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The Journal of Neuroscience, March 15, 2002, 22(6):2246-2254
Microglial Activation and  -Amyloid Deposit Reduction
Caused by a Nitric Oxide-Releasing Nonsteroidal
Anti-Inflammatory Drug in Amyloid Precursor Protein Plus Presenilin-1
Transgenic Mice
Paul T.
Jantzen1,
Karen E.
Connor1,
Giovanni
DiCarlo1,
Gary L.
Wenk3,
John L.
Wallace4,
Amyn M.
Rojiani2,
Domenico
Coppola2,
Dave
Morgan1, and
Marcia N.
Gordon1
Departments of 1 Pharmacology and
2 Interdisciplinary Oncology, Alzheimer's Research
Laboratory, University of South Florida, Tampa, Florida 33612, 3 Division of Neural Systems, Memory, and Aging, University
of Arizona, Tucson, Arizona 85724, and 4 Department of
Pharmacology and Therapeutics, University of Calgary, Calgary, Alberta,
T2N 4N1, Canada
3-4-(2-Fluoro- -methyl-[1,1'-biphenyl]-4-acetyloxy)-3-methoxyphenyl]-2-propenoic
acid 4-nitrooxy butyl ester (NCX-2216), a nitric oxide (NO)-releasing
derivative of the cyclooxygenase-1-preferring nonsteroidal
anti-inflammatory drug (NSAID) flurbiprofen, dramatically reduced both
 -amyloid (A) loads and Congo red staining in doubly transgenic
(Tg) amyloid precursor protein plus presenilin-1 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, a marker for microglial activation. In contrast, ibuprofen at
375 ppm in diet caused modest reductions in A load but not Congo red
staining, suggesting that the effects of this nonselective NSAID were
restricted primarily to nonfibrillar deposits. We detected no effects
of the cyclooxygenase-2-selective NSAID celecoxib at 175 ppm on amyloid
deposition. In short-term studies of 12-month-old Tg mice, we found
that the microglia-activating properties of NCX-2216 (7.5 mg · kg 1 · d1,
s.c.) were present after 2 weeks of treatment. Microglia were not
activated by NCX-2216 in non-Tg mice lacking A deposits, nor were
microglia activated in Tg animals by flurbiprofen (5 mg · kg1 · d1) alone.
These data are consistent with the argument that activated microglia
can clear A deposits. We conclude that the NO-generating component
of NCX-2216 confers biological actions that go beyond those of typical
NSAIDs. In conclusion, NCX-2216 is more efficacious than ibuprofen or
celecoxib in clearing A deposits from the brains of Tg mice,
implying potential benefit in the treatment of Alzheimer's dementia.
Key words:
Alzheimer's disease; microglia; MHC-II; -amyloid; NSAIDs; transgenic mice
Copyright © 2002 Society for Neuroscience 0270-6474/02/2262246-09$05.00/0
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