Abstract | BACKGROUND AND PURPOSE: 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.
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Authors | Kazuhide Hayakawa, Kenichi Mishima, Masanori Nozako, Mai Hazekawa, Shohei Mishima, Masayuki Fujioka, Kensuke Orito, Nobuaki Egashira, Katsunori Iwasaki, Michihiro Fujiwara |
Journal | Stroke
(Stroke)
Vol. 39
Issue 3
Pg. 951-8
(Mar 2008)
ISSN: 1524-4628 [Electronic] United States |
PMID | 18258837
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- HMGB1 Protein
- Neuroprotective Agents
- Minocycline
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Topics |
- Animals
- Apoptosis
(drug effects)
- Atrophy
- Brain
(drug effects, metabolism, pathology, physiopathology)
- Brain Ischemia
(complications, pathology, physiopathology)
- Dose-Response Relationship, Drug
- Drug Administration Schedule
- HMGB1 Protein
(antagonists & inhibitors, blood)
- In Situ Nick-End Labeling
- Infarction, Middle Cerebral Artery
(complications)
- Injections, Intraperitoneal
- Male
- Mice
- Microglia
(drug effects, metabolism)
- Minocycline
(administration & dosage, pharmacology)
- Nervous System Diseases
(etiology, physiopathology)
- Neuroprotective Agents
(administration & dosage, pharmacology)
- Psychomotor Performance
(drug effects)
- Survival Analysis
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