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Microglial activation and β-amyloid deposit reduction caused by a nitric oxide-releasing nonsteroidal anti-inflammatory drug in amyloid precursor protein plus presenilin-1 transgenic mice


Year of Publication:
Contact PI Name:
David Morgan
Contact PI Affiliation:
University of South Florida College of Medicine, Tampa, Florida, USA
Paul T. Jantzen, Karen E. Connor, Giovanni DiCarlo, Gary L. Wenk, John L. Wallace, Amyn M. Rojiani, Domenico Coppola, Marcia N. Gordon
Primary Reference (PubMED ID):
Funding Source:
National Institute on Aging (NIA)
Benjamin Research Trust
Study Goal and Principal Findings:

  The goal of this study was to test the working hypothesis that the benefit of NSAID use in diminishing the risk of AD is attributable to suppression of the microglial response. To this end the authors compared the effects of ibuprofen, a prototypical and nonselective NSAID with celecoxib, a COX2-selective inhibiting NSAID, and the NO-releasing derivative of the COX1 NSAID flurbiprofen - NCX-2216, on beta amyloid deposition and microglial activation in the APP/PS1 mouse model of beta amyloid deposition. Results found that NCX-2216 dramatically reduced both beta-amyloid load and Congo red staining in APP/PS1 mice when administered at 375 ppm in diet between 7 and 12 months of age. This reduction was associated with a dramatic increase in the number of microglia expressing major histocompatibility complex-II antigen(MHC-II), a marker for microglial activation.  In contrast, treatment with ibuprofen, administered at 375 ppm in diet,between 7-12 months of age, caused modest reductions in Abeta load but not Congo red staining, suggesting that the effects of this nonselective NSAID were restricted primarily to nonfibrillar deposits. Ibuprofen treatment was not associated with increase in the number microglia expressing the MHC-II marker of microglial activation. Celecoxib administered at 175ppm in diet at 7-12 months of age had no effect on either beta amyloid load, Congo red straining or, the number of activated microglia. In short-term studies of 12-month-old Tg mice, data showed  that the microglia-activating properties of NCX-2216 were present after 2 weeks of treatment. Microglia were not activated by NCX-2216 in non-Tg mice lacking Abeta deposits, nor were microglia activated in Tg animals by flurbiprofen.  In conclusion, these data identify an unexpected activation of microglia by a nitro-NSAID in a mouse model of amyloid deposition and imply that the NO-generating component of NCX-2216 confers biological activities that go beyond those of typical NSAIDs.  These results may impact the design of human trials to evaluate these drugs as therapeutics in AD patients.


Therapeutic Agent

Therapeutic Information:
Therapy Type:
Small Molecule
Therapeutic Agent:
Therapeutic Target:
Cyclooxygenase 1 (COX 1)
Therapy Type:
Small Molecule
Therapeutic Agent:
Therapeutic Target:
Cyclooxygenase 2 (COX 2)
Therapy Type:
Small Molecule
Therapeutic Agent:
Therapeutic Target:
Cyclooxygenase 1 (COX 1)
Therapeutic Target:
Cyclooxygenase 2 (COX 2)

Animal Model

Model Information:
Model Type:
Strain/Genetic Background:
Not Reported

Experimental Design

Is the following information reported in the study?:
Power/Sample Size Calculation
Randomized into Groups
Blinded for Treatment
Blinded for Outcome Measures
Pharmacokinetic Measures
Pharmacodynamic Measures
Toxicology Measures
ADME Measures
Route of Delivery
Duration of Treatment
Frequency of Administration
Age of Animal at the Beginning of Treatment
Age of Animal at the End of Treatment
Sex as a Biological Variable
Study Balanced for Sex as a Biological Variable
Number of Premature Deaths
Number of Excluded Animals
Statistical Plan
Genetic Background
Inclusion/Exclusion Criteria Included
Conflict of Interest
Experiment Notes

In the long-term administration study, we selected the dosage of ibuprofen (375 ppm in diet or ~62.5 mg / kg 1 / d 1 per animal; n = 7 transgenic and 8 nontransgenic mice) that Lim et al. (J Neurosci 20:5709–5714,2000) found to be effective at reducing A. We estimated an equivalent dosage of celecoxib (175 ppm or ~30 mg/ kg 1 / d 1 per animal; n = 7 transgenic and 7 nontransgenic mice) based on the relative human daily dosages of celecoxib and ibuprofen. We similarly estimated an equivalent dosage of NCX-2216 (375 ppm in diet or ~62.5 mg / kg 1 / d 1 per animal; n =7 transgenic mice) so that the ratio of the mass of flurbiprofen consumed relative to ibuprofen in the first diet would approximate the relative human dosages of these drugs.


Outcome Measured
Outcome Parameters
beta Amyloid Load
Fibrillar beta Amyloid Deposits
Activated Microglia
Tissue Histopathological Profile