Delayed treatment with minocycline ameliorates neurologic impairment through activated microglia expressing a high-mobility group box1-inhibiting mechanism

Kazuhide Hayakawa, Kenichi Mishima, Masanori Nozako, Mai Hazekawa, Shohei Mishima, Masayuki Fujioka, Kensuke Orito, Nobuaki Egashira, Katsunori Iwasaki, Michihiro Fujiwara

Research output: Contribution to journalArticle

110 Citations (Scopus)

Abstract

BACKGROUND AND PURPOSE - 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.

Original languageEnglish
Pages (from-to)951-958
Number of pages8
JournalStroke
Volume39
Issue number3
DOIs
Publication statusPublished - Mar 1 2008

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Minocycline
Microglia
Nervous System
Brain Ischemia
DNA Nucleotidylexotransferase
Middle Cerebral Artery Infarction
Brain
Western Blotting
Tetracycline
Brain Injuries
Atrophy
Cytokines
Anti-Bacterial Agents

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine
  • Neuroscience(all)
  • Medicine(all)

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Delayed treatment with minocycline ameliorates neurologic impairment through activated microglia expressing a high-mobility group box1-inhibiting mechanism. / Hayakawa, Kazuhide; Mishima, Kenichi; Nozako, Masanori; Hazekawa, Mai; Mishima, Shohei; Fujioka, Masayuki; Orito, Kensuke; Egashira, Nobuaki; Iwasaki, Katsunori; Fujiwara, Michihiro.

In: Stroke, Vol. 39, No. 3, 01.03.2008, p. 951-958.

Research output: Contribution to journalArticle

Hayakawa, K, Mishima, K, Nozako, M, Hazekawa, M, Mishima, S, Fujioka, M, Orito, K, Egashira, N, Iwasaki, K & Fujiwara, M 2008, 'Delayed treatment with minocycline ameliorates neurologic impairment through activated microglia expressing a high-mobility group box1-inhibiting mechanism', Stroke, vol. 39, no. 3, pp. 951-958. https://doi.org/10.1161/STROKEAHA.107.495820
Hayakawa, Kazuhide ; Mishima, Kenichi ; Nozako, Masanori ; Hazekawa, Mai ; Mishima, Shohei ; Fujioka, Masayuki ; Orito, Kensuke ; Egashira, Nobuaki ; Iwasaki, Katsunori ; Fujiwara, Michihiro. / Delayed treatment with minocycline ameliorates neurologic impairment through activated microglia expressing a high-mobility group box1-inhibiting mechanism. In: Stroke. 2008 ; Vol. 39, No. 3. pp. 951-958.
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AU - Mishima, Kenichi

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AU - Hazekawa, Mai

AU - Mishima, Shohei

AU - Fujioka, Masayuki

AU - Orito, Kensuke

AU - Egashira, Nobuaki

AU - Iwasaki, Katsunori

AU - Fujiwara, Michihiro

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N2 - BACKGROUND AND PURPOSE - 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.

AB - BACKGROUND AND PURPOSE - 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.

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