinflammation played a key role in the process of depression. High mobility group protein box 1 (HMGB1) has been proved to function as a pro-inflammatory cytokine. In this study, we used a social defeat (SD) stress to induce inflammatory response, aiming to explore the relationship between HMGB1 and neuroinflammation. We found that the expression of HMGB1 decreased in mice exposure to SD stress, but showed a high expression of cytoplasmic HMGB1 and a high expression of RAGE, which could be rescued by ICA and ICT. So, we speculated that the translocation of HMGB1 from the nucleus to the cytoplasm might play an important role in neuroinflammatory process, and HMGB1-RAGE signaling was involved in this process. Furthermore, we also found that TLR4-XBP1s-ER stress related NF-κB signaling activation was also involved in HMGB1-related neuroinflammation. However, ICA and ICT treatment activated NF-κB signaling, and we also observed the translocation of HMGB1 into the nucleus and the increased number of neurons in mice hippocampus, indicating that the activation of NF-κB signaling might be related to neuroregeneration. Moreover, recombinant human HMGB1 protein (rHMGB1) pretreatment could suppress HMGB1-RAGE signaling and TLR4-XBP1s-ER stress related NF-κB signaling, resulted in a suppressed microglia activation in mice hippocampus. We supposed that ICA and ICT could ameliorate neuroinflammation in hippocampus via suppressing HMGB1-RAGE signaling and show neuroprotective effects via activating TLR4- NF-κB signaling at the same time, resulting in improving depressive behaviors in mice.