title: Ibuprofen attenuates oxidative damage through NOX2 inhibition in Alzheimer's disease.
abstract: Considerable evidence points to important roles for inflammation in Alzheimer's disease (AD) pathophysiology. Epidemiological studies have suggested that long-term nonsteroidal anti-inflammatory drug (NSAID) therapy reduces the risk for Alzheimer's disease; however, the mechanism remains unknown. We report that a 9-month treatment of aged R1.40 mice resulted in 90% decrease in plaque burden and a similar reduction in microglial activation. Ibuprofen treatment reduced levels of lipid peroxidation, tyrosine nitration, and protein oxidation, demonstrating a dramatic effect on oxidative damage in vivo. Fibrillar β-amyloid (Aβ) stimulation has previously been demonstrated to induce the assembly and activation of the microglial nicotinamide adenine dinucleotide phosphate (NADPH) oxidase leading to superoxide production through a tyrosine kinase-based signaling cascade. Ibuprofen treatment of microglia or monocytes with racemic or S-ibuprofen inhibited Aβ-stimulated Vav tyrosine phosphorylation, NADPH oxidase assembly, and superoxide production. Interestingly, Aβ-stimulated Vav phosphorylation was not inhibited by COX inhibitors. These findings suggest that ibuprofen acts independently of cyclooxygenase COX inhibition to disrupt signaling cascades leading to microglial NADPH oxidase (NOX2) activation, preventing oxidative damage and enhancing plaque clearance in the brain.
authors.affiliation: Alzheimer Research Laboratory, Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, OH 44106-4928, USA.
authors.forename: Brandy L
authors.initials: BL
authors.lastname: Wilkinson
authors.forename: Paige E
authors.initials: PE
authors.lastname: Cramer
authors.forename: Nicholas H
authors.initials: NH
authors.lastname: Varvel
authors.forename: Erin
authors.initials: E
authors.lastname: Reed-Geaghan
authors.forename: Qingguang
authors.initials: Q
authors.lastname: Jiang
authors.forename: Alison
authors.initials: A
authors.lastname: Szabo
authors.forename: Karl
authors.initials: K
authors.lastname: Herrup
authors.forename: Bruce T
authors.initials: BT
authors.lastname: Lamb
authors.forename: Gary E
authors.initials: GE
authors.lastname: Landreth
mesh_terms: D000544:Alzheimer Disease / Q000209:etiology* / Q000517:prevention & control*; D016229:Amyloid beta-Peptides; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology* / Q000627:therapeutic use; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D007052:Ibuprofen / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D009000:Monocytes / Q000378:metabolism; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors* / Q000502:physiology; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D058225:Plaque, Amyloid; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D051567:Proto-Oncogene Proteins c-vav; D015398:Signal Transduction / Q000502:physiology
chemical_list: D016229:Amyloid beta-Peptides; D000894:Anti-Inflammatory Agents, Non-Steroidal; D051567:Proto-Oncogene Proteins c-vav; D019255:NADPH Oxidases; D011505:Protein-Tyrosine Kinases; D007052:Ibuprofen