The neurorestorative benefit of GW3965 treatment of stroke in mice.
The neurorestorative benefit of GW3965 treatment of stroke in mice.
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DOI：
10.1161/strokeaha.112.677682
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发表时间：
2013-01
期刊：
影响因子：
8.3
通讯作者：
Chen J
中科院分区：
文献类型：
--
作者：
Cui X;Chopp M;Zacharek A;Cui Y;Roberts C;Chen J
GW 3965是一种人工合成的肝脏X受体激动剂，可升高高密度脂蛋白胆固醇（HDL-C），并具有抗动脉粥样硬化和抗炎特性。我们检验了GW 3965治疗中风增加血管重塑、促进缺血脑中突触蛋白表达和轴突生长并改善小鼠功能结果的假设。使小鼠经历短暂的大脑中动脉闭塞（MCAo），并在MCAo后24小时开始每天不使用或使用不同剂量的GW 3965（5、10或20 mg/kg）治疗，持续14天。进行神经功能测试、血液HDL-C测量和免疫染色。小鼠脑内皮细胞，原代培养的动脉外植体和原代皮层神经元培养物也在体外。与MCAo对照动物相比，GW 3965治疗中风显著增加血液HDL-C水平，突触蛋白表达，轴突密度，血管生成和动脉生成，以及缺血脑中的Angiopoietin 1，Tie 2和occludin表达，并改善功能结果（P<0.05，n=10）。在体外，GW 3965和HDL也显着增加毛细血管样管的形成和动脉外植体细胞迁移以及神经突生长。血管生成素1抑制剂可减弱GW 3965诱导的血管形成、动脉细胞迁移和神经突起生长（P<0.05，n=6/组）。这些数据首次表明，GW 3965促进突触蛋白表达、轴突生长，并增加血管重塑，这可能有助于改善卒中后的功能结局。增加血管生成素1/Tie 2信号传导活性可能在GW 3965诱导的脑可塑性和中风神经恢复中发挥重要作用。
GW3965, a synthetic liver X receptor agonist, elevates high-density lipoprotein cholesterol (HDL-C) and has anti-atherosclerosis and anti-inflammation properties. We tested the hypothesis that GW3965 treatment of stroke increases vascular remodeling, promotes synapticprotein expression and axonal growth in the ischemic brain and improves functional outcome in mice. Mice were subjected to transient middle cerebral artery occlusion (MCAo) and treated without or with different doses of GW3965 (5, 10 or 20 mg/kg) starting 24 hours after MCAo daily for 14 days. Neurological functional tests, blood HDL-C measurement, and immunostaining were performed. Mouse brain endothelial cells, primary cultured artery explants and primary cortical neurons cultures were also employed in vitro. GW3965 treatment of stroke significantly increased blood HDL-C level, synaptic protein expression, axonal density, angiogenesis and arteriogenesis, and Angiopoietin1, Tie2 and occludin expression in the ischemic brain and improved functional outcome compared with MCAo control animals (P<0.05, n=10). In vitro, GW3965 and HDL also significantly increased capillary-like tube formation and artery explant cell migration as well as neurite outgrowth. Inhibition o f A n giopoietin1 attenuated GW3965-induced tube-formation, artery cell migration and neurite outgrowth (P<0.05, n=6/group). These data indicate, for the first time, that GW3965 promotessynaptic protein expression, axonal growth, and increases vascular remodeling which may contribute to improvement of functional outcome after stroke. Increasing Angiopoietin1/Tie2 signaling activity may play an important role in GW3965-induced brain plasticity and neurological recovery from stroke.