Metformin attenuates blood-brain barrier disruption in mice following middle cerebral artery occlusion.
Metformin attenuates blood-brain barrier disruption in mice following middle cerebral artery occlusion.
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二甲双胍可减轻小鼠大脑中动脉闭塞后血脑屏障的破坏
DOI：
10.1186/s12974-014-0177-4
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发表时间：
2014-10-15
影响因子：
9.3
通讯作者：
Yang GY
中科院分区：
文献类型：
--
作者：
Liu Y;Tang G;Li Y;Wang Y;Chen X;Gu X;Zhang Z;Wang Y;Yang GY
研究背景在临床试验中，广泛使用的降糖药二甲双胍可降低卒中发生率并减轻慢性炎症。然而，二甲双胍在缺血性卒中中的作用尚不清楚。在此，我们观察了二甲双胍对小鼠缺血性卒中的影响，并进一步探讨了其可能的机制。方法98只成年雄性CD-1小鼠建立90分钟短暂性大脑中动脉闭塞模型。二甲双胍(200 mg/kg)连续给药14天。观察tMCAO后神经行为结果、脑梗塞体积、炎症因子、血脑屏障(BBB)通透性和AMPK信号通路。结果二甲双胍治疗组小鼠TMCAO后脑梗塞体积较对照组缩小(P<； 0.0 5)。二甲双胍治疗的小鼠的神经行为结果显著改善(P<； 0.05)。二甲双胍可降低MPO+细胞、Gr1+细胞、MPO活性和血脑屏障通透性(P<； )。此外，二甲双胍还能激活AMPK的磷酸化，抑制NF-κB的激活，下调细胞因子(IL-1β、IL-6、α)和ICAM-1的表达(P<； 0.05)。此外，二甲双胍还激活了AMPK信号通路，减轻了缺氧缺糖诱导的bEND.3细胞ICAM-1的表达(P<； )。结论二甲双胍以AMPK依赖的方式下调ICAM-1的表达，可通过减轻中性粒细胞的浸润而有效地预防脑缺血损伤，提示二甲双胍是一种有前景的卒中治疗药物。
BackgroundMetformin, a widely used hypoglycemic drug, reduces stroke incidence and alleviates chronic inflammation in clinical trials. However, the effect of metformin in ischemic stroke is unclear. Here, we investigated the effect of metformin on ischemic stroke in mice and further explored the possible underlying mechanisms.MethodsNinety-eight adult male CD-1 mice underwent 90-minute transient middle cerebral artery occlusion (tMCAO). Metformin (200 mg/kg) was administrated for up to 14 days. Neurobehavioral outcomes, brain infarct volume, inflammatory factors, blood-brain barrier (BBB) permeability and AMPK signaling pathways were evaluated following tMCAO. Oxygen glucose deprivation was performed on bEND.3 cells to explore the mechanisms of metformin in inhibiting inflammatory signaling pathways.ResultsInfarct volume was reduced in metformin-treated mice compared to the control group following tMCAO (P< 0.05). Neurobehavioral outcomes were greatly improved in metformin-treated mice (P< 0.05). MPO+cells, Gr1+cells, MPO activity and BBB permeability were decreased after metformin administration (P< 0.05). In addition, metformin activated AMPK phosphorylation, inhibited NF- κB activation, down-regulated cytokine (IL-1 β, IL-6, TNF- α) and ICAM-1 expression following tMCAO (P< 0.05). Furthermore, metformin activated AMPK signaling pathway and alleviated oxygen-glucose deprivation-induced ICAM-1 expression in bEND.3 cells (P< 0.05). Compound C, a selective AMPK inhibitor, eliminated this promotional effect.ConclusionsMetformin down-regulated ICAM-1 in an AMPK-dependent manner, which could effectively prevent ischemia-induced brain injury by alleviating neutrophil infiltration, suggesting that metformin is a promising therapeutic agent in stroke therapy.
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DOI：
10.1097/00004647-199607000-00007
发表时间：
1996-07-01
影响因子：
6.3
作者：
Chopp, M;Li, Y;Prostak, J
通讯作者：
Prostak, J
影响因子：
82.9
作者：
Shibata, R;Sato, K;Walsh, K
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Walsh, K
影响因子：
8.3
作者：
Hattori, Yoshiyuki;Suzuki, Kunihiro;Kasai, Kikuo
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Kasai, Kikuo
DOI：
10.1073/pnas.0610068104
发表时间：
2007-04-24
影响因子：
11.1
作者：
Dasgupta, Biplab;Milbrandt, Jeffrey
通讯作者：
Milbrandt, Jeffrey
影响因子：
16.6
作者：
Martin-Montalvo, Alejandro;Mercken, Evi M.;Mitchell, Sarah J.;Palacios, Hector H.;Mote, Patricia L.;Scheibye-Knudsen, Morten;Gomes, Ana P.;Ward, Theresa M.;Minor, Robin K.;Blouin, Marie-Jose;Schwab, Matthias;Pollak, Michael;Zhang, Yongqing;Yu, Yinbing;Becker, Kevin G.;Bohr, Vilhelm A.;Ingram, Donald K.;Sinclair, David A.;Wolf, Norman S.;Spindler, Stephen R.;Bernier, Michel;de Cabo, Rafael
通讯作者：
de Cabo, Rafael