title: MCP-induced protein 1 mediates the minocycline-induced neuroprotection against cerebral ischemia/reperfusion injury in vitro and in vivo.
abstract: BACKGROUND
  Minocycline, a broad-spectrum tetracycline antibiotic, has shown anti-inflammatory and neuroprotective effects in ischemic brain injury. The present study seeks to determine whether monocyte chemotactic protein-induced protein 1 (MCPIP1), a recently identified modulator of inflammatory reactions, is involved in the cerebral neuroprotection conferred by minocycline treatment in the animal model of focal cerebral ischemia and to elucidate the mechanisms of minocycline-induced ischemic brain tolerance.
  
  
  METHODS
  Focal cerebral ischemia was induced by middle cerebral artery occlusion (MCAO) for 2 h in male C57BL/6 mice and MCPIP1 knockout mice followed by 24- or 48-h reperfusion. Twelve hours before ischemia or 2 h after MCAO, mice were injected intraperitoneally with 90 mg/kg of minocycline hydrochloride. Thereafter, the animals were injected twice a day, at a dose of 90 mg/kg after ischemia until sacrificed. Transcription and expression of MCPIP1 gene was monitored by quantitative real-time PCR (qRT-PCR), Western blot, and immunohistochemistry. The neurobehavioral scores, infarction volumes, and proinflammatory cytokines in brain and NF-κB signaling were evaluated after ischemia/reperfusion.
  
  
  RESULTS
  MCPIP1 protein and mRNA levels significantly increased in mouse brain undergoing minocycline pretreatment. Minocycline treatment significantly attenuated the infarct volume, neurological deficits, and upregulation of proinflammatory cytokines in the brain of wild type mice after MCAO. MCPIP1-deficient mice failed to evoke minocycline-treatment-induced tolerance compared with that of the control MCPIP1-deficient group without minocycline treatment. Similarly, in vitro data showed that minocycline significantly induced the expression of MCPIP1 in primary neuron-glial cells, cortical neurons, and reduced oxygen glucose deprivation (OGD)-induced cell death. The absence of MCPIP1 blocked minocycline-induced protection on neuron-glial cells and cortical neurons treated with OGD.
  
  
  CONCLUSIONS
  Our in vitro and in vivo studies demonstrate that MCPIP1 is an important mediator of minocycline-induced protection from brain ischemia.
authors.affiliation: School of Basic Medicine, Zhejiang Chinese Medical University, Hangzhou, 310053, Zhejiang, China. jinzq@hotmail.com.
authors.forename: Zhuqing
authors.initials: Z
authors.lastname: Jin
authors.affiliation: Burnett School of Biomedical Sciences, University of Central Florida College of Medicine, 4000 Central Florida Boulevard, Orlando, FL, 32816, USA. jian.liang@ucf.edu.
authors.forename: Jian
authors.initials: J
authors.lastname: Liang
authors.affiliation: Burnett School of Biomedical Sciences, University of Central Florida College of Medicine, 4000 Central Florida Boulevard, Orlando, FL, 32816, USA. jwang7882@gmail.com.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Burnett School of Biomedical Sciences, University of Central Florida College of Medicine, 4000 Central Florida Boulevard, Orlando, FL, 32816, USA. pappachan.kolattukudy@ucf.edu.
authors.forename: Pappachan E
authors.initials: PE
authors.lastname: Kolattukudy
mesh_terms: D000818:Animals; D001929:Brain Edema / Q000209:etiology; D020520:Brain Infarction / Q000175:diagnosis / Q000209:etiology; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005947:Glucose / Q000172:deficiency; D000860:Hypoxia / Q000517:prevention & control; D020244:Infarction, Middle Cerebral Artery / Q000150:complications*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008911:Minocycline / Q000627:therapeutic use*; D009460:Neurologic Examination; D009474:Neurons / Q000187:drug effects; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D015427:Reperfusion Injury / Q000209:etiology* / Q000517:prevention & control*; D012260:Ribonucleases / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors
chemical_list: D016207:Cytokines; D005904:Glial Fibrillary Acidic Protein; D018696:Neuroprotective Agents; D012260:Ribonucleases; C541320:Zc3h12a protein, mouse; D010751:Phosphopyruvate Hydratase; D008911:Minocycline; D005947:Glucose