Outline

• Methods and Results.
  
• Discussion.
  
• Acknowledgment
  
• REFERENCES
  

Methods and Results.^
Only 13 records in the MEDLINE, EMBASE, BIOSIS, and SCISEARCH databases directly mention both indomethacin and AD (as of June 1995). Our strategy was to look for indirect literature connections [4] showing that indomethacin produces physiologic effects, X, that have been separately studied in relationship to AD. To find such indirect connections, we searched MEDLINE (1966 to July 1995) to create a local computer file of 5,008 titles containing the word ``indomethacin'' and a second local file of 7,022 titles containing the word ``Alzheimer.'' The computer was then used to prepare a list of all words or phrases that occurred in both sets of titles. ``Noninteresting'' words were automatically excluded with the help of a precompiled 5,000-word stoplist plus additional manual editing, leaving 103 terms for further consideration. Thirty of these terms were substances or physiologic processes (``X terms'') that are affected by indomethacin. For each such X term, we assessed whether articles on indomethacin and X, together with articles on X and AD, suggested plausible, yet previously unnoticed, biologic links between indomethacin and AD.

For most X terms, such a relationship was absent, weak, or equivocal, although a few X terms indicated effects that might possibly ameliorate AD: (1) Indomethacin decreases plasma membrane fluidity in various cell types, whereas membrane fluidity is elevated in some patients with AD. (2) Indomethacin stimulates killer T-cell activity, which is decreased in AD according to one report. (3) Indomethacin inhibits M_2-muscarinic receptor action, whereas M_2-muscarinic receptor antagonists have been proposed as potential therapeutic reagents in AD. (4) Indomethacin inhibits lipid peroxidation in a number of systems, whereas lipid peroxidation is elevated in AD brains. (5) Indomethacin enhances thyrotropin-releasing hormone-mediated thyroid-stimulating hormone release from the pituitary, whereas some patients with AD are reported to have deficits in this release.

More significantly, we found a possible adverse effect: Indomethacin inhibits effects of, or release of, acetylcholine in several systems, including smooth muscle and peripheral neurons. Several papers have indicated that indomethacin inhibits a variety of CNS cholinergic responses as well. [5-7]

Discussion.^
These studies did not examine the basal forebrain or cerebral cortex specifically, and their findings cannot be extrapolated directly to human subjects. Nevertheless, because cholinergic deficits may contribute to cognitive dysfunction in AD, we believe that investigators should be aware of this link. Further research may be warranted to verify that indomethacin does not have clinically significant effects on the cholinergic system that would limit its efficacy in AD.

Acknowledgment^
We thank Dr. Marsel Mesulam (Northwestern University) for encouragement and helpful discussion.

REFERENCES^
1. Rogers J, Kirby LC, Hempelman SR, et al. Clinical trial of indomethacin in Alzheimer's disease. Neurology 1993;43:1609-1611. [Medline Link] [BIOSIS Previews Link] [Context Link]

2. Rich JB, Rasmusson DX, Folstein MF, Carson KA, Kawas C, Brandt J. Nonsteroidal anti-inflammatory drugs in Alzheimer's disease. Neurology 1995;45:51-55. [Fulltext Link] [Medline Link] [BIOSIS Previews Link]

3. Breitner JCS, Gau BA, Welsh KA, et al. Inverse association of antiinflammatory treatments and Alzheimer's disease: initial results of a co-twin control study. Neurology 1994;44:227-232. [Medline Link] [BIOSIS Previews Link] [Context Link]

4. Swanson DR. Medical literature as a potential source of new knowledge. Bull Med Libr Assoc 1990;78:29-37. [Medline Link] [CINAHL Link] [Context Link]

5. Bernardini R, Chiarenza A, Calogero AE, Gold PW, Chrousos GP. Arachidonic acid metabolites modulate rat hypothalamic corticotropinreleasing hormone secretion in vitro. Neuroendocrinology 1989;50:708-715. [Medline Link] [Context Link]

6. Inoue M, Crofton JT, Share L. Interactions between brain acetylcholine and prostaglandins in control of vasopressin release. Am J Physiol 1991;261(2 Pt 2):R420-R426. [Context Link]

7. Buccafusco JJ, Lapp CA, Aronstam RS, Hays AC, Shuster LC. Role of prostanoids in the regulation of central cholinergic receptor sensitivity. J Pharmacol Exp Ther 1993;266:314-322. [Medline Link] [BIOSIS Previews Link] [Context Link]

Accession Number: 00006114-199602000-00058