Ibuprofen attenuates oxidative damage through NOX2 inhibition in Alzheimer's disease.
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.
Wilkinson
Brandy L
BL
Alzheimer Research Laboratory, Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, OH 44106-4928, USA.
Cramer
Paige E
PE
Varvel
Nicholas H
NH
Reed-Geaghan
Erin
E
Jiang
Qingguang
Q
Szabo
Alison
A
Herrup
Karl
K
Lamb
Bruce T
BT
Landreth
Gary E
GE
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
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