Acetaminophen protects brain endothelial cells against oxidative stress

Abstract

Increasing evidence suggests that acetaminophen has unappreciated anti-oxidant and antiinflammatory 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 (p<0.001) 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 (p<0.001) 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.

Acetaminophen and NAPQI are toxic to auditory cells via oxidative and endoplasmic reticulum stress-dependent pathways

“…The observed anti-oxidant effect of APAP at short periods of exposure was at odds with the abundant literature about its effects on hepatocytes, but consistent with reports that APAP acts as an anti-inflammatory and anti-oxidant compound in neurons both in vitro and in vivo. For example, APAP protects hippocampal neurons and PC12 cultures from oxidative stress by lowering cytoplasmic levels of peroxides and reducing of lipid peroxidation (Bisaglia et al, 2002), and cerebral cortical cultured neurons and brain endothelial cells exposed to the superoxide-generating compound menadione (Tripathy et al, 2009a; Tripathy et al, 2009b). In rats, APAP induces apoptosis of cortical neurons (Posadas et al, 2010), but significantly attenuates superoxide production by the neurotoxin quinolinic acid, a metabolite implicated in the pathogenesis of neurodegenerative diseases (Maharaj et al, 2006).…”

Acetaminophen from liver to brain: New insights into drug pharmacological action and toxicity

“…This peroxide-mediated inhibition of COX activity can also explain why APAP is not active in peripheral sites of inflammation, where the concentration of peroxide is greater than that encountered in brain. Similarly, low doses of APAP has been suggested to reduce the oxidative stress (20; 21) that has been implicated in prostaglandin release and fever (22; 23). …”

“…APAP also decreases oxidative damage produced in neuronal cultures by other neurotoxic compound, such as 6-hydroxydopamine (80). Finally, a recent study using cultured brain endothelial cells showed reductions in inflammatory responses to oxidative stress in the presence of low doses of APAP (21). …”

Acetaminophen attenuates lipopolysaccharide-induced cognitive impairment through antioxidant activity

“…can inhibit quinolinic acid (QA)-induced lipid peroxidation, superoxide anion generation, and cell damage in the rat hippocampus [24]. Tripathy et al [25, 26] showed that low-dose APAP reduces inflammatory protein release from cultured brain neuronal and endothelial cells exposed to oxidant stress and increases expression of the anti-apoptotic protein Bcl-2 in brain neurons. Naziroglu et al [27] also reported that APAP (5–100 mg/kg) can reduce brain and microsomal lipid peroxidation, while it also increases brain vitamin E levels and microsomal glutathione peroxidase (GSH-Px) activity.…”