Stroke is the third leading cause of death and the most prevalent cause of permanent disability. This application evolves from the findings that chronic alcohol use is strongly associated with atherosclerosis and stroke with not well define underlying molecular/cellular mechanisms. Here, we propose to examine the hypothesis that immune cell adhesion and cholesterol deposit at the site of oxidative injury in capillary walls causes formation cholesterol crystals (CC) to activate NLRP3 inflammasome for induction of atherosclerosis in heavy chronic alcohol intake. The clinical relevant of this application is that Joint therapy of acetyl-L-carnitine (ALC) and Lipitor can prevent this alcohol-elicited CC formation and atherosclerotic lesions. We will address this innovative idea in our recently developed unique animal model of human disease with two objectives. Our first objective is to examine if immune cell adhesion and cholesterol deposit at the vasculature enhances CC formation, NLRP3 activation and atherosclerotic lesions in response to dose-time-/and temperature-dependent effects of alcohol. After establishing this kinetic profile, we will then address the molecular mechanisms of CC-induced activation of NLRP3 and downstream caspase 1 signaling pathways in primary human brain endothelial cell culture. Our second objective is to evaluate if a joint therapy of ALC/Lipitor can reverse the early development of atherosclerosis in chronic alcohol intake. This will assess the protective effect of ALC/Lipitor from alcohol-induced atherosclerotic bulging, brain infarct volume, intracranial blood pressure and in vivo imaging of CC using cyclodextrin nanoparticles specific to CC by MR brain imaging.
The elevation of cholesterol in chronic alcohol intake causes the formation of cholesterol crystals (CC) in the brain capillary. CC-induced activation of NLRP3 inflammasome in the capillary leads to early atherosclerosis development. A significant clinical relevant of this application is that a Joint therapy of acetyl-L-carnitine and Lipitor can prevent this alcohol-elicited CC formation and atherosclerotic lesions in the brain.
|Mishra, Vikas; Skotak, Maciej; Schuetz, Heather et al. (2016) Primary blast causes mild, moderate, severe and lethal TBI with increasing blast overpressures: Experimental rat injury model. Sci Rep 6:26992|