PMID- 27318303 OWN - NLM STAT- MEDLINE DCOM- 20170711 LR - 20220408 IS - 1873-7544 (Electronic) IS - 0306-4522 (Linking) VI - 331 DP - 2016 Sep 7 TI - Compound C induces the ramification of murine microglia in an AMPK-independent and small rhogtpase-dependent manner. PG - 24-39 LID - S0306-4522(16)30248-2 [pii] LID - 10.1016/j.neuroscience.2016.06.018 [doi] AB - Microglial cells are the pivotal immune cells of the central nervous system. Adult microglia cells under physiological conditions are in a ramification state with extensively branched processes. Upon disease stimulation, they retract their processes and become activated. Induction of ramification is an attracting strategy to terminate the excessive activation of microglia. Here, we investigated the influence of compound C (CC) on microglial shape. Results showed that CC reversibly induced a ramification of murine microglia in both basal and inflammatory conditions. These pro-ramification effects were independent of adenosine 5'-monophosphate-activated protein kinase (AMPK) inhibition as both AMPKalpha1 and AMPKalpha2 silence failed to induce microglial ramification. The ramification state of microglia induced by CC was associated with a decrease in pro-inflammatory factors and an increase in brain-derived neurotrophic factors (BDNF) protein and phagocytic activity. Mechanistic studies confirmed that the phosphatidylinositol 3-kinase (PI3K)-protein kinase B (Akt) signal, extracellular signal-regulated kinase 1/2 (ERK1/2) or small RhoGTPase activation mediated the effect of CC on microglial shape change based on the following observations: (i) CC induced a significant activation of the small RhoGTPase Rac1 and Cdc42; (ii) CC promoted the phosphorylation of ERK1/2 and Akt; (iii) inhibition of Rac1, Cdc42, ERK1/2, or the PI3K-Akt signal abolished the effect of CC on microglial shape change. These signal mechanisms were also ascertained in primary microglia. Our results explore a potential agent that promotes microglial ramification, and provide an alternative explanation for the neuroprotective effects of CC in various disease models such as brain ischemia and subarachnoid hemorrhage. CI - Copyright (c) 2016 IBRO. Published by Elsevier Ltd. All rights reserved. FAU - Huang, C AU - Huang C AD - Department of Pharmacology, School of Pharmacy, Nantong University, #19 Qixiu Road, Nantong, Jiangsu Province 226001, China; Key Laboratory of Inflammation and Molecular Drug Target of Jiangsu Province, #19 Qixiu Road, Nantong, Jiangsu Province 226001, China. FAU - Lu, X AU - Lu X AD - Department of Pharmacology, School of Pharmacy, Nantong University, #19 Qixiu Road, Nantong, Jiangsu Province 226001, China; Key Laboratory of Inflammation and Molecular Drug Target of Jiangsu Province, #19 Qixiu Road, Nantong, Jiangsu Province 226001, China. FAU - Wang, J L AU - Wang JL AD - Department of Pharmacology, School of Pharmacy, Nantong University, #19 Qixiu Road, Nantong, Jiangsu Province 226001, China; Key Laboratory of Inflammation and Molecular Drug Target of Jiangsu Province, #19 Qixiu Road, Nantong, Jiangsu Province 226001, China. FAU - Tong, L J AU - Tong LJ AD - Department of Pharmacology, School of Pharmacy, Nantong University, #19 Qixiu Road, Nantong, Jiangsu Province 226001, China; Key Laboratory of Inflammation and Molecular Drug Target of Jiangsu Province, #19 Qixiu Road, Nantong, Jiangsu Province 226001, China. FAU - Ling, Y AU - Ling Y AD - Department of Pharmacology, School of Pharmacy, Nantong University, #19 Qixiu Road, Nantong, Jiangsu Province 226001, China; Key Laboratory of Inflammation and Molecular Drug Target of Jiangsu Province, #19 Qixiu Road, Nantong, Jiangsu Province 226001, China. FAU - Jiang, B AU - Jiang B AD - Department of Pharmacology, School of Pharmacy, Nantong University, #19 Qixiu Road, Nantong, Jiangsu Province 226001, China; Key Laboratory of Inflammation and Molecular Drug Target of Jiangsu Province, #19 Qixiu Road, Nantong, Jiangsu Province 226001, China. FAU - Yang, R R AU - Yang RR AD - Department of Anesthesiology, Affiliated Hospital of Nantong University, Jiangsu Province, #20 Xisi Road, Nantong, Jiangsu Province 226001, China. Electronic address: charliechao888888@163.com. FAU - Zhang, W AU - Zhang W AD - Department of Pharmacology, School of Pharmacy, Nantong University, #19 Qixiu Road, Nantong, Jiangsu Province 226001, China; Key Laboratory of Inflammation and Molecular Drug Target of Jiangsu Province, #19 Qixiu Road, Nantong, Jiangsu Province 226001, China. Electronic address: asicampa@aliyun.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20160616 PL - United States TA - Neuroscience JT - Neuroscience JID - 7605074 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Enzyme Inhibitors) RN - 0 (Pyrazoles) RN - 0 (Pyrimidines) RN - EC 2.7.1.- (Phosphatidylinositol 3-Kinases) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.24 (Mapk1 protein, mouse) RN - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 1) RN - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 3) RN - EC 2.7.11.31 (AMP-Activated Protein Kinases) RN - EC 3.6.5.2 (rho GTP-Binding Proteins) SB - IM MH - AMP-Activated Protein Kinases/antagonists & inhibitors/*metabolism MH - Animals MH - Brain-Derived Neurotrophic Factor/metabolism MH - Cell Line MH - Dose-Response Relationship, Drug MH - Enzyme Inhibitors/*pharmacology MH - Mice MH - Microglia/*cytology/*drug effects/enzymology MH - Mitogen-Activated Protein Kinase 1/metabolism MH - Mitogen-Activated Protein Kinase 3/metabolism MH - Phagocytosis/drug effects/physiology MH - Phosphatidylinositol 3-Kinases/metabolism MH - Proto-Oncogene Proteins c-akt/metabolism MH - Pyrazoles/*pharmacology MH - Pyrimidines/*pharmacology MH - Time Factors MH - rho GTP-Binding Proteins/*metabolism OTO - NOTNLM OT - AMPK OT - compound C OT - microglia OT - ramification EDAT- 2016/06/19 06:00 MHDA- 2017/07/14 06:00 CRDT- 2016/06/19 06:00 PHST- 2016/02/09 00:00 [received] PHST- 2016/06/10 00:00 [revised] PHST- 2016/06/10 00:00 [accepted] PHST- 2016/06/19 06:00 [entrez] PHST- 2016/06/19 06:00 [pubmed] PHST- 2017/07/14 06:00 [medline] AID - S0306-4522(16)30248-2 [pii] AID - 10.1016/j.neuroscience.2016.06.018 [doi] PST - ppublish SO - Neuroscience. 2016 Sep 7;331:24-39. doi: 10.1016/j.neuroscience.2016.06.018. Epub 2016 Jun 16.