title: Delayed treatment with minocycline ameliorates neurologic impairment through activated microglia expressing a high-mobility group box1-inhibiting mechanism.
abstract: OBJECTIVE
  Minocycline, a semisynthetic tetracycline antibiotic, has been reported to ameliorate brain injury and inhibit microglial activation after focal cerebral ischemia. However, the cerebroprotective mechanism of minocycline remains unclear. In the present study, we investigated that mechanism of minocycline in a murine model of 4-hour middle cerebral artery (MCA) occlusion.
  
  
  METHODS
  One day after 4-hour MCA occlusion, minocycline was administered intraperitoneally for 14 days. Neurologic scores were measured 1, 7, and 14 days after cerebral ischemia. Motor coordination was evaluated at 14 days by the rota-rod test at 10 rpm. Activated microglia and high-mobility group box1 (HMGB1), a cytokine-like mediator, were also evaluated by immunostaining and Western blotting. In addition, terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling immunostaining was carried out 14 days after cerebral ischemia.
  
  
  RESULTS
  Repeated treatment with minocycline (1, 5, and 10 mg/kg) for 14 days improved neurologic score, motor coordination on the rota-rod test, and survival in a dose-dependent manner. Minocycline decreased the expression of Iba1, a marker of activated microglia, as assessed by both immunostaining and Western blotting. Moreover, minocycline decreased the activation of microglia expressing HMGB1 within the brain and also decreased both brain and plasma HMGB1 levels. Additionally, minocycline significantly decreased the number of terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling-positive cells and prevented ischemic brain atrophy 14 days after cerebral ischemia.
  
  
  CONCLUSIONS
  Our results suggest that minocycline inhibits activated microglia expressing HMGB1 and decreases neurologic impairment induced by cerebral ischemia. Minocycline will have a palliative action and open new therapeutic possibilities for treatment of postischemic injury via an HMGB1-inhibiting mechanism.
authors.affiliation: Department of Neuropharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University, Nanakuma 8-19-1, Fukuoka City, Fukuoka, 814-0180 Japan.
authors.forename: Kazuhide
authors.initials: K
authors.lastname: Hayakawa
authors.forename: Kenichi
authors.initials: K
authors.lastname: Mishima
authors.forename: Masanori
authors.initials: M
authors.lastname: Nozako
authors.forename: Mai
authors.initials: M
authors.lastname: Hazekawa
authors.forename: Shohei
authors.initials: S
authors.lastname: Mishima
authors.forename: Masayuki
authors.initials: M
authors.lastname: Fujioka
authors.forename: Kensuke
authors.initials: K
authors.lastname: Orito
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Egashira
authors.forename: Katsunori
authors.initials: K
authors.lastname: Iwasaki
authors.forename: Michihiro
authors.initials: M
authors.lastname: Fujiwara
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001284:Atrophy; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D002545:Brain Ischemia / Q000150:complications* / Q000473:pathology / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D024243:HMGB1 Protein / Q000037:antagonists & inhibitors* / Q000097:blood; D020287:In Situ Nick-End Labeling; D020244:Infarction, Middle Cerebral Artery / Q000150:complications; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism*; D008911:Minocycline / Q000008:administration & dosage* / Q000494:pharmacology; D009422:Nervous System Diseases / Q000209:etiology / Q000503:physiopathology*; D018696:Neuroprotective Agents / Q000008:administration & dosage* / Q000494:pharmacology; D011597:Psychomotor Performance / Q000187:drug effects; D016019:Survival Analysis
chemical_list: D024243:HMGB1 Protein; D018696:Neuroprotective Agents; D008911:Minocycline