 |
 Previous Article | Next Article 
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
This article has been cited by other articles:
|
|
|
|
 
L. A. Kotilinek, M. A. Westerman, Q. Wang, K. Panizzon, G. P. Lim, A. Simonyi, S. Lesne, A. Falinska, L. H. Younkin, S. G. Younkin, et al.
Cyclooxygenase-2 inhibition improves amyloid-{beta}-mediated suppression of memory and synaptic plasticity
Brain,
March 1, 2008;
131(3):
651 - 664.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. P. Imbimbo, E. Del Giudice, D. Colavito, A. D'Arrigo, M. D. Carbonare, G. Villetti, F. Facchinetti, R. Volta, V. Pietrini, M. F. Baroc, et al.
1-(3',4'-Dichloro-2-fluoro[1,1'-biphenyl]-4-yl)-cyclopropanecarboxylic Acid (CHF5074), a Novel {gamma}-Secretase Modulator, Reduces Brain beta-Amyloid Pathology in a Transgenic Mouse Model of Alzheimer's Disease without Causing Peripheral Toxicity
J. Pharmacol. Exp. Ther.,
December 1, 2007;
323(3):
822 - 830.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Moreno, W. E. Wu, T. Lee, A. Brickman, R. Mayeux, T. R. Brown, and S. A. Small
Imaging the Abeta-Related Neurotoxicity of Alzheimer Disease
Arch Neurol,
October 1, 2007;
64(10):
1467 - 1477.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H.-g. Lee, X. Zhu, R. J. Castellani, A. Nunomura, G. Perry, and M. A. Smith
Amyloid-beta in Alzheimer Disease: The Null versus the Alternate Hypotheses
J. Pharmacol. Exp. Ther.,
June 1, 2007;
321(3):
823 - 829.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. M. Malm, H. Iivonen, G. Goldsteins, V. Keksa-Goldsteine, T. Ahtoniemi, K. Kanninen, A. Salminen, S. Auriola, T. Van Groen, H. Tanila, et al.
Pyrrolidine Dithiocarbamate Activates Akt and Improves Spatial Learning in APP/PS1 Mice without Affecting {beta}-Amyloid Burden
J. Neurosci.,
April 4, 2007;
27(14):
3712 - 3721.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Yamamoto, T. Kiyota, M. Horiba, J. L. Buescher, S. M. Walsh, H. E. Gendelman, and T. Ikezu
Interferon-{gamma} and Tumor Necrosis Factor-{alpha} Regulate Amyloid-{beta} Plaque Deposition and {beta}-Secretase Expression in Swedish Mutant APP Transgenic Mice
Am. J. Pathol.,
February 1, 2007;
170(2):
680 - 692.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Malm, M. Ort, L. Tahtivaara, N. Jukarainen, G. Goldsteins, J. Puolivali, A. Nurmi, R. Pussinen, T. Ahtoniemi, T.-K. Miettinen, et al.
beta-Amyloid infusion results in delayed and age-dependent learning deficits without role of inflammation or beta-amyloid deposits
PNAS,
June 6, 2006;
103(23):
8852 - 8857.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. R. Ranaivo, J. M. Craft, W. Hu, L. Guo, L. K. Wing, L. J. Van Eldik, and D. M. Watterson
Glia as a Therapeutic Target: Selective Suppression of Human Amyloid-beta-Induced Upregulation of Brain Proinflammatory Cytokine Production Attenuates Neurodegeneration
J. Neurosci.,
January 11, 2006;
26(2):
662 - 670.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. A Boothby and P. L Doering
Vitamin C and Vitamin E for Alzheimer's Disease
Ann. Pharmacother.,
December 1, 2005;
39(12):
2073 - 2079.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
X. Liang, Q. Wang, T. Hand, L. Wu, R. M. Breyer, T. J. Montine, and K. Andreasson
Deletion of the Prostaglandin E2 EP2 Receptor Reduces Oxidative Damage and Amyloid Burden in a Model of Alzheimer's Disease
J. Neurosci.,
November 2, 2005;
25(44):
10180 - 10187.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. P. Townsend and D. Pratico
Novel therapeutic opportunities for Alzheimer's disease: focus on nonsteroidal anti-inflammatory drugs
FASEB J,
October 1, 2005;
19(12):
1592 - 1601.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Koenigsknecht-Talboo and G. E. Landreth
Microglial Phagocytosis Induced by Fibrillar {beta}-Amyloid and IgGs Are Differentially Regulated by Proinflammatory Cytokines
J. Neurosci.,
September 7, 2005;
25(36):
8240 - 8249.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. T. Heneka, M. Sastre, L. Dumitrescu-Ozimek, A. Hanke, I. Dewachter, C. Kuiperi, K. O'Banion, T. Klockgether, F. Van Leuven, and G. E. Landreth
Acute treatment with the PPAR{gamma} agonist pioglitazone and ibuprofen reduces glial inflammation and A{beta}1-42 levels in APPV717I transgenic mice
Brain,
June 1, 2005;
128(6):
1442 - 1453.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Yamamoto, M. Horiba, J. L. Buescher, D. Huang, H. E. Gendelman, R. M. Ransohoff, and T. Ikezu
Overexpression of Monocyte Chemotactic Protein-1/CCL2 in {beta}-Amyloid Precursor Protein Transgenic Mice Show Accelerated Diffuse {beta}-Amyloid Deposition
Am. J. Pathol.,
May 1, 2005;
166(5):
1475 - 1485.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. P. Lim, F. Calon, T. Morihara, F. Yang, B. Teter, O. Ubeda, N. Salem Jr, S. A. Frautschy, and G. M. Cole
A Diet Enriched with the Omega-3 Fatty Acid Docosahexaenoic Acid Reduces Amyloid Burden in an Aged Alzheimer Mouse Model
J. Neurosci.,
March 23, 2005;
25(12):
3032 - 3040.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. G. Ramirez, C. Blazquez, T. G. del Pulgar, M. Guzman, and M. L. de Ceballos
Prevention of Alzheimer's Disease Pathology by Cannabinoids: Neuroprotection Mediated by Blockade of Microglial Activation
J. Neurosci.,
February 23, 2005;
25(8):
1904 - 1913.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. M. Barten, V. L. Guss, J. A. Corsa, A. Loo, S. B. Hansel, M. Zheng, B. Munoz, K. Srinivasan, B. Wang, B. J. Robertson, et al.
Dynamics of {beta}-Amyloid Reductions in Brain, Cerebrospinal Fluid, and Plasma of {beta}-Amyloid Precursor Protein Transgenic Mice Treated with a {gamma}-Secretase Inhibitor
J. Pharmacol. Exp. Ther.,
February 1, 2005;
312(2):
635 - 643.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. A. Lanz, G. J. Fici, and K. M. Merchant
Lack of Specific Amyloid-{beta}(1-42) Suppression by Nonsteroidal Anti-Inflammatory Drugs in Young, Plaque-Free Tg2576 Mice and in Guinea Pig Neuronal Cultures
J. Pharmacol. Exp. Ther.,
January 1, 2005;
312(1):
399 - 406.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
I. E. Camacho, L. Serneels, K. Spittaels, P. Merchiers, D. Dominguez, and B. De Strooper
Peroxisome Proliferator-Activated Receptor {gamma} Induces a Clearance Mechanism for the Amyloid-{beta} Peptide
J. Neurosci.,
December 1, 2004;
24(48):
10908 - 10917.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Sung, H. Yang, K. Uryu, E. B. Lee, L. Zhao, D. Shineman, J. Q. Trojanowski, V. M.-Y. Lee, and D. Pratico
Modulation of Nuclear Factor-{kappa}B Activity by Indomethacin Influences A{beta} Levels but Not A{beta} Precursor Protein Metabolism in a Model of Alzheimer's Disease
Am. J. Pathol.,
December 1, 2004;
165(6):
2197 - 2206.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Krezowski, D. Knudson, C. Ebeling, R. Pitstick, R. K. Giri, D. Schenk, D. Westaway, L. Younkin, S. G. Younkin, K. H. Ashe, et al.
Identification of loci determining susceptibility to the lethal effects of amyloid precursor protein transgene overexpression
Hum. Mol. Genet.,
September 15, 2004;
13(18):
1989 - 1997.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. I. Fonseca, J. Zhou, M. Botto, and A. J. Tenner
Absence of C1q Leads to Less Neuropathology in Transgenic Mouse Models of Alzheimer's Disease
J. Neurosci.,
July 21, 2004;
24(29):
6457 - 6465.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. L. McGeer and E. McGeer
Immunotherapy for Alzheimer's Disease
Sci. Aging Knowl. Environ.,
July 7, 2004;
2004(27):
pe29 - pe29.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
J. L. Wallace, M. N. Muscara, G. de Nucci, S. Zamuner, G. Cirino, P. del Soldato, and E. Ongini
Gastric Tolerability and Prolonged Prostaglandin Inhibition in the Brain with a Nitric Oxide-Releasing Flurbiprofen Derivative, NCX-2216 [3-[4-(2-Fluoro-{alpha}-methyl-[1,1'-biphenyl]-4-acetyloxy)-3-methoxyphenyl]-2-propenoic acid 4-nitrooxy butyl ester]
J. Pharmacol. Exp. Ther.,
May 1, 2004;
309(2):
626 - 633.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Mani, F. Cheng, B. Havsmark, M. Jonsson, M. Belting, and L.-A. Fransson
Prion, Amyloid {beta}-derived Cu(II) Ions, or Free Zn(II) Ions Support S-Nitroso-dependent Autocleavage of Glypican-1 Heparan Sulfate
J. Biol. Chem.,
October 3, 2003;
278(40):
38956 - 38965.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. A. Sagi, S. Weggen, J. Eriksen, T. E. Golde, and E. H. Koo
The Non-cyclooxygenase Targets of Non-steroidal Anti-inflammatory Drugs, Lipoxygenases, Peroxisome Proliferator-activated Receptor, Inhibitor of {kappa}B Kinase, and NF{kappa}B, Do Not Reduce Amyloid {beta}42 Production
J. Biol. Chem.,
August 22, 2003;
278(34):
31825 - 31830.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Q. Yan, J. Zhang, H. Liu, S. Babu-Khan, R. Vassar, A. L. Biere, M. Citron, and G. Landreth
Anti-Inflammatory Drug Therapy Alters {beta}-Amyloid Processing and Deposition in an Animal Model of Alzheimer's Disease
J. Neurosci.,
August 20, 2003;
23(20):
7504 - 7509.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Takahashi, I. Hayashi, Y. Tominari, K. Rikimaru, Y. Morohashi, T. Kan, H. Natsugari, T. Fukuyama, T. Tomita, and T. Iwatsubo
Sulindac Sulfide Is a Noncompetitive gamma -Secretase Inhibitor That Preferentially Reduces Abeta 42 Generation
J. Biol. Chem.,
May 9, 2003;
278(20):
18664 - 18670.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. M. Wilcock, G. DiCarlo, D. Henderson, J. Jackson, K. Clarke, K. E. Ugen, M. N. Gordon, and D. Morgan
Intracranially Administered Anti-Abeta Antibodies Reduce beta -Amyloid Deposition by Mechanisms Both Independent of and Associated with Microglial Activation
J. Neurosci.,
May 1, 2003;
23(9):
3745 - 3751.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Wyss-Coray, F. Yan, A. H.-T. Lin, J. D. Lambris, J. J. Alexander, R. J. Quigg, and E. Masliah
Prominent neurodegeneration and increased plaque formation in complement-inhibited Alzheimer's mice
PNAS,
August 6, 2002;
99(16):
10837 - 10842.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
