Novel therapeutic opportunities for Alzheimer's disease: Focus on nonsteroidal anti-inflammatory drugs

FASEB Journal

Volumn 19, Issue 12, 2005, Pages 1592-1601

  Townsend, Kirk P ^a   Praticó, Domenico ^a  

^a John Morgan Building ^*

Author keywords

Amyloid beta; APP metabolism; Central nervous system; Coxibs; Cyclooxygenase; Inflammation; NSAIDs

Indexed keywords

5 (4 CHLOROPHENYL) 1 (4 METHOXYPHENYL) 3 TRIFLUOROMETHYL 1H PYRAZOLE; ACETYLSALICYLIC ACID; AMYLOID BETA PROTEIN; CELECOXIB; CYCLOOXYGENASE 2 INHIBITOR; DICLOFENAC; DIFLUNISAL; FENOPROFEN; FLURBIPROFEN; IBUPROFEN; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; INDOMETACIN; KETOPROFEN; MECLOFEN; MISOPROSTOL; NABUMETONE; NAPROXEN; NIMESULIDE; NONSTEROID ANTIINFLAMMATORY AGENT; PARECOXIB; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR; PIOGLITAZONE; PIROXICAM; PROSTAGLANDIN SYNTHASE; ROFECOXIB; SC 125; SULINDAC; SULINDAC SULFIDE; UNCLASSIFIED DRUG; VALDECOXIB;

ALZHEIMER DISEASE; AMYLOIDOSIS; ANTIINFLAMMATORY ACTIVITY; CARDIOVASCULAR DISEASE; CELL CULTURE; CHRONIC INFLAMMATION; CLINICAL TRIAL; DISEASE MODEL; DRUG DISCRIMINATION; DRUG EFFECT; DRUG EFFICACY; DRUG POTENCY; DRUG STRUCTURE; DRUG USE; GASTROINTESTINAL SYMPTOM; HUMAN; NEUROFIBRILLARY TANGLE; NONHUMAN; PRIORITY JOURNAL; REVIEW; RISK REDUCTION; TRANSGENIC ANIMAL;

AGED; AGED, 80 AND OVER; ALZHEIMER DISEASE; ANIMALS; ANIMALS, GENETICALLY MODIFIED; ANTI-INFLAMMATORY AGENTS, NON-STEROIDAL; CELL CULTURE TECHNIQUES; CYCLOOXYGENASE INHIBITORS; DISEASE MODELS, ANIMAL; ENZYME-LINKED IMMUNOSORBENT ASSAY; FLURBIPROFEN; HUMANS; IBUPROFEN; INDOMETHACIN; INFLAMMATION; MODELS, BIOLOGICAL; MODELS, CHEMICAL; MODELS, GENETIC; NF-KAPPA B; PEPTIDES; PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORS; PPAR GAMMA; PROSTAGLANDIN-ENDOPEROXIDE SYNTHASES;

EID: 26444475416     PISSN: 08926638     EISSN: None     Source Type: Journal    
DOI: 10.1096/fj.04-3620rev     Document Type: Review

References (88)

1. Clark, C. M. (2000) Clinical manifestations and diagnostic evaluation of patients with Alzheimer's disease. In Neurodegenerative Dementias: Clinical Features and Pathological Mechanisms (Clark, C. M., and Trojanowski, J. Q., eds) pp. 95-114, McGraw-Hill, New York
2. National Institute on Aging and Reagan Institute Working Group on Diagnostic Criteria for the Neuropathological Assessment of Alzheimer's disease. (1997) Neurobiol. Aging 18 (Suppl.14), S11-S12
3. Pratico, D., and Trojanowski, J. Q. (2000) Inflammatory hypotheses: novel mechanisms of Alzheimer's neurodegeneration and new therapeutic targets? Neurobiol. Aging 21, 441-445
4. Neuroinflammation Working Group (2000) Inflammation and Alzheimer's disease. Neurobiol. Aging 21, 383-421
5. McGeer, P. L., and McGeer, E. G. (2001) Polymorphisms in inflammatory genes and the risk of Alzheimer disease. Arch. Neurol. 58, 1790-1792
6. in t'Veld, B. A., Ruitenberg, A., Hofman, A., Launer, L. J., van Duijn, C. M., Stijnen, T., Breteler, M. M., and Stricker, B. H. (2001) Nonsteroidal antiinflammatory drugs and the risk of Alzheimer's disease. N. Engl. J. Med. 345, 1515-1521
7. Etminan, M., Gill, S., and Samii, A. (2003) Effect of non-steroidal anti-inflammatory drugs on risk of Alzheimer's disease: systematic review and meta-analysis of observational studies. Br. Med. J. 327, 128
8. Szekely, C. A., Thorne, J. E., Zandi, P. P., Ek, M., Messias, E., Breitner, J. C., and Goodman, S. N. (2004) Nonsteroidal anti-inflammatory drugs for the prevention of Alzheimer's disease: a systematic review. Neuroepidemiology 23, 159-169
9. Aisen, P. S., Schafer, K. A., Grundman, M., Pfeiffer, E., Sano, M., Davis, K. L., Farlow, M. R., Jin, S., Thomas, R. G., and Thal, L. J. (2003) Effects of rofecoxib or naproxen vs. placebo on Alzheimer disease progression: a randomized controlled trial. J. Am. Med. Assoc. 289, 2819-2826
10. Reines, S. A., Block, G. A., Morris, J. C., Liu, G., Nessly, M. L., Lines, C. R., Norman, B. A., and Baranak, C. C. (2004) Rofecoxib: no effect on Alzheimer's disease in a 1-year, randomized, blinded, controlled study. Neurology 62, 66-71
11. Vane, J. R. (1971) Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nature (London) 231, 232-235
12. Dubois, R. N., Abramson, S. B., Crofford, L., Gupta, R. A., Simon, L. S., Van De Putte, L. B., and Lipsky, P. E. (1998) Cyclooxygenase in biology and disease. FASEB J. 12, 1063-1073
13. Smith, W. L., DeWitt, D. L., and Garavito, R. M. (2000) Cyclooxygenases: structural, cellular, and molecular biology. Annu. Rev. Biochem. 69, 145-182
14. Chandrasekharan, N. V., Dai, H., Roos, K. L., Evanson, N. K., Tomsik, J., Elton, T. S., and Simmons, D. L. (2002) COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: cloning, structure, and expression. Proc. Natl. Acad. Sci. USA 99, 13926-13931
15. Dinchuk, J. E., Liu, R. Q., and Trzaskos, J. M. (2003) COX-3: in the wrong frame in mind. Immunol. Lett. 86, 121
16. Kitamura, Y., Shimohama, S., Koike, H., Kakimura, J., Matsuoka, Y., Nomura, Y., Gebicke-Haerter, P. J., and Taniguchi, T. (1999) Increased expression of cyclooxygenases and peroxisome proliferator-activated receptor-gamma in Alzheimer's disease brains. Biochem. Biophys. Res. Commun. 254, 582-586
17. Pasinetti, G. M. (1998) Cyclooxygenase and inflammation in Alzheimer's disease: experimental approaches and clinical interventions. J. Neurosci. Res. 54, 1-6
18. Oka, A., and Takashima, S. (1997) Induction of cyclo-oxygenase 2 in brains of patients with Down's syndrome and dementia of Alzheimer type: specific localization in affected neurones and axons. NeuroReport 8, 1161-1164
19. Hoozemans, J. J., Rozemuller, A. J., Janssen, I., De Groot, C. J., Veerhuis, R., and Eikelenboom, P. (2001) Cyclooxygenase expression in microglia and neurons in Alzheimer's disease and control brain. Acta Neuropathol. (Berlin) 101, 2-8
20. Ho, L., Pieroni, C., Winger, D., Purohit, D. P., Aisen, P. S., and Pasinetti, G. M. (1999) Regional distribution of cyclooxygenase-2 in the hippocampal formation in Alzheimer's disease. J. Neurosci. Res. 57, 295-303
21. Ho, L., Purohit, D., Haroutunian, V., Luterman, J. D., Willis, F., Naslund, J., Buxbaum, J. D., Mohs, R. C., Aisen, P. S., and Pasinetti, G. M. (2001) Neuronal cyclooxygenase 2 expression in the hippocampal formation as a function of the clinical progression of Alzheimer disease. Arch. Neurol. 58, 487-492
22. Yermakova, A. V., Rollins, J., Callahan, L. M., Rogers, J., and O'Banion, M. K. (1999) Cyclooxygenase-1 in human Alzheimer and control brain: quantitative analysis of expression by microglia and CA3 hippocampal neurons. J. Neuropathol. Exp. Neurol. 58, 1135-1146
23. Lukiw, W. J., and Bazan, N. G. (1997) Cyclooxygenase 2 RNA message abundance, stability, and hypervariability in sporadic Alzheimer neocortex. J. Neurosci. Res. 50, 937-945
24. Yermakova, A. V., and O'Banion, M. K. (2001) Downregulation of neuronal cyclooxygenase-2 expression in end stage Alzheimer's disease. Neurobiol. Aging 22, 823-836
25. Matsuoka, Y., Picciano, M., Malester, B., LaFrancois, J., Zehr, C., Daeschner, J. M., Olschowka, J. A., Fonseca, M. I., O'Banion, M. K., Tenner, A. J., et al. (2001) Inflammatory responses to amyloidosis in a transgenic mouse model of Alzheimer's disease. Am. J. Pathol. 158, 1345-1354
26. Quadros, A., Patel, N., Crescentini, R., Crawford, F., Paris, D., and Mullan, M. (2003) Increased TNFalpha production and Cox-2 activity in organotypic brain slice cultures from APPsw transgenic mice. Neurosci. Lett. 353, 66-68
27. Sung, S., Yang, H., Uryu, K., Lee, E. B., Zhao, L., Shineman, D., Trojanowski, J. Q., Lee, V. M., and Pratico, D. (2004) 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. 165, 2197-2206
28. Xiang, Z., Ho, L., Yemul, S., Zhao, Z., Qing, W., Pompl, P., Kelley, K., Dang, A., Teplow, D., and Pasinetti, G. M. (2002) Cyclooxygenase-2 promotes amyloid plaque deposition in a mouse model of Alzheimer's disease neuropathology. Gene Exp. 10, 271-278
29. Schwab, J. M., and Schluesener, H. J. (2003) Cyclooxygenases and central nervous system inflammation: conceptual neglect of cyclooxygenase 1. Arch. Neurol. 60, 630-632
30. Graham, S. H., and Hickey, R. W. (2003) Cyclooxygenases in central nervous system diseases: a special role for cyclooxygenase 2 in neuronal cell death. Arch. Neurol. 60, 628-630
31. Ferrari, R. A., Ward, S.J., Zobre, C. M., Van Liew, D. K., Perrone, M. H., Connell, M. J., and Haubrich, D. R. (1990) Estimation of the in vivo effect of cyclooxygenase inhibitors on prostaglandin E2 levels in mouse brain. Eur. J. Pharmacol. 179, 25-34
32. Netland, E. E., Newton, J. L., Majocha, R. E., and Tate, B. A. (1998) Indomethacin reverses the microglial response to amyloid beta-protein. Neurobiol. Aging 19, 201-204
33. Prosperi, C., Scali, C., Barba, M., Bellucci, A., Giovannini, M. G., Pepeu, G., and Casamenti, F. (2004) Comparison between flurbiprofen and its nitric oxide-releasing derivatives HCT-1026 and NCX-2216 on Abeta(1-42)-induced brain inflammation and neuronal damage in the rat. Int. J. Immunopathol. Pharmacol. 17, 317-330
34. May, M. J., and Ghosh, S. (1998) Signal transduction through NF-kappa B. Immunol. Today 19, 80-88
35. Baldwin, A. S., Jr. (1996) The NF-kappa B and I kappa B proteins: new discoveries and insights. Annu. Rev. Immunol. 14, 649-683
36. Yoshiyama, Y., Arai, K., and Hattori, T. (2001) Enhanced expression of I-kappaB with neurofibrillary pathology in Alzheimer's disease. NeuroReport 12, 2641-2645
37. Mattson, M. P., and Camandola, S. (2001) NF-kappaB in neuronal plasticity and neurodegenerative disorders. J. Clin. Invest. 107, 247-254
38. Tomita, S., Fujita, T., Kirino, Y., and Suzuki, T. (2000) PDZ domain-dependent suppression of NF-kappaB/p65-induced Abeta42 production by a neuron-specific X11-like protein. J. Biol. Chem. 275, 13056-13060
39. Ferrer, I., Marti, E., Lopez, E., and Tortosa, A. (1998) NF-κB immunoreactivity is observed in association with beta A4 diffuse plaques in patients with Alzheimer's disease. Neuropathol. Appl. Neurobiol. 24, 271-277
40. Lemberger, T., Desvergne, B., and Wahli, W. (1996) Peroxisome proliferator-activated receptors: a nuclear receptor signaling pathway in lipid physiology. Annu. Rev. Cell Dev. Biol. 12, 335-363
41. Vamecq, J., and Latruffe, N. (1999) Medical significance of peroxisome proliferator-activated receptors. Lancet 354, 141-148
42. Ricote, M., Li, A. C., Willson, T. M., Kelly, C. J., and Glass, C. K. (1998) The peroxisome proliferator-activated receptor-gamma is a negative regulator of macrophage activation. Nature (London) 391, 79-82
43. Jiang, C., Ting, A. T., and Seed, B. (1998) PPAR-gamma agonists inhibit production of monocyte inflammatory cytokines. Nature (London) 391, 82-86
44. Bishop-Bailey, D., and Warner, T. D. (2003) PPARgamma ligands induce prostaglandin production in vascular smooth muscle cells: indomethacin acts as a peroxisome proliferator-activated receptor-gamma antagonist. FASEB J. 17, 1925-1927
45. Combs, C. K., Johnson, D. E., Karlo, J. C., Cannady, S. B., and Landreth, G. E. (2000) Inflammatory mechanisms in Alzheimer's disease: inhibition of beta-amyloid-stimulated proinflammatory responses and neurotoxicity by PPARgamma agonists. J. Neurosci. 20, 558-567
46. Sastre, M., Bewachter, I., Landreth, G. E., Willson, T. M., Klockgether, T., van Leuven, F., and Heneka, M. T. (2003) Nonsteroidal anti-inflammatory drugs and peroxisome proliferator-activated receptor-gamma agonists modulate immunostimulated processing of amyloid precursor protein through regulation of beta-secretase. J. Neurosci. 23, 9796-9804
47. Brune, S., Kolsch, H., Ptok, U., Majores, M., Schulz, A., Schlosser, R., Rao, M. L., Maier, W., and Heun, R. (2003) Polymorphism in the peroxisome proliferator-activated receptor alpha gene influences the risk for Alzheimer's disease. J. Neural Transm. 110, 1041-1050
48. Sauder, S., Kolsch, H., Lutjohann, D., Schulz, A., von Bergmann, K., Maier, W., and Heun, R. (2005) Influence of peroxisome proliferator-activated receptor gamma gene polymorphism on 24S-hydroxycholesterol levels in Alzheimer's patients. J. Neural Transm. 2005 Jan 24 [Epub ahead of print]
49. Heneka, M. T., Sastre, M., Dumitrescu-Ozimek, L., Hanke, A., Bewachter, I., Kuiperi, C., O'Banion, K., Klockgether, T., Van Leuven, F., and Landreth, G. E. (2005) Acute treatment with the PPARgamma agonist pioglitazone and ibuprofen reduces glial inflammation and Abeta1-42 levels in APPV717I transgenic mice. Brain 128, 1442-1453
50. Van, Q., Zhang, J., Liu, H., Babu-Khan, S., Vassar, R., Biere, A. L., Citron, M., and Landreth, G. (2003) Anti-inflammatory drug therapy alters beta-amyloid processing and deposition in an animal model of Alzheimer's disease. J. Neurosci. 23, 7504-7509
51. Maeshiba, Y., Kiyota, Y., Yamashita, K., Yoshimura, Y., Motohashi, M., and Tanayama, S. (1997) Disposition of the new antidiabetic agent pioglitazone in rats, dogs, and monkeys. Arzneimittelforschung 47, 29-35
52. Selkoe, D. J. (1999) Translating cell biology into therapeutic advances in Alzheimer's disease. Nature (London) 399, A23-A31
53. Jarrett, J. T., Berger, E. P., and Lansbury, P. T., Jr. (1993) The carboxy terminus of the beta amyloid protein is critical for the seeding of amyloid formation: implications for the pathogenesis of Alzheimer's disease. Biochemistry 32, 4693-4697
54. Kowalska, A. (2004) Genetic basis of neurodegeneration in familial Alzheimer's disease. Pol. J. Pharmacol. 56, 171-178
55. Yankner, B. A., Dawes, L. R., Fisher, S., Villa-Komaroff, L., Oster-Granite, M. L., and Neve, R. L. (1989) Neurotoxicity of a fragment of the amyloid precursor associated with Alzheimer's disease. Science 245, 417-420
56. Cleary, J. P., Walsh, D. M., Hofmeister, J. J., Shankar, G. M., Kuskowski, M. A., Selkoe, D. J., and Ashe, K. H. (2005) Natural oligomers of the amyloid-beta protein specifically disrupt cognitive function. Nat. Neurosci. 8, 79-84
57. Thomas, T., Nadackal, T. G., and Thomas, K. (2001) Aspirin and non-steroidal anti-inflammatory drugs inhibit amyloid-beta aggregation. NeuroReport 12, 3263-3267
58. Boutaud, O., Ou, J. J., Chaurand, P., Caprioli, R. M., Montine, T. J., and Gates, J. A. (2002) Prostaglandin H2 (PGH2) accelerates formation of amyloid beta1-42 oligomers. J. Neurochem. 82, 1003-1006
59. Harris, J. R. (2002) In vitro fibrillogenesis of the amyloid beta 1-42 peptide: cholesterol potentiation and aspirin inhibition. Micron 33, 609-626
60. Gandy, S. (2005) The role of cerebral amyloid β accumulation in common forms of Alzheimer's disease. J. Clin. Invest. 115, 1121-1129
61. Kojro, E., and Fahrenholz, F. (2005) The non-amyloidogenic pathway: structure and function of alpha-secretases. Subcell. Biochem. 38, 105-127
62. Skovronsky, D. M., Lee, V. M., and Pratico, D. (2001) Amyloid precursor protein and amyloid beta peptide in human platelets. Role of cyclooxygenase and protein kinase C. J. Biol. Chem. 276, 17036-17043
63. Avramovich, Y., Amit, T., and Youdim, M. B. (2002) Non-steroidal anti-inflammatory drugs stimulate secretion of non-amyloidogenic precursor protein. J. Biol. Chem. 277, 31466-31473
64. Lee, R. K., and Wurtman, R. J. (2000) Regulation of APP synthesis and secretion by neuroimmunophilin ligands and cyclooxygenase inhibitors. Ann. N. Y. Acad. Sci. 920, 261-268
65. Weggen, S., Eriksen, J. L., Das, P., Sagi, S. A., Wang, R., Pietrzik, C. U., Findlay, K. A., Smith, T. E., Murphy, M. P., Bulter, T., et al. (2001) A subset of NSAIDs lower amyloidogenic Abeta42 independently of cyclooxygenase activity. Nature (London) 414, 212-216
66. Eriksen, J. L., Sagi, S. A., Smith, T. E., Weggen, S., Das, P., McLendon, D. C., Ozols, V. V. Jessing, K. W., Zavitz, K. H., Koo, E. H., et al. (2003) NSAIDs and enantiomers of flurbiprofen target gamma-secretase and lower Abeta 42 in vivo. J. Clin. Invest. 112, 440-449
67. Sagi, S. A., Weggen, S., Eriksen, J., Golde, T. E., and Koo, E. H. (2003) 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. 278, 31825-31830
68. Takahashi, Y., Hayashi, I., Tominari, Y., Rikimaru, K., Morohashi, Y., Kan, T., Natsugari, H., Fukuyama, T., Tomita, T., and Iwatsubo, T. (2003) Sulindac sulfide is a noncompetitive gamma-secretase inhibitor that preferentially reduces Abeta 42 generation. J. Biol. Chem. 278, 18664-18670
69. Gasparini, L., Rusconi, L., Xu, H., del Soldato, P., and Ongini, E. (2004) Modulation of beta-amyloid metabolism by non-steroidal anti-inflammatory drugs in neuronal cell cultures. J. Neurochem. 88, 337-348
70. Schwab, C., Hosokawa, M., and McGeer, P. L. (2004) Transgenic mice overexpressing amyloid beta protein are an incomplete model of Alzheimer disease. Exp. Neurol. 188, 52-64
71. Lim, G. P., Yang, F., Chu, T., Chen, P., Beech, W., Teter, B., Tran, T., Ubeda, O., Ashe, K. H., Frautschy, S. A., et al. (2000) Ibuprofen suppresses plaque pathology and inflammation in a mouse model for Alzheimer's disease. J. Neurosci. 20, 5709-5714
72. Jantzen, P. T., Connor, K. E., DiCarlo, G., Wenk, G. L., Wallace, J. L., Rojiani, A. M., Coppola, D., Morgan, D., and Gordon, M. N. (2002) Microglial activation and beta -amyloid deposit reduction caused by a nitric oxide-releasing nonsteroidal anti-inflammatory drug in amyloid precursor protein plus presenilin-1 transgenic mice. J. Neurosci. 22, 2246-2254
73. Lanz, T. A., Fici, G. J., and Merchant, K. M. (2005) 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. 312, 399-406
74. Zhou, Y., Su, Y., Li, B., Liu, F., Ryder, J. W., Wu, X., Gonzalez-DeWhitt, P. A., Gelfanova, V., Hale, J. E., May, P. C., et al. (2003) Nonsteroidal anti-inflammatory drugs can lower amyloidogenic Abeta42 by inhibiting Rho. Science 302, 1215-1217
75. Reid, G., Wielinga, P., Zelcer, N., van der Heijden, I., Kuil, A., De Haas, M., Wijnholds, J., and Borst, P. (2003) The human multidrug resistance protein MRP4 functions as a prostaglandin efflux transporter and is inhibited by nonsteroidal antinflammatory drugs. Proc. Natl. Acad. Sci. USA 100, 9244-9249
76. Morihara, T., Chu, T., Ubeda, O., Beech, W., and Cole, G. M. (2002) Selective inhibition of Abeta42 production by NSAID R-enantiomers. J. Neurochem. 83, 1009-1012
77. Weggen, S., Eriksen, J. L., Sagi, S. A., Pietrzik, C. U., Ozols, V., Fauq, A., Golde, T. E., and Koo, E. H. (2003) Evidence that nonsteroidal anti-inflammatory drugs decrease amyloid beta 42 production by direct modulation of gamma-secretase activity. J. Biol. Chem. 278, 31831-31837
78. Searfoss, G. H., Jordan, W. H., Calligaro, D. O., Galbreath, E. J., Schirtzinger, L. M., Berridge, B. R., Gao, H., Higgins, M. A., May, P. C., and Ryan, T. P. (2003) Adipsin, a biomarker of gastrointestinal toxicity mediated by a functional gamma-secretase inhibitor. J. Biol. Chem. 278, 46107-46116
79. Rogers, J., Kirby, L. C., Hempelman, S. R., Berry, D. L., McGeer, P. L., Kaszniak, A. W., Zalinski, J., Cofield, M., Mansukhani, L., Willson, P., et al. (1993) Clinical trial of indomethacin in Alzheimer's disease. Neurology 43, 1609-1611
80. Thal, L. J., Ferris, S. H., Kirby, L., Block, G. A., Lines, C. R., Yuen, E., Assaid, C., Nessly, M. L., Norman, B. A., Baranak, C. C., et al. (2005) A Randomized, Double-Blind, Study of Rofecoxib in Patients with Mild Cognitive Impairment. Neuropsychopharmacology 2005 March 2 [Epub ahead of print]
81. Couzin, J. (2004) Clinical trials. Halt of Celebrex study threatens drug's future, other trials. Science 306, 2170
82. Ritschel, W. A., and Kerns, K. G. L. (1999) In Handbook of Basic Pharmacokinetics, pp. 563-593, American Pharmaceutical Association, Washington, D.C.
83. Quinn, J., Montine, T. J., Morrow, J., Woodward, W. R., Kulhanek, D., and Eckenstein, F. (2003) Inflammation and cerebral amyloidosis are disconnected in an animal model of Alzheimer's disease. J. Neuroimmunol. 137, 32-41
84. Rich, J. B., Rasmusson, D. X., Folstein, M. F., Carson, K. A., Kawas, C., and Brandt, J. (1995) Nonsteroidal anti-inflammatory drugs in Alzheimer's disease. Neurology 45, 51-55
85. Anthony, J. C., Breitner, J. C., and Zandi, P. P. (2000) Reduced prevalence of AD in users of NSAIDs and H2 receptor antagonists: The Cache County study. Neurology 54, 2066-2071
86. Stewart, W. F., Kawas, C., Corrada, M., and Metter, E. J. (1997) Risk of Alzheimer's disease and duration of NSAID use. Neurology 48, 626-632
87. Scharf, S., Mander, A., Ugoni, A., Vajda, F., and Christophidis, N. (1999) A double-blind, placebo-controlled trial of diclofenac/misoprostol in Alzheimer's disease. Neurology 53, 197-201
88. Sainati, S. M., Ingram, D. M., Talwalker, S., and Geis, G. S. (2000) Sixth Int'l Stockholm/Springfield Symposium on Advances in Alzheimer's Therapy Abstract book. In Vol. 180, Skokie, IL