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.
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.
Authors: Frederick M Lartey; G-One Ahn; Rehan Ali; Sahar Rosenblum; Zheng Miao; Natasha Arksey; Bin Shen; Marta Vilalta Colomer; Marjan Rafat; Hongguang Liu; Miguel A Alejandre-Alcazar; John W Chen; Theo Palmer; Frederick T Chin; Raphael Guzman; Billy W Loo; Edward Graves Journal: Mol Imaging Biol Date: 2014-12 Impact factor: 3.488
Authors: Dennis W Simon; Rajesh K Aneja; Henry Alexander; Michael J Bell; Hülya Bayır; Patrick M Kochanek; Robert S B Clark Journal: J Neurotrauma Date: 2017-08-22 Impact factor: 5.269
Authors: Mengzhou Xue; Elena I Mikliaeva; Steve Casha; David Zygun; Andrew Demchuk; V Wee Yong Journal: Am J Pathol Date: 2010-01-28 Impact factor: 4.307