Endothelial nitric oxide synthase regulates white matter changes via the BDNF/TrkB pathway after stroke in mice.
Endothelial nitric oxide synthase regulates white matter changes via the BDNF/TrkB pathway after stroke in mice.
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DOI：
10.1371/journal.pone.0080358
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Chen J
中科院分区：
文献类型：
--
作者：
Cui X;Chopp M;Zacharek A;Ning R;Ding X;Roberts C;Chen J
脑卒中引起的白色物质（WM）损伤与神经功能缺损有关，但其机制尚不清楚。在这项研究中，我们调查是否内皮型一氧化氮合酶（eNOS）影响中风后WM损伤。成年雄性野生型（WT）和eNOS敲除（eNOS-/-）小鼠经受大脑中动脉闭塞。进行功能评估、梗死体积测量、免疫染色和原代皮质细胞培养。为了深入了解eNOS-/-对WM损伤的作用机制，还进行了体内和体外eNOS、脑源性神经营养因子（BDNF）及其受体TrkB的测量。WT和eNOS-/-小鼠的梗死体积、同侧纹状体WM束的髓鞘密度和脑缺血边缘的髓鞘蛋白表达无显著差异。然而，eNOS-/-小鼠表现出显著的：1）功能结果降低，同时在同侧纹状体WM束中总轴突密度和磷酸化高分子量神经丝密度降低。相关性分析显示，轴突密度与神经功能结局显著正相关; 2）与WT小鼠相比，中风后同侧纹状体中少突胶质细胞/少突胶质细胞祖细胞数量减少; 3）缺血边缘中突触素、BDNF和TrkB表达减少（n = 12/组，p<0.05）。 原代皮层细胞培养证实，来源于eNOS-/-小鼠的神经元中神经元轴突生长的减少是由BDNF/TrkB的减少介导的（n = 6/组，p<0.05）。 我们的数据表明，eNOS在中风后WM损伤中起着关键作用，并且eNOS-/-诱导的BDNF/TrkB通路的减少可能有助于增加WM损伤，从而降低功能结果。
Stroke induced white matter (WM) damage is associated with neurological functional deficits, but the underlying mechanisms are not well understood. In this study, we investigate whether endothelial nitric oxide synthase (eNOS) affects WM-damage post-stroke. Adult male wild-type (WT) and eNOS knockout (eNOS-/-) mice were subjected to middle cerebral artery occlusion. Functional evaluation, infarct volume measurement, immunostaining and primary cortical cell culture were performed. To obtain insight into the mechanisms underlying the effects of eNOS-/- on WM-damage, measurement of eNOS, brain-derived neurotrophic factor (BDNF) and its receptor TrkB in vivo and in vitro were also performed. No significant differences were detected in the infarction volume, myelin density in the ipsilateral striatal WM-bundles and myelin-based protein expression in the cerebral ischemic border between WT and eNOS-/- mice. However, eNOS-/- mice showed significantly: 1) decreased functional outcome, concurrent with decreases of total axon density and phosphorylated high-molecular weight neurofilament density in the ipsilateral striatal WM-bundles. Correlation analysis showed that axon density is significantly positive correlated with neurological functional outcome; 2) decreased numbers of oligodendrocytes / oligodendrocyte progenitor cells in the ipsilateral striatum; 3) decreased synaptophysin, BDNF and TrkB expression in the ischemic border compared with WT mice after stroke (n = 12/group, p<0.05). Primary cortical cell culture confirmed that the decrease of neuronal neurite outgrowth in the neurons derived from eNOS-/- mice is mediated by the reduction of BDNF/TrkB (n = 6/group, p<0.05). Our data show that eNOS plays a critical role in WM-damage after stroke, and eNOS-/--induced decreases in the BDNF/TrkB pathway may contribute to increased WM-damage, and thereby decrease functional outcome.
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