Alzheimer’s Disease- Part XVIII: NO releasing-NSAIDs

Another potential player in the Alzheimer’s disease drug treatment arena

Drug companies are "combing the bushes" for a drug that will cure Alzheimer’s disease (AD). Our aging population and the 4 million plus Alzheimer’s disease cases in the United States make it an attractive market for drug development. Recently, the NY Times (Nov. 22, 2001) carried an article entitled "Hints of an Alzheimer’s Aid in Anti-Inflammatory Drugs". The study, done in Rotterdam by Dr. Bruno H. C. Stricker of the Erasmus Medical Center in Rotterdam, appeared in New England Journal of Medicine. The researchers studied two groups of patients, aged 50 years or more, over an average of 6.8 years. "In the group that took no anti-inflammatory drugs, 210 out of 2,553 developed dementia. But 3 out of 233 who had taken the drugs for at least two years developed it. The dose did not appear to be important…" (NY Times November 22, 2001). The sole medication that affected Alzheimer’s disease was the anti-inflammatory drugs. The National Institute on Aging presently has two clinical trials in progress to evaluate the use of anti- inflammatory drugs in delaying Alzheimer’s disease development or progression.

This was not the first time NSAIDs have been suggested as a possible aid in slowing the progress of AD. McGreer et al in 1990 suggested anti-inflammatory drugs as a treatment modality. Again in 1996, McGreer was part of a group of researchers who explored inflammation and Alzheimer’s disease pathogenesis. In 1999 Flynn and Theesen in the Annuals Of Pharmacotherapy (Vol. 33: 840-849) indicated that NSAIDs slow the progress, or delay, the onset of AD. They suggested that NSAIDs "might inhibit the level of neuronal COX-2 enzyme", which is elevated in patients with AD. In the journal Neurobiology of Aging (2000; 21:381-429), Akiyana and colleagues felt "that epidemiological studies documented that NSAIDs reduce the prevalence of AD". They suggested that this was not seen in all NSAIDs and that the reason it delayed the progression of AD was not directly related to inhibition of COX-2 activity, which is the principle pharmacological agent of NSAIDs. They pointed out that NSAIDs also "increase the Aß (1-38) isoform", suggesting that the "NSAIDs subtly alter ?-secretase activity without superficially perturbing other amyloid precursor protein (APP) processing pathways". The secreted form of APP may be degraded and release amyloidogenic fragments containing the ßA4 that leads to diffuse ßA4 plaques resulting in Alzheimer’s disease. Prevent this from happening then would stop AD from developing.

NSAIDs are among the most widely prescribed drug worldwide owing to its varying therapeutic properties i. e. anti-inflammatory, antipyretic and analgesic properties. The first nonaspirin NSAIDs was introduced in 1964, and there are now nearly 20 on the market. Common NSAID products include diclofenac, piroxicam (Feldene), and indomethacin. In the over-the-counter market, we have acetaminophen, ibuprofen, naproxen and ketoprofen among others.

NSAIDs are commonly used to treat the symptoms of arthritis, gout, bursitis, painful menstruation, and headache. They act by inhibiting arachidonic acid, a precursor of prostaglandins, leukotrienes, and other compounds that are involved in the inflammatory, neurochemical, and neuropathological processes associated with AD. According to Hauss-Wegrzyniak et al "[T]hese inflammatory, neurochemical, behavioral and neuropathological changes include, but are not limited to, the following: 1) an increase in the number of activated astrocytes; 2) an increase in the number and density of OX-6-positive reactive microglia, particularly within the hippocampus, entorhinal cortex and basal forebrain; 3) an increase in the levels of interleukin-1ß, tumor necrosis factor-alpha and ß-amyloid precursor protein mRNA, particularly within the temporal lobe regions and basal forebrain; the degeneration of hippocampal pyramidal neurons; 4) the degeneration of hippocampal pyramidal neurons; and 5)a significant impairment in working memory".

The difficulty with extended use of NSAID is found in its adverse effects. An estimated 3-4 million Americans take NSAIDs daily. Although they are often considered easier to tolerate than aspirin, and most do not have as strong an anticlotting effect as aspirin, NSAIDS can have serious side effects, particularly gastrointestinal ulcers and upper gastrointestinal tract bleeding and perforation in those who take the drugs on a regular basis. NSAID-related gastropathy has been reported to result in more than 2,000 deaths in the United States each year. Singh at al reports an annual incidence of GI bleeding and perforation approaching 2% of the users.

Biochemists saw the need to develop a drug that protects against mucosal injury by NSAIDs, and has the same potential effect as the NSAIDs. This has given rise to a new class of drugs called nitric oxide (NO)-releasing NSAIDs. To do this, chemists added a radical, nitrobutyl or nitrosothiol, by using a short-chain ester linkage. This allows the NO-NSAIDs to retain their anti-inflammatory and antipyretic activity and exhibit reduced gastrointestinal toxicity while enhancing vasodilation, reducing blood platelet adhesion and acting as a buffer against memory loss. It is now undergoing both pre-clinical testing, and phase I and II status testing. The table below is the latest information we have on this:

Current status of NO-releasing NSAIDs in Development






Phase II (as of 11/14/01)






Phase II






Phase I




The information below comes directly from each of the above drug company’s web site. We do not endorse any of these companies:

* AstraZeneca is one of the top investors in pharmaceutical research and development in the world. Last year, the company spent $2.6 billion on R&D—that’s $10 million every working day. AstraZeneca’s Global R&D organization is headquartered in Sodertalje, Sweden. R&D "Centers of Excellence" for discovery, development, and operations functions are distributed among eight major R&D sites in Sweden, the United Kingdom and North America

Nitric Oxide (NO) is a highly diffusible and lipid soluble free radical which reacts with other free radicals, oxygen, and transition metals such as iron. Rapid degeneration of NO occurs when it binds with an iron group of hemoglobin. NO and oxygen interaction results in NO2 production which rapidly consumes more NO to form N203, an excellent nitrosating agent of thiol-containing proteins.

NO is now recognized as an important modulator of an enormous number of physiological functions. Synthesis of NO in the endothelial cells, which line the inner walls of blood vessels, in response to physical an chemical stimuli, has been found to play a crucial role in maintaining vasodilation and is essential for regulation of blood pressure. Moreover, NO inhibits aggregation and adhesion of platelets to the wall of blood vessels and significantly reduces the formation of blood clots. Taken together these effects account for the major role NO plays protecting against stroke. Furthermore, NO is involved in the pathogenesis of conditions such as septic shock and certain states of cirrhosis and in inflammation.

In the CNS, NO is a neurotransmitter that underpins several functions, including the function of memory. In the periphery, there is a widespread network of nerves, previously recognized as noradrenergic and noncholinergic, to mediate some forms of neurogenic vasodilation and regulate various GI, respiratory and genitourinary functions. Parts of these actions are mediated by NO activation of soluble guanylate cyclase (sGC) leading to the subsequent intracellular increase in concentration of cyclic guanosine monophosphate (cGMP) in target cells. Low levels of NO exert beneficial effects by enhancing mucosal defense, thus protecting against injury by NSAIDs as shown in a study by Lanas and his colleagues. (Study indicated that NO releasing medications, such as nitroglycerine (a vasodilator), resulted in a reduction in the incidence of gastric lesions in those who took NSAIDs.)

It will be a number of years before any NO-release containing drug is commercially available. In the meantime, there are four drugs approved by the FDA for treatment of Alzheimer’s disease progress. Our hope is that the future will bring more focused drugs that target the process of AD and/or prevent it from occurring. In the meantime, evidence is building up that nonsteroidal anti-inflammatory drugs decrease the risk of Alzheimer’s disease and that it "should be initiated in adults before age-associated inflammatory processes within the brain have a chance to develop" (Hauss-Wegrzyniak et al). Adverse side effects would seem the limiting factor.


Akiyana H., et al. Inflammation and Alzheimer’s disease Neurobiol Aging 2000; 21:381-421

Flynn BL & Theesen KA. Pharmacologic management of Alzheimer’s disease Part III: nonsteroidal anti-inflammatory drugs: emerging protective evidence? Ann Pharmacother 1999; 33:840-849.

Hauss-Wegrzyniak B, Vraniak P, Wenk GL. The effects of a novel NSAID on chronic neuroinflammation are age dependent. Neurobiol Aging 1999; 20(3): 305-313.

Kolata, Gina. Hints of an Alzheimer’s Aid In Anti-Inflammatory Drugs. New York Times 2001, November 22.

Lanas A., Bajador E., Serrano P. et al. Nitrodilators, low dose aspirin and other NSAIDs, and the risk of gastrointestinal bleeding. N Eng J Med 2000; 343:843-849.

McGreer PL, McGreer EG, Rogers J, Sibley J. Anti-inflammatory drugs and Alzheimer’s disease. Lancet 1990; 335:1037.

Rogers J, Webster S, Lue L-H, Brachova L, Civin WH, Emmerling M, Skivers B, Walker D, McGreer Pl. Inflammation and Alzheimer’s disease pathogenesis. Neurobiol Aging 1996; 17:681-686.

Singh G, Ramey DR., NSAID induced gastrointestinal complications: the ARAMI perspective 1997. J Rheumatol 1998; 25:8-10.

Other references consulted:

Cicala C., Iannaro A., Fiorucci S. et al. NO-naproxen modulates inflammation, nociception and down-regulates T-cell response in rat Freund’s adjustment arthritis. Br J Pharmacol 2000; 130:1399-1345.

Fiorucci S., Antonelli E., Burgaud JL., Morelli A. Nitric Oxide-Releasing NSAIDs: a Review of There Current Status. Drug Safety 2001; 24(11): 801-811.

Mayer B & Hemmens B. Biosynthesis and action of nitric oxide in mammalian cells. Trends Biochem Sci 1997; 22:477-489.

Mukherjee D et al. Cardivascular Risks of COX-2 Inhibitors. Amer J Med Assoc 2001; 286:954-959.

Weggen S, Erickson JL, Sagi SA et al. A subset of NSAIDs lower amyloidogenic Aß 42 independently of cyclooxygenase activity. Nature 2001; 414:212-216

See: Alzheimer's Disease Part I-Medications for Alzheimer's.
See: Alzheimer’s Disease Part II- Selegiline and AD.
See: Alzheimer's Disease Part III- Use of Gingko Biloba in memory problems of Alzheimer patients.
See: Alzheimer's Disease PartIV-Alternative Treatment.
See: Alzheimer's Disease Part V-Possible New Drugs for Alzheimer's Disease Treatment.
See: Alzheimer's Part VI -Early Diagnosis.
See: Alzheimer's Part VII -New Medication-Metrifonate
See:Alzheimer's Disease PartVIII - Implications of Longer Life Expectancies
See: Alzheimer's Part IX-Ethical Care Principles
See: Alzheimer's Disease Part X-Estrogen and Alzheimer's Disease
See: Alzheimer's Disease Part XI-Pocket Smell Test
See: Alzheimer's Disease Part XII-MAO-B
See: Alzheimer's Disease Part XIII-Critical Flicker Fusion Threshold Test
See: Alzheimer's Disease Part XIV-Donepezil
See" Alzheimer's Disease Part XV-Cerebroylsin
See: Alzheimer's Disease Part XVI-MCI
See: Alzheimer's Disease Part XVII-Research Summary
See: Alzheimer's Disease Part XIX-Vitamin E
See: Alzheimer's Disease-Part XX-Clinical Trials
See: Alzheimer's Disease Part XXI-The Brain
See Dementia with Lewy Bodies- Part XXII-by Gourete Broderick
See: Alzheimer's Disease-Part XXIII-HMG
See: Alzheimer's Disease-Part XXIV-A Prequel
See: Alzheimer's Disease-Part XXV-Psychosis
See: Alzheimer's Disease-Part XXVI-Amyloid-beta Hypothesis Controversy
See: Alzheimer's Disease-Part XXVII- AD and Diabetes
See: Alzhemeir's Disease-Part XXVIII - Insulin and AD


Harold Rubin, MS, ABD, CRC, Guest Lecturer
December 16, 2001

To e-mail: or

Return to Home