Fellowship for Lei Chen: Novel Mechanisms for Nanoparticle-Induced Cerebrovascular Toxicity in an Experimental Stroke Model

The blood-brain barrier (BBB) is responsible for both the limited penetration of plasma content into the brain and the active exchange of metabolites and drugs between the blood and brain sides. Tight junctions seal brain endothelial cells along the cerebral microvessels and are responsible for low paracellular permeability and high electrical resistance of the brain endothelium. The loss or disruption of tight junctions contributes to the BBB breakdown in several pathological conditions, including stroke. The vascular toxicity of manufactured nanoparticles is an emerging health problem due to an increased production and risk of exposure. Our preliminary data indicate that nanoparticles of aluminum oxide (nano-alumina) can alter mitochondrial membrane potential, induce cellular oxidative stress, and decrease expression of tight junction proteins both in brain endothelial cells and brain capillaries. Interestingly, exposure to nano-alumina increased the BBB permeability and potentiated brain injury in an experimental stroke model in mice. Based on these results, we hypothesize that nano-alumina can contribute to the development of stroke through activation of redox-regulated signaling mechanisms, leading to the dysfunction of the brain endothelium, and the disruption of the BBB. Specific Aims of the current proposal are: 1. To study the hypothesis that exposure to nano-alumina can enhance brain injury in an experimental stroke model by induction of mitochondrial dysfunction and oxidative stress in brain capillaries. 2. To study the hypothesis that nano-alumina-induced alterations of the Ras and Rho signaling in brain capillaries contribute to diminished expression of tight junction proteins and disruption of the blood-brain barrier integrity in an experimental stroke model. The proposed studies are based on an experimental stroke model induced by a transient occlusion of the middle cerebral artery. The results of the present proposal are likely to increase our knowledge on vascular toxicity of nanoparticles and to identify novel mechanisms of nano-alumina-induced disruption of the BBB. The findings resulting from the present proposal may be applicable not only to stroke, but also to other neuropathological disorders where alumina, nanoparticles, and/or disruption of the BBB play detrimental roles.