Acetaminophen protects brain endothelial cells against oxidative.pdfVIP

Acetaminophen protects brain endothelial cells against oxidative stress Debjani Tripathy and Paula Grammas* Garrison Institute on Aging, Texas Tech University Health Sciences Center, Lubbock, Texas Abstract Increasing evidence suggests that acetaminophen has unappreciated anti-oxidant and anti- inflammatory properties. Drugs that affect oxidant and inflammatory stress in the brain are of interest because both processes are thought to contribute to the pathogenesis of neurodegenerative disease. The objective of this study is to determine whether acetaminophen affects the response of brain endothelial cells to oxidative stress. Cultured brain endothelial cells are pretreated with acetaminophen and then exposed to the superoxide-generating compound menadione (25 μM). Cell survival, inflammatory protein expression, and antioxidant enzyme activity are measured. Menadione causes a significant (p0.001) increase in endothelial cell death as well as an increase in RNA and protein levels of tumor necrosis factor alpha, interleukin-1, macrophage inflammatory protein alpha, and RANTES. Menadione also evokes a significant (p0.001) increase in the activity of the antioxidant enzyme superoxide dismutase (SOD). Pretreatment of endothelial cell cultures with acetaminophen (25–100 μM) increases endothelial cell survival and inhibits menadione-induced expression of inflammatory proteins and SOD activity. In addition, we document, for the first time, that acetaminophen increases expression of the anti-apoptotic protein Bcl2. Suppressing Bcl2 with siRNA blocks the pro-survival effect of acetaminophen. These data show that acetaminophen has anti-oxidant and anti-inflammatory effects on the cerebrovasculature and suggest a heretofore unappreciated therapeutic potential for this drug in neurodegenerative diseases such as Alzheimer’s disease that are characterized by oxidant and inflammatory stress. Keywords cerebroprotective; anti-oxidant; endothelial cells; acetaminophen Introduction Acet