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PMID: 20696495 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Ibuprofen attenuates oxidative damage through NOX2 inhibition in Alzheimer's disease.

Neurobiology of aging ·Vol. 33 ·No. 1 ·2012-01-00 ·Pages 197.e21-32

Wilkinson BL, Cramer PE, Varvel NH, Reed-Geaghan E, Jiang Q, Szabo A, Herrup K, Lamb BT, Landreth GE

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.

MeSH Terms
Alzheimer Disease/etiology,prevention & control Amyloid beta-Peptides Animals Anti-Inflammatory Agents, Non-Steroidal/pharmacology,therapeutic use Cells, Cultured Enzyme Activation/drug effects Ibuprofen/pharmacology,therapeutic use Male Mice Mice, Transgenic Microglia/enzymology,metabolism,pathology Monocytes/metabolism NADPH Oxidases/antagonists & inhibitors,physiology Oxidative Stress/drug effects Phosphorylation/drug effects Plaque, Amyloid Protein-Tyrosine Kinases/physiology Proto-Oncogene Proteins c-vav Signal Transduction/physiology
Chemicals
Amyloid beta-Peptides Anti-Inflammatory Agents, Non-Steroidal Proto-Oncogene Proteins c-vav NADPH Oxidases Protein-Tyrosine Kinases Ibuprofen
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Wilkinson Brandy L
Alzheimer Research Laboratory, Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, OH 44106-4928, USA.
Cramer Paige E
Varvel Nicholas H
Reed-Geaghan Erin
Jiang Qingguang
Szabo Alison
Herrup Karl
Lamb Bruce T
Landreth Gary E
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Article Info
Journal
Neurobiology of aging
Abbr.
Neurobiol Aging
ISSN
1558-1497
DOI
10.1016/j.neurobiolaging.2010.06.014
Published
2012-01-00
Epub
2010-00-08
Pages
197.e21-32
Language
English
Region
United States
NLM ID
8100437
PMCID
PMC2980562
Subset
IM
Grants
NIA NIH HHS · R01 AG016740-10 · United States
NIA NIH HHS · AG024494 · United States
NIA NIH HHS · R01 AG024494-04 · United States
NIA NIH HHS · F32 AG24031 · United States
NIA NIH HHS · R01 AG024494-05 · United States
NIA NIH HHS · R01 AG016740-09 · United States
NINDS NIH HHS · F31-NS057867 · United States
NIA NIH HHS · R01 AG023012-08 · United States
NIA NIH HHS · AG023012 · United States
NIA NIH HHS · R01 AG016740 · United States
NINDS NIH HHS · F31 NS057867 · United States
NIA NIH HHS · R01 AG023012-07 · United States
NIA NIH HHS · R01 AG024494 · United States
NIA NIH HHS · R01 AG023012 · United States
NIA NIH HHS · F32 AG024031 · United States
NIA NIH HHS · AG16740 · United States
External Links
PubMed source DOI: 10.1016/j.neurobiolaging.2010.06.014 PMC Full Text View journal details
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