Molecular Neuroscience and Vascular Biology Laboratory, Department of Neurosurgery and Graduate Center for Nutritional Sciences, University of Kentucky Medical Center, Lexington, Kentucky, USA.
Nanomedicine. 2013 Feb;9(2):212-21. doi: 10.1016/j.nano.2012.05.017. Epub 2012 Jun 9.
The current study focused on blood-brain barrier disruption and neurovascular damage induced by engineered nanomaterials. Exposure to nanoalumina, but not to nanocarbon, induced a dose-dependent mitochondrial potential collapse, increased autophagy of brain endothelial cells, and decreased expression of the tight-junction proteins occludin and claudin-5. Inhibition of autophagy by pretreatment with Wortmannin attenuated the effects of nanoalumina on decreased claudin-5 expression; however, it did not affect the disruption of occludin. These findings were confirmed in mice by administration of nanoalumina into the cerebral circulation. Systemic treatment with nanoalumina elevated autophagy-related genes and autophagic activity in the brain, decreased tight-junction protein expression, and elevated blood-brain barrier permeability. Finally, exposure to nanoalumina, but not to nanocarbon, increased brain infarct volume in mice subjected to a focal ischemic stroke model. Overall, our study reveals that autophagy constitutes an important mechanism involved in nanoalumina-induced neurovascular toxicity in the central nervous system.
In this paper, the effects of nanoalumina on the permeability of the blood-brain barrier is reported, suggesting that autophagy is an important mechanism in nanoalumina-induced neurovascular toxicity.
本研究聚焦于工程纳米材料引起的血脑屏障破坏和神经血管损伤。暴露于纳米氧化铝而非纳米碳会导致线粒体膜电位的剂量依赖性崩溃，增加脑内皮细胞的自噬，并降低紧密连接蛋白 occludin 和 claudin-5 的表达。用 Wortmannin 预处理抑制自噬可减弱纳米氧化铝对 claudin-5 表达降低的作用；然而，它并不影响 occludin 的破坏。这些发现通过将纳米氧化铝注入脑循环在小鼠中得到了证实。纳米氧化铝全身治疗可增加脑中与自噬相关的基因和自噬活性，降低紧密连接蛋白的表达，并增加血脑屏障通透性。最后，暴露于纳米氧化铝而非纳米碳会增加局灶性缺血性中风模型中小鼠的脑梗死体积。总的来说，我们的研究揭示了自噬是纳米氧化铝诱导的中枢神经系统神经血管毒性的一个重要机制。
本文报道了纳米氧化铝对血脑屏障通透性的影响，提示自噬是纳米氧化铝诱导的神经血管毒性的一个重要机制。
