Arches. Photo by Daniel Chia
HOPES: Huntington's Outreach Project for Education, at Stanford
Jun
29
2010

NSAIDs

Drug Summary: NSAIDs (Non-steroidal anti-inflammatory drugs) are compounds that significantly reduce the inflammatory response. Common examples of NSAIDs include ibuprofen (Motrin®, Advil®) and naproxen (Aleve®). Studies have shown that chronic inflammatory responses occur in vulnerable areas of the brains of HD patients. These inflammatory responses are believed to be a contributing factor to the death of nerve cells. Because of this, researchers believe that anti-inflammatory therapy could be beneficial in delaying the onset or slowing the progression of HD. Unfortunately, a study in a mouse model of HD found that treatment with aspirin or rofecoxib – two common NSAIDs – did not improve symptoms of the disease; HD mice receiving treatment actually died earlier than untreated HD mice. Therefore, NSAIDs are unlikely to have therapeutic potential for people with HD.

NSAIDs and inflammation^

Nonsteroidal anti-inflammatory drugs work by interfering with the cyclooxygenase pathway. The normal process begins with fatty acids, most of which we get through our diet. These fatty acids undergo a series of processes that result in the production of prostaglandins. Prostaglandins are molecules that have various functions in the body. Some prostaglandins act as important inflammatory mediators that contribute to the progression of inflammation.

Enzymes known as cyclooxygenase (COX) are responsible for converting the fatty acids we eat into prostaglandins. Recent research has shown that there are two types of cyclooxygenase: COX-1 and COX-2. Each type of cyclooxygenase facilitates the production of different types of prostaglandins. In particular, COX-1 is involved in the production of prostaglandins that are needed for various regulatory functions in the body, such as the maintenance of the stomach lining. COX-2, on the other hand, is involved in the production of prostaglandins that mediate inflammation.

NSAIDs inhibit part of the inflammatory response by blocking the active sites of the COX enzymes, preventing the conversion of fatty acids to prostaglandins. Although COX-2 is the enzyme of concern with regards to inflammation, most NSAIDs in the market today block both forms of COX enzymes. Side effects such as gastrointestinal pain have been associated with NSAID use due to the inhibition of COX-1′s essential role in maintaining various processes in the body.

Drugs that selectively inhibit COX-2 have recently become available and are approved for use as arthritis medications. Examples of such COX-2 inhibitors recently developed include Merck’s rofecoxib (Vioxx®) and Searle’s celecoxib (Celebrex®). Because of their selectivity for COX-2, these newer drugs are expected to avoid the serious side effects associated with the more common NSAIDs. Studies have yet to show how these selective COX-2 inhibitors function in animal models of brain inflammation, although some studies have reported that inhibitors similar to the COX-2 inhibitors are able to decrease brain damage induced by different causes. Both COX-2 drugs are currently in clinical trial for the treatment and/or prevention of Alzheimer’s Disease.

Some NSAIDs also play the role of PPAR-gamma activators. PPAR-gamma are proteins that act to suppress the expression of genes that code for molecules involved in inflammation. By activating PPAR-gamma, NSAIDs further suppress the inflammatory response.

Types of NSAIDs^

There are many different types of NSAIDs. NSAIDs vary in their strength, duration of action, and the way in which they are eliminated from the body. Some common types of NSAIDs include:

Aspirin.^

Aspirin (acetylsalicylic acid) is part of a group of drugs called salicylates. They are a relatively inexpensive, safe form of NSAID that have been popular since they were first introduced in 1899. Aspirin is widely used for relieving pain and reducing fever in adults. Aspirin also relieves mild itching and reduces swelling and inflammation. Because of its effect on pain, swelling and inflammation, aspirin is often recommended for treating inflammatory diseases such as arthritis, as well as many other conditions and injuries.

Children and teenagers are advised not to take aspirin because aspirin use in these age groups is associated with a rare and serious brain and liver disorder called Reye’s syndrome.

Acetaminophen.^

Acetaminophen relieves mild pain and reduces fever as effectively as aspirin. It has been found to work well for people who cannot take aspirin because of aspirin-related allergic reactions or stomach irritation. In addition, acetaminophen is safe for use by infants, children and teenagers. However, acetaminophen has been found to be associated with liver disease in some people. Common brands of acetaminophen include Tylenol® and Tempra®.

Note: Some sources indicate that acetaminophen merely acts as a pain reliever, but has little or no known anti-inflammatory mechanisms. Despite the lack of known anti-inflammatory effects, acetaminophen is still often categorized as an NSAID and has been used in Alzheimer’s Disease studies as an NSAID. For our purposes, we will categorize acetaminophen together with the other NSAIDs in our site. For more information on this issue, click here.

Ibuprofen.^

Ibuprofen is effective for relief of pain, fever and inflammation. For many people, it is an effective alternative to aspirin for the treatment of arthritis. It inhibits prostaglandin synthesis and acts as a PPAR-gamma activator. It can be less irritating to the stomach than aspirin for some and does not cause severe liver disease associated with acetaminophen. There is less information on the effects of ibuprofen in children, so acetaminophen is still considered by many doctors to be the safest drug for children and teenagers. Common brand names include Motrin® and Advil®.

Other^

Other types of NSAIDs include naproxen, ketoprofen, and indomethacin. Some studies have indicated that NSAIDs interact with a number of other medications. Some drugs/supplements that have been reported to cause adverse side effects when taken with aspirin include blood thinners like warfarin, and Ginkgo biloba. Studies have shown that compounds such as warfarin and Ginkgo biloba could interact with aspirin to produce excessive bleeding. It is also advised that multiple administration of more than one type of NSAID should be avoided, due to an increased risk of side effects.

NSAIDs and HD^

Because increased inflammatory activity has been observed to be associated with damage in HD brains, NSAID treatment may have beneficial effects on people with HD. However, few studies have actually been done to investigate the effects of anti-inflammatory drugs in people with HD. Currently, research on anti-inflammatory drug use is based on animal models of Alzheimer’s Disease (AD) and Parkinson’s Disease (PD). These studies on AD and PD models have shown favorable, but still far from conclusive, results. Because damage from inflammation is also associated with both AD and PD, there is reason to hope that studies on the effects of anti-inflammatory drugs can be applied to HD as well.

Despite the information offered by some completed studies, many questions still remain unanswered. For example, how long should medication with anti-inflammatory drugs last? What type of anti-inflammatory drug should be used? NSAIDs are merely one of many types of anti-inflammatory medications available today. More studies need to be done to determine the best NSAID, dosage, and duration of use for people with neurological disorders.

The following section focuses on some of the studies done on the effects of NSAID use on various neurological diseases.

Research on NSAIDs^

Lim, et al. (2000) tested the impact of orally administered ibuprofen in a mouse model of Alzheimer’s Disease (AD). Ibuprofen is both a COX-1 and COX-2 inhibitor as well as a PPAR-gamma activator. The researchers hypothesized that by blocking prostaglandin synthesis, inflammation as well as its consequent damage to the nerve cells might be reduced.

Mice that exhibited various pathological changes characteristic of AD were used in the study. Some characteristics of these mice included increased microglial activation and elevated levels of two cytokines that are commonly elevated in people with AD. Cytokines are one of the immune system’s “weapons” and play important roles in inflammation.

The AD mice also showed an increase in the accumulation of the protein amyloid. These amyloid accumulations form plaques in AD cells. Plaque formation is believed to affect proper brain functioning and contribute to AD progression. To assess the efficacy of ibuprofen, the researchers measured the changes in cytokine levels as well as changes in activated microglia levels and plaque formation.

To determine the effects of ibuprofen treatment, the mice were divided into two groups: One group was given food containing no drug while another was given food containing ibuprofen for 6 months. 56 mg per 1 kg of body weight of ibuprofen was administered to the mice each day. Doses in this range are known to decrease prostaglandin levels in the mouse brain but are less effective in suppressing inflammation in people with arthritis. The researchers observed that the ibuprofen-treated mice showed a decrease in cytokine levels and activated microglia, as well as decreased plaque formation. It is therefore possible that ibuprofen may have beneficial effects on people with AD. However, more tests need to be done to determine the proper dosage that is both safe and effective for treating people with such neurological diseases.

Casper, et al. (2000) examined the effects of three types of NSAIDs (aspirin, acetaminophen, and ibuprofen) on damage caused by toxicity due to glutamate. Glutamate has been found to initiate various mechanisms that result in cell death. One way by which glutamate mediates cell death is by activating COX-2, thereby increasing the production of inflammatory prostaglandins. (For more information on HD and glutamate, click here.)

By adding NSAIDs to cells exposed to glutamate, the researchers hypothesized that the NSAIDs would decrease glutamate toxicity by inhibiting the COX enzymes. Inhibition of COX could then lead to decreased inflammation and decreased damage.

In the experiment, a mixture of nerve cells and glial cells were divided into three groups, and each group was exposed to one of the three drugs. A separate group of nerve cell-glial cell mixture was not exposed to any drug at all, and was used as a means of comparison to evaluate the effects of the drugs. Glutamate was later added to all four groups of nerve cells. Exposure to glutamate resulted in a significant reduction in the number of nerve cells but cells treated with any one of the three NSAIDs showed decreased cell death compared to the untreated group.

Although structurally distinct, all three NSAIDs tested have been shown to inhibit cyclooxygenases (COX). Previous studies had shown strong evidence that long-term NSAID use reduced the risk of AD; however, these studies could not identify the protective mechanism involved. This study revealed that NSAIDs can protect nerve cells from death induced by glutamate. HD cells have been observed to be very susceptible to glutamate-mediated cell death. It is therefore possible that NSAID treatment could reduce glutamate-mediated cell death in the HD brain.

Norflus et al. (2004): Scientists studied two NSAIDs – rofecoxib and acetylsalicylate (commonly known as aspirin) – in a mouse model of HD. These particular NSAIDs were chosen because they have shown promise in animal models of other neurodegenerative diseases, and because they are commonly used in humans – so positive results would easily translate to human medicine. Mice treated with aspirin were given 200 mg/kg each day, a dose that had been used successfully in other studies; mice treated with rofecoxib were given 15 mg/kg, which is equivalent to the maximum possible dose that humans can receive.

Despite high hopes, scientists found that these NSAIDs did not protect against the damage done by the disease. None of the symptoms typically displayed by HD mice – weight loss, shorter life, behavioral changes, death of brain cells, and motor symptoms – were improved by treatment. In fact, HD mice treated each day with aspirin or rofecoxib died earlier than untreated HD mice, probably due to the toxicity of the drug. The researchers concluded that anti-inflammatory medicines like NSAIDs do not have therapeutic benefit at doses that humans can tolerate. They speculated that inflammatory pathways don’t seem to be a major contributor to disease pathogenesis in HD, and suggest that other avenues of research would be more worth pursuing.

For further reading^

  1. Lim, et al. “Ibuprofen Suppresses Plaque Pathology and Inflammation in a Mouse Model for Alzheimer’s Disease.” The Journal of Neuroscience. 2000, August, 20(15):5709-5714.
    This study reported that ibuprofen treatment resulted in improved outcomes in a mouse model of Alzheimer’s Disease.
  2. Casper, et al. “Ibuprofen protects dopaminergic neurons against glutamate toxicity in vitro.” Neuroscience Letters. 2000, 289: 201-204.
    This study reported that NSAIDs treatment resulted in improved outcomes in cells exposed to toxic amounts of glutamate.
  3. Norflus F, Nanje A, Gutekunst CA, Shi G, Cohen J, Bejarano M, Fox J, Ferrante RJ, Hersch SM. Anti-inflammatory treatment with acetylsalicylate or rofecoxib is not neuroprotective in Huntington’s disease transgenic mice. Neurobiol Dis. 2004 Nov;17(2):319-25. This study looked at NSAID treatment in HD mice, and concluded that NSAID treatment is not a potential treatment for HD

-E. Tan, 6/15/02; Revised by P. Chang, 5/7/03, Updated M. Hedlin 10/7/11