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

Paul T. Jantzen, Karen E. Connor, Giovanni DiCarlo, Gary L. Wenk, John L. Wallace, Amyn M. Rojiani, Domenico Coppola, Dave Morgan, Marcia N. Gordon

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)2246-2254
Number of pages9
JournalJournal of Neuroscience
Volume22
Issue number6
StatePublished - Mar 15 2002

Fingerprint

Presenilin-1
Amyloid beta-Protein Precursor
Amyloid Plaques
Microglia
Transgenic Mice
Celecoxib
Nitric Oxide
Anti-Inflammatory Agents
Flurbiprofen
Congo Red
Pharmaceutical Preparations
Ibuprofen
Amyloid
Staining and Labeling
Diet
Cyclooxygenase 1
Genetically Modified Animals
Differentiation Antigens
Non-Steroidal Anti-Inflammatory Agents
Cyclooxygenase 2

Keywords

  • Alzheimer's disease
  • MHC-II
  • Microglia
  • NSAIDs
  • Transgenic mice
  • β-amyloid

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

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. / Jantzen, Paul T.; Connor, Karen E.; DiCarlo, Giovanni; Wenk, Gary L.; Wallace, John L.; Rojiani, Amyn M.; Coppola, Domenico; Morgan, Dave; Gordon, Marcia N.

In: Journal of Neuroscience, Vol. 22, No. 6, 15.03.2002, p. 2246-2254.

Research output: Contribution to journalArticle

Jantzen, Paul T. ; Connor, Karen E. ; DiCarlo, Giovanni ; Wenk, Gary L. ; Wallace, John L. ; Rojiani, Amyn M. ; Coppola, Domenico ; Morgan, Dave ; Gordon, Marcia N. / 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. In: Journal of Neuroscience. 2002 ; Vol. 22, No. 6. pp. 2246-2254.
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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

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AU - Connor, Karen E.

AU - DiCarlo, Giovanni

AU - Wenk, Gary L.

AU - Wallace, John L.

AU - Rojiani, Amyn M.

AU - Coppola, Domenico

AU - Morgan, Dave

AU - Gordon, Marcia N.

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