RT Journal Article
SR Electronic
T1 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
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 2246
OP 2254
DO 10.1523/JNEUROSCI.22-06-02246.2002
VO 22
IS 6
A1 Paul T. Jantzen
A1 Karen E. Connor
A1 Giovanni DiCarlo
A1 Gary L. Wenk
A1 John L. Wallace
A1 Amyn M. Rojiani
A1 Domenico Coppola
A1 Dave Morgan
A1 Marcia N. Gordon
YR 2002
UL http://www.jneurosci.org/content/22/6/2246.abstract
AB 3-4-(2-Fluoro-α-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 β-amyloid (Aβ) 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 Aβ 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 · d−1, s.c.) were present after 2 weeks of treatment. Microglia were not activated by NCX-2216 in non-Tg mice lacking Aβ deposits, nor were microglia activated in Tg animals by flurbiprofen (5 mg · kg−1 · d−1) alone. These data are consistent with the argument that activated microglia can clear Aβ 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 Aβ deposits from the brains of Tg mice, implying potential benefit in the treatment of Alzheimer's dementia.