Autophagy is involved in nanoalumina-induced cerebrovascular toxicity.
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.


BACKGROUND
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.
Molecular Neuroscience and Vascular Biology Laboratory, Department of Neurosurgery and Graduate Center for Nutritional Sciences, University of Kentucky Medical Center, Lexington, Kentucky, USA.
Lei
L
Chen
Bei
B
Zhang
Michal
M
Toborek
D000537:Aluminum Oxide / Q000737:chemistry / Q000633:toxicity*; D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D002460:Cell Line; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D049329:Nanostructures / Q000737:chemistry / Q000633:toxicity*; D010539:Permeability; D059748:Proteolysis / Q000187:drug effects
D000537:Aluminum Oxide