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Ibuprofen and other non-steroidal anti-inflammatory drugs (NSAIDs)
Some years ago, researchers noticed that people with severe arthritis
have strikingly low rates of Alzheimer's disease. More recently, Japanese
researchers noted a similar unusually low rate of Alzheimer's disease
in people being treated for leprosy. Treatment of both leprosy and arthritis
involves large doses of medications known as nonsteroidal anti-inflammatory
drugs (NSAIDs). These drugs include such common, over-the-counter medications
as ibuprofen (Motrin, Advil, Nuprin), naproxen (Aleve), and aspirin, plus
many prescription drugs -- but not acetaminophen (Tylenol). Several studies
have supported the speculation that NSAIDs might prevent Alzheimer's disease,
or even help treat it. In 1993, researchers divided 44 people with mild
to moderate Alzheimer's into two groups. One group took a placebo; the
other, 100 or 150 mg/day of the NSAID indomethacin (Indocin). After six
months, the placebo group showed an 8.4% decline in cognitive test scores.
But the indomethacin group registered a 1.3% improvement.
Researchers at the Johns Hopkins Alzheimer's Disease Research Center
tested 210 people with the disease over time to see how rapidly they lost
cognitive ability. Some showed rapid mental deterioration, while others
declined more slowly. Then the researchers reviewed everyone's medical
records to see who had been taking NSAIDs. They found that as NSAID use
increased, the rate of mental deterioration decreased.
Finally, as part of the 38-year Baltimore Longitudinal Study of Aging,
researchers from the National Institute on Aging assessed NSAID use in
1,828 elderly people, 110 of whom developed Alzheimer's from 1980 to 1995.
Every two years, all subjects filled out extensive food and drug surveys,
and were given a battery of cognition and memory tests. People who took
NSAIDs more than occasionally for at least two years were 30% to 60% less
likely to develop Alzheimer's disease. As duration of NSAID use increased,
Alzheimer's risk decreased. All NSAIDs other than aspirin significantly
reduced risk. Aspirin did not reach statistical significance, but
there was a trend toward lower risk with increased duration of more-than-occasional
aspirin use. The main problem with NSAIDs
is that they carry a significant risk of stomach distress, and gastrointestinal
bleeding. According to these studies, many different NSAIDs have Alzheimer's-protective
effects, including: Ibuprofen (Motrin, Advil, Nuprin), Naproxen (Naprosyn,
Aleve, Anaprox), Indomethacin (Indocin). Meclofenamate (Meclomen), and
Aspirin (possibly).
Anti-inflammatories such as Ibuprofen help protect against nerve cell
death that results from the generation of free radicals in the brain.
When nerve cells die in the brain, other cells called glial cells mount
anti-inflammatory responses and shoot off free radicals. These are usually
intended to kill invading agents like bacteria, but if the response is
too strong the glial cells can kill the nerve cells with these free radicals.
So this can be reduced with non-steroidal anti-inflammatory drugs like
ibuprofen. Check with your doctor about the best dose because of the
gastrointestinal side effects.
- Rogers, J., et al. "Clinical Trial of Indomethacin
in Alzheimer's Disease," Neurology (1993) 43:1609
- Rich, J.B., et al. "Nonsteroidal Anti-Inflammatory
Drugs in Alzheimer's Disease," Neurology (1995) 45:51
- Stephenson, J. "More Evidence Links NSAIDs, Estrogen
with Reduced Alzheimer's Risk," Journal of the American Medical Association
(May 8, 1996) 275:1389
Update: 8 November 2001
Anti-inflammatory Drugs Side-Step COX Cascade To Target Ab . If anti-inflammatory
drugs are, in fact, helping some patients counteract the neurodegeneration
of Alzheimer's disease, the benefit may not come from the most obvious
effects of those drugs.
Eddie Koo and Sascha Weggen report in today's issue of Nature
that a subset of nonsteroidal anti-inflammatory drugs (NSAIDs) lower toxic
amyloid-b (Ab) levels independent of effects on inflammatory processes.
A number of factors have pointed to inflammatory processes in Alzheimer's
disease, including elevated levels of inflammatory molecules and the presence
of astrocytes and microglia surrounding amyloid plaques. In addition,
epidemiological studies have hinted that regular use of NSAIDs reduces
the risk of AD. The assumption has been that it was the direct anti-inflammatory
action of NSAIDs, principally against cyclooxygenase (COX) activity,
that conferred this benefit. Koo and colleagues looked in another direction,
at the effects of NSAIDs on the Ab42 peptide, which is widely considered
the culprit in AD.
They found that the NSAIDs ibuprofen, indomethacin*, and sulindac
sulphide
decrease, by as much as 80%, the amount of Ab42 secreted from a variety
of cultured cells. In contrast, other NSAIDs (e.g., sulindac sulphone,
naproxen) did not reduce Ab42 levels. Because naproxen is a COX
inhibitor, the results suggested that COX inhibition is not essential
to the reduction of Ab42. Evidence supporting this hypothesis came
from an experiment in which sulindac sulphide successfully reduced Ab42
in cells deficient in COX enzymes.
Extending their work to the Tg2576 mouse model of AD, which produces
mutant human b-amyloid precursor protein, the researchers found that
ibuprofen, but not naproxen, significantly reduced levels of Ab42 (but
not of the less toxic Ab40). A second focus of this study was to examine
how NSAIDs affect the mechanism whereby the AbPP protein is cleaved to
produce either the Ab42 peptide or other, less toxic, forms. Recent efforts
to inhibit Ab42 production by targeting the g-secretase enzyme have run
into the problem that g -secretase inhibition also interferes with normal
physiological processes, in particular proteolysis of the notch receptor.
Koo et al. discovered that sulindac sulphide did not interfere with notch
processing.
They also found that NSAID treatment apparently lowered Ab42 production
by raising the levels of the shorter peptide Ab38. For their part,
the researchers anticipate the development of "'anti-amyloid' drugs that
selectively target production of the highly amyloidogenic Ab42 species
without inhibiting either COX activity or the vital physiological functions
of g-secretase." -Hakon Heimer.
-
* Indomethacin has been found to protect mild-to-moderately impaired
AD patients from some of the decline they would otherwise show.
Updates:
September, 2002 Journal: Neurology
John Breitner's huge group of researchers found substantial reductions
in AD rates among people who used aspirin or other anti-inflammatory drugs
for at least 2 years; long term use that preceded AD by at least several
years was best.
June, 2006 Journal: New England Journal of Medicine (t' Veld BA, Ruitenberg
A, Hofman A, et al) "The relative risk of Alzheimer's disease was
0.95 (95 percent confidence interval) in subjects with short-term use
of NSAIDs, 0.83 (95 percent confidence interval) in those with intermediate-term
use, and 0.20 (95 percent confidence interval) in those with long-term
use.....The long-term use of NSAIDs may protect against Alzheimer's disease
but not against vascular dementia."
May, 2008: A longer
study of nearly 50,000 US vets who acquired AD diagnoses and nearly
200,000 who never became demented (over 5 years) confirmed substantial
reductions in the risk of AD with Ibuprofin and other NSAIDs.
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