Inflammation, what we commonly know as the swelling, redness, heat, and pain that often accompany injuries, is one of our body’s most important natural defense mechanisms against internal and external threats. The inflammatory process protects our body from damage and disease by releasing cells and mediators that combat foreign substances and help prevent infection. However, these same inflammatory elements can also be deadly to the body when “switched on” too long, a condition known as chronic inflammation. Research has indicated that chronic inflammation is common in the nerve cells of patients with HD, and that it may be a powerful mediator of HD’s neurodegenerative damage.
Because the constant pain that often accompanies chronic inflammation is often a source of complaint in many diseases, there are a relatively large number of anti-inflammatory drugs and therapies available. However, most of these treatments target inflammation at a general level, and were not designed to block the inflammatory response specifically in the nerve cells affected by HD. As such, they can lead to unwanted side effects. The following anti-inflammatory drugs and supplements presented below have either the theoretical potential to alleviate inflammatory damage in the brains of patients with HD, or have been tested on other neurological diseases in which inflammation is a disease mechanism, such as Alzheimer’s disease. Some experiments and/or clinical trials of these treatments have been done on either animals or human patients with HD.
Important information about Huntington’s disease and inflammation^
Studies of the HD brain indicate that long-term inflammation plays a significant role in the progression of HD. Given this finding, scientists are trying to understand the specific role of inflammation and are investigating the possibility of anti-inflammatory drugs as HD therapies.
The process of inflammation can be thought of as our body going into battle. Both inflammation and wars are responses to outside threats. Inflammation is a complex process that causes swelling, redness, warmth, and pain. It’s our body’s natural response to injury and plays an important role in healing and fighting infection. Similar to war, inflammation has its own troops: immune cells that secrete various molecules and enzymes that kill foreign invaders. Inflammation destroys and kills the injury-causing agent through a variety of mechanisms. Short-term inflammation protects the body from damage and disease. However, long-term or chronic inflammation, much like a drawn-out war, can lead to damage, not only to the foreign substances, but to the body itself as well.
Studies of the HD brain indicate that chronic inflammation plays a significant role in the progression of HD. Our body’s immune system has the ability to recognize foreign substances and launch various defense mechanisms to get rid of these potentially harmful substances. Scientists believe that the immune system recognizes the expanded glutamine tract in the altered huntingtin protein as “foreign” and tries to get rid of it, resulting in chronic inflammation and damage.
Studies have also shown that excitotoxic amino acids such as glutamate induce a direct activation and proliferation of cells involved in inflammation. Since glutamate activity is also implicated in the progression of HD, it is possible that the glutamate molecules in the HD brain induce an inflammatory response.
The inflammatory response results in the activation of various types of cells and the production of different molecules that can lead to cell death. An example of cells activated by the inflammatory response are the microglia (a type of immune cell) which have been found to be highly activated in the HD brain.
What are glial cells?^
Nerve cell bodies and axons are surrounded by glial cells. Glial cells outnumber nerve cells by about five to one in the nervous system. Although their names come from the Greek word for glue, glial cells do not actually hold other cells together. Furthermore, glial cells do not conduct nerve impulses, and are thus not essential for processing information. Rather, they serve as supporting elements to the brain and act as scavengers, removing debris after injury or neuronal death. Two types of glial cells produce the fatty coating that covers large axons of the nerve cells.
There are many different types of glial cells in the nervous system. Glial cells such as the oligodendrocytes produce the fatty coating in nerve cells, the astrocytes maintain ionic balance, while the microglia get rid of unwanted substances.
Glial cells and HD^
Research has shown that there is a marked increase in microglia in the HD brain. Microglia play the role of immune cells in the brain. They are sometimes called “brain macrophages” because they perform many of the same functions that macrophages in our body do. Macrophages are immune cells found all over our body that act as scavengers, engulfing dead cells, foreign substances, and other debris.
In the brain, the microglia act as macrophages, getting rid of unwanted substances by engulfing them and “eating” them.
Microglia are normally inactive. They become active in the brain following a variety of debilitating events such as infection, trauma, and decreased blood and oxygen flow. Once activated, the microglia are then able to remove dying neurons and other cells.
In the HD brain, an increase in activated microglia is found along the vicinity of nerve cells that contain neuronal inclusions (NIs) – accumulation of the huntingtin protein. This finding suggests that the huntingtin protein accumulation influences the activation of reactive microglia. Nerve cell injury due to excitotoxins such as glutamate also induces long-term microglial activation in the brain. Excitotoxins are excitatory amino acids found in increased concentrations in the nervous system and cause damage and cell death. (For more on excitotoxins, click here.)
Microglia and other inflammatory mediators^
Aside from engulfing foreign substances, activated microglia are also capable of producing various substances that act as mediators of the inflammatory response. Although these mediators play an important role in inflammation, they are also potentially neurotoxic substances that can contribute to widespread central nervous system injury. Examples of inflammatory mediators include free radicals, proteases, excitatory amino acids, complement proteins, cytokines, and certain prostaglandins. These substances are the microglia’s “weapons”: they act to kill the foreign substance that invade our body. However, as stated before, chronic inflammation results in chronic release of these substances, which can eventually lead to considerable damage and cell death.
The exact mechanisms of these substances are not covered in this section. More information on each of the various inflammatory mediators can be found in various sources listed in the references section.
These mediators each have different roles in the inflammatory response, but for our purposes, it is sufficient to know that all of them contribute to inflammation and are found in increased concentrations in the brains of people with neurological diseases such as HD and AD. Drugs that could lower the concentrations of these molecules are therefore attractive treatment agents for people with diseases where inflammation plays a prominent role.
Inflammation and disease^
Inflammation, whether in the brain or in other parts of the body, is almost always a secondary response to some primary disease-causing substance or event. Despite the fact that inflammation is a secondary response, it is still an important mechanism that can protect or damage the cell, depending on its severity and length of occurrence. In head trauma, for example, the blow to the head is the primary event. However, what may be of greater concern is the secondary inflammatory response that will result from the primary event. When it continues for a long period of time, inflammation is likely to cause more neuron loss than the initial injury. Given that chronic inflammation has been reported in the brains of people with HD, anti-inflammatory compounds that will delay the inflammatory response or eradicate it altogether may be potential HD treatments to consider.
Various inflammatory mediators are released by our immune cells during times when harmful agents invade our body. Long-term release of some of these inflammatory mediators has been observed in the cells of people with HD. An understanding of how these mediators work and how to block their release could be helpful in looking for ways to delay the progression of HD.
Our body must defend itself against many different disease-causing substances such as viruses, bacteria, and parasites, as well as tumors and a number of various harmful agents. To combat these disease-causing substances or events, our body has developed many mechanisms to defend itself against such an “attack.” One of the ways by which our body protects itself is by triggering an inflammatory response. Early scientists considered inflammation as our body’s primary defense system. However, inflammation is more than just a simple defense system, because when left unchecked, it could lead to debilitating diseases such as arthritis or even death. Long-term inflammation is also linked to the progression of neurological diseases such as Alzheimer’s Disease and Huntington’s Disease.
The development of inflammatory reactions is controlled by various molecules released by our body’s immune cells. Our immune cells act as the body’s “soldiers”, and they guard the body against attack by releasing “weapons” in the form of inflammatory mediators. One type of immune cell found to be present in extraordinarily high concentrations in the HD brain is the microglia. The microglia have been observed to release various inflammatory mediators that contribute to the long-term occurrence of inflammation in the HD brain, resulting in damage and cell death.
We will go over some of the most common inflammatory mediators released by the body’s immune cells in order to understand how the inflammatory response works. In general, most of the mediators that we will talk about in this section have one of two roles: amplification of the immune response, or destruction of the foreign substance.
Free radicals are atoms or molecules that are highly reactive with other cellular structures because they contain unpaired electrons. As free radicals react with cellular structures, they lead to cellular injury and eventually, cell death. Free radicals may also trigger activation of various proteins that in turn activate the inflammatory response.
Although the majority of the research on HD focuses on free radical generation due to impaired electron transport chain functioning, the concept of free radical toxicity actually has its roots in inflammation biology. (Click here for more information on free radicals and antioxidants.) The secretion of reactive oxygen and nitrogen free radical species by inflammatory cells is a major mechanism for attacking foreign substances. Large amounts of free radicals are produced by activated microglia, and chronic release of free radicals result in neuronal injury and cell death.
Excitotoxins such as glutamate and quilonic acid are excitatory molecules that are released by immune cells and are known to cause damage to the body. They can also result in cognitive impairment when found in increased concentrations in the brain. Glutamate has specifically been found to initiate various mechanisms that ultimately lead to cell death. (For more information on glutamate, click here.)
Complement is a set of many proteins activated in sequence when cells are exposed to a foreign substance. Once the proteins are activated, nine of them come together to form the membrane attack complex (MAC). When assembled on a cell membrane, MAC forms a ring-like structure that allows the movement of ions and small molecules into and out of the cell, disrupting the normal state of the cell.
The complement system is a potent mechanism for initiating and amplifying inflammation. One of the most damaging effects induced by the formation of MAC is the entry of calcium ions (Ca2+) into the cell. The Ca2+ ions are capable of activating various Ca2+-dependent proteins that contribute to cell death. If a sufficient number of MACs have assembled on the cell, cell death eventually occurs.
Studies have reported that a number of complement proteins are expressed at a higher level in HD brains compared to non-HD brains. The increased number of activated microglia induced by the altered huntingtin protein most likely causes the higher levels of complement proteins in HD brains.
Cytokines are proteins that are secreted by various types of immune cells and serve as signaling chemicals. The central role of cytokines is to control the direction, amplitude, and duration of the inflammatory response.
There are two main groups of cytokines: pro-inflammatory and anti-inflammatory. Pro-inflammatory cytokines are produced predominantly by activated immune cells such as microglia and are involved in the amplification of inflammatory reactions. Anti-inflammatory cytokines are involved in the reduction of inflammatory reactions. Table 1 lists some of the most common proinflammatory and inflammatory cytokines.
|Pro-inflammatory cytokines||Anti-inflammatory cytokines|
Table 1: List of common pro-inflammatory and anti-inflammatory cytokines
Prostaglandins are produced in most tissues of the body and have varying actions. They are short-lived, hormone-like chemicals that regulate cellular activities on a moment-to-moment basis. Prostaglandins fall into 3 series – PG1, PG2, and PG3. PG1 and PG3 are known to have anti-inflammatory effects as they decrease inflammation, increase oxygen flow, prevent cell aggregation, and decrease pain. PG2 are known to have pro-inflammatory effects, since their effects are opposite to those of PG1 and PG3. Table 2 shows a comparison of the effects of the different prostaglandins.
|PG1 and PG3 (anti-inflammatory)||PG2 (pro-inflammatory)|
|Decrease pain||Increase pain|
|Increase oxygen flow||Decrease oxygen flow|
|Dilate airways||Constrict airways|
|Decrease inflammation||Increase inflammation|
Table 2: Prostaglandins
Because of the negative effects of chronic inflammation, it is speculated that people with HD would most likely benefit from an increase in Series 1 and 3 prostaglandins and a decrease in Series 2 prostaglandins.
For further reading^
- Inflammation: http://nic.savba.sk/logos/books/scientific/node4.html
This page contains detailed information about inflammation. It goes over all phases of the inflammatory response in a technical manner. Although not as easy to understand as other sites, this page has vast amounts of information for the person seeking to understand the many aspects of inflammation.
- Mulitple Sclerosis Glossary: http://www.albany.net/~tjc/gloss.html
This page contains a glossary of words relevant to multiple sclerosis (MS) – an auto-immune disease that affects the nervous system. It is useful for looking up terms and concepts about the nervous system and immune system.
- Neuroinflammation Working Group. “Inflammation and Alzheimer’s Disease.” Neurobiology of Aging. 2000; 21: 383-421.
This article contains detailed, comprehensive information on the inflammatory response and Alzheimer’s Disease (AD). It has information on the many studies done on the role of inflammation on the pathology of AD as well as the trials conducted on various anti-inflammatory compounds.
- Sapp, et al. “Early and Progressive Accumulation of Reactive Microglia in the Huntington Disease Brain”.Journal of Neuropathology and Experimental Neurology. 2001; 60(2): 161-172.
This article contains information on a study done that investigated the presence of reactive microglia in postmortem brains of people with HD. The study reported that increased levels of reactive microglia are present in HD brains.
- Singhrao, et al. “Increased Complement Biosynthesis By Microglia and Complement Activation on Neurons in Huntington’s Disease.” Experimental Neurology. 1999 Oct; 159(2):362-376.
This article contains the full details on a study done to investigate the levels of inflammatory response proteins in HD nerve cells. The study reported that increased levels of those proteins are found in HD nerve cells.
-E. Tan, 9/21/01 and P. Chang, 5/6/03More
Drug Summary: Folic acid, also known as vitamin B11 and naturally found in the form of folate, is important in many biological processes. A recent study conducted over three years with healthy adults 50-70 years old showed that folic acid supplements equal to twice the recommended daily value improved memory and slowed decline in muscle skills and information processing. The supplements used contained 800 micrograms (mcg) of folic acid, while the recommended daily value is 400 mcg. It should be noted that the study was conducted on healthy individuals and further research is needed to determine if there are similar benefits from folic acid supplements for people with neurodegenerative disorders such as Alzheimer’s and HD. Although the mechanism(s) through which folic acid protects the brain are not yet clearly defined, there is evidence that it works at least in part through regulation of a molecule called homocysteine.
- What is homocysteine and why is it important in HD?
- Why is the re-methylation of homocysteine important?
- Folic Acid and HD
- How can I increase my folate intake?
- What is the right amount of folate?
- What are the possible side effects and risks associated with supplemental folic acid?
- What other lifestyle factors influence homocysteine levels?
- What have studies shown regarding homocysteine and folic acid?
- Research on homocysteine and folic acid
- What is the final word on folic acid supplements, homocysteine levels and their impacts on HD?
- For further reading
What is homocysteine and why is it important in HD?^
Homocysteine is an amino acid closely related to two other amino acids called methionine and cysteine. Homocysteine comes in several different forms. All of these forms are measured together to determine a person’s total homocysteine level (abbreviated tHcy). Certain forms of homocysteine may cause damage through oxidative effects and negative protein interactions. Oxidative stress is thought to play a major role in the HD disease mechanism. (For more information about the role of oxidative stress in HD mechanisms, click here.) Furthermore, it has also been reported that homocysteine can act as a partial activator of NMDA receptors. In HD, nerve cells in the striatum that express NMDA receptors are known to be the most susceptible to damage and the first to degenerate. Extra activation of NMDA receptors due to high levels of homocysteine could make excitotoxic cell damage easier and more severe. (For more information about the role of excitotoxicity in HD, click here.) Having high overall levels of homocysteine may not cause HD, but it seems to contribute to the progression of the disease.
Homocysteine is formed during the metabolism of methionine in the methionine cycle. It is processed and turned into other molecules through two different pathways: trans-sulfuration and re-methylation.
- Some homocysteine is converted to cysteine via the trans-sulfuration pathway. This pathway leads to the degradation of homocysteine and its removal from the body through urine. The trans-sulfuration pathway is composed of two reactions. Cysteine, the product of these two reactions, is a precursor to glutathione. Glutathione is a molecule that is very important in preventing oxidative damage to cells.
- The second pathway for homocysteine metabolism is called re-methylation. The process of re-methylation simply adds a methyl group (a carbon atom with three hydrogen atoms attached) to the sulfur atom of the homocysteine molecule, thereby modifying its overall structure and function. In this case, the addition of a methyl group changes the homocysteine molecule into a molecule called methionine. The addition of the methyl group is dependent on two enzymes (enzymes are proteins that that help chemical reactions to take place). One of the enzymes, called methyltetrahydrofolate (methylTHF), depends on folic acid because it is formed during the folic acid cycle.
All of this might sound very complicated, so let’s review what we just learned. Folic acid helps to keep homocysteine levels low by aiding one of the two processing pathways. High homocysteine levels are associated with many health problems and may contribute to the progression of HD; consequently, it is important to keep homocystein levels low. In the first processing pathway, homocysteine becomes cysteine, which can become glutathione. The first pathway is important to people with HD because glutathione can help protect against oxidative damage. So, breaking down harmful homocysteine into helpful glutathione is a positive effect of the first pathway. In the second processing pathway, homocysteine becomes methionine, whose creation depends on an enzyme that needs folic acid. By having enough folic acid in the body, we can ensure that homocysteine levels will be kept low, so that the homocysteine does not have significant damaging effects.
Why is the re-methylation of homocysteine important?^
The second pathway of homocysteine processing, the one influenced by folic acid, is called re-methylation. It is important for two reasons. The first reason is that it helps to lower total homocysteine levels. The second, perhaps more significant reason it is important is that the molecule formed by re-methylation is used to form another molecule called S-Adenosylmethionine (SAM). SAM is used to methylate (to methylate is to add a group of atoms called a methyl group) DNA, RNA, proteins, and other important molecules.
What does methylation do? Methylation of DNA is a major biological control of gene expression. While it is usually associated with gene silencing, methylation can also activate genes in some instances. In other words, methylation systems are absolutely essential for proper cell function because they are such important controls over how genes are used by cells. Also, methylation of proteins can change how the protein functions. (For more information on methylation, click here.) The re-methylation pathway of homocysteine processing is therefore also necessary because it results in products needed for regulation of gene expression and normal cell function.
- It reduces the total amount of homocysteine available to cause problems like oxidative stress, inflammation, and increased sensitivity to excitotoxicity.
- It results in products that cells need to control gene expression and function properly.
Folic Acid and HD^
By lowering total homocysteine levels, folic acid may also lower the oxidative damage that some forms of homocysteine can cause to nerve cells. Lowering homocysteine levels could also lower the risk for homocysteine-mediated apoptosis (programmed cell death) and for excitotoxic cell death (because homocysteine is a partial activator of NMDA receptors). In addition to these possible direct benefits, lowering homocysteine levels also has cardiovascular benefits that result from fewer negative protein interactions, less oxidative damage, and reduced inflammation throughout the body. Increasing cardiovascular health also increases blood flow to the brain, where it is important for the maintenance of nerve cell health and function. The cardiovascular benefits of lower homocysteine levels could be especially important for people with HD; cardiovascular disease, along with pneumonia, is a leading cause of death among people with HD. Although there is still a lack of definitive knowledge regarding the complete interactions of folic acid, homocysteine, and neuroprotection in the brain, research is ongoing.
How can I increase my folate intake?^
Your body treats folate and folic acid as if they are the same molecule. Folate is found naturally, while folic acid is man-made, however both work just the same. Folic acid can be taken as a dietary supplement in the form of a pill. Folate is perhaps best found in a nutritionally well-balanced diet. Folate is naturally found in leafy green vegetable like spinach and turnip greens, as well as in fruits, dried beans, and peas. The Food and Drug Administration (FDA) requires that folic acid be added to cereals, enriched bread, flour, pasta, and other grain products. Studies have shown that a folate rich diet is as effective as folic acid supplements at reducing blood plasma homocysteine concentrations. (To see a table of common foods and the amounts of folate they contain, click here).
What is the right amount of folate?^
The recommended daily allowance for folate intake in adults is 400 mcg. Pregnant women require more folate. Individual requirements may vary from person to person, so it is a good idea to talk with your doctor before taking any supplements.
What are the possible side effects and risks associated with supplemental folic acid?^
The Office of Dietary Supplements rates the health risk of folic acid as “low.” (To read the informative ODS fact sheet on folic acid click here). Because it is a water-soluble vitamin excess folic acid simply leaves the body through urine. However, folic acid may react with some anticonvulsant drugs. Even though it is low risk, it is still important to check with your doctor before taking folic acid supplements.
What other lifestyle factors influence homocysteine levels?^
Homeocysteine levels are generally lower in women than in men, and they tend to increase with age in both genders. Certain drugs can influence homocysteine levels by interfering with absorption of co-factors or increasing the breakdown of vitamins necessary for homocysteine processing. Smoking, high alcohol intake, and high coffee intake also increase the breakdown and decrease the absorption of vitamins. High homocysteine levels are also associated with obesity, lack of physical exercise, and stress. Certain enzyme defects can impair homocysteine metabolism and lead to high total homocysteine levels. Homocysteine levels can be minimized and managed through a combination of folic acid intake and healthy lifestyle choices.
What have studies shown regarding homocysteine and folic acid?^
Many studies have found correlations between high homocysteine levels and an increased risk for cardiovascular disease and mental decline. (It is important to keep in mind the difference between correlation and causation: correlational studies do not prove that a factor causes a condition; correlation simply shows that the two are associated with each other.) High homocysteine levels have also been correlated with an increased risk for Alzheimer’s disease. While it is known that folate/folic acid, along with other B vitamins, positively influences the processing of homocysteine, and that total homocysteine levels with can be lowered with folic acid supplementation, some controversy remains over the effects of folic acid with regard to influence over mental function. A recent study that showed improved memory function and slowed decline in muscle skills and information processing in older adults who were provided with supplemental folic acid takes a step toward resolving this debate and provides encouraging results. Research is still ongoing in this area. With many long-term experiments running around the world, more definitive evidence should be available in the near future.
Research on homocysteine and folic acid^
Kruman et al. (2000) found that homocysteine induces apoptosis (programmed cell death) in the nerve cells of the hippocampus (a specific region of the brain involved in memory) in rats. Homocysteine causes the cells to die by activating a DNA repair enzyme called Poly-ADP-Ribose Polymerase (PARP). The activation of too much PARP uses up the energy of the cell, which results in cell death. Exposure of rat nerve cells to homocysteine led to significant activation of PARP, which in turn led to apoptosis. An inhibitor of PARP protected cells exposed to homocysteine, showing that PARP is indeed involved in the homocysteine mediated cell damage mechanism.
This study also found that levels of free radicals in the mitochondria increased after exposure to homocysteine, implicating another disease mechanism proposed to act in HD. Moreover, homocysteine was also found to sensitize nerve cells to oxidative damage and increase vulnerability to excitotoxic insult from glutamate. (For more information on glutamate’s role in HD, click here.)
While these experiments were conducted using a specific kind of rat nerve cell, homocysteine may also have similar effects in other nerve cells. It has been previously shown that homocysteine is rapidly taken up by other types of nerve cells through a specific membrane transporter. The study concludes by suggesting that dietary folic acid intake could have some helpful effects in combating neurodegenerative disorders because of its ability to regulate homocysteine metabolism.
DiFrancisco-Donoghue et al. (2012) studied the effects of B vitamins on homocysteine levels in patients with Parkinson’s disease. The researchers found that participants who took vitamins B6, B12, and folic acid (5 mg/day) daily for 6 weeks had lower homocysteine levels than a control group.
Kruman et al. (2005) showed that dietary folate deficiency dramatically increases homocysteine levels in mice and inhibits proliferation of neuroprogenitor cells in the adult mouse hippocampus. There is evidence that these neuroprogenitor cells can, under normal conditions, be mobilized to repair damage by replacing nerve cells that have died, even in the adult brain. High homocysteine levels could contribute to neurodegeneration through blocking this repair mechanism.
Andrich et al. (2003) compared total homocysteine (tHcy) levels of both previously treated and untreated people with HD. They found that treated HD patients had significantly higher homocysteine levels than both the untreated group and the control group of people without HD. Treated patients also had, on average, more advanced HD, as indicated by higher scores on the Unified Huntington’s Disease Rating Scale (UHDRS). The difference between the homocysteine levels of people with HD who had been previously treated and those with HD who had not been treated was not due to the effects of drug treatments. The authors therefore hypothesized that total homocysteine levels could be a biomarker for neurodegeneration and that homocysteine might have a pathological role in neurodegeneration. Monitoring total homocysteine levels and using folic acid supplements to keep them low could be particularly helpful for people with HD. Because long-term studies have not yet been performed, it is not yet possible to say for certain if folic acid supplements can help slow neurodegeneration in HD through lowering homocysteine levels.
What is the final word on folic acid supplements, homocysteine levels and their impacts on HD?^
Current research indicates that increased dietary folic acid intake, along with the elimination of unhealthy lifestyle practices, will lower homocysteine levels and is probably effective as a pre-emptive treatment to help prevent damage to nerve cells in the brain and to the cardiovascular system. Keep in mind that it is almost always easier to prevent damage from occurring in the first place than it is to repair the damage that has already been done. While researchers currently do not know just how effective folic acid supplements are at preventing neurodegeneration, a large and constantly growing body of research data looks encouraging. The improvement in memory with folic acid supplements found by a recent study among healthy elderly people suggests that folic acid supplements might have benefits that are even greater than simply preventing damage.
For further reading^
This website covers many topics related to homocysteine in depth and in a way that is clear and easy to understand.
- Andrich et al. “Hyperhomocysteinaemia in treated patients with Huntington’s disease homocysteine in HD.” Movement Disorders. 2004 Feb. 19(2):226-228.
A short, straightforward presentation of the data and findings showing that treated HD patients have higher tHcy levels than both a control group without the HD allele and people with the HD allele but who have not been treated (and as a group have lower ratings on the UHDRS than the treated patients).
- Kruman et al. “Homocysteine Elicits a DNA Damage Response in Neurons That Promotes Apoptosis and Hypersensitivity to Excitotoxicity.” The Journal of Neuroscience. 2000 Sept. 20(18):6920-6926.
This technical paper describes the finding that homocysteine induces apoptosis in hippocampal rat nerve cells, sensitizes nerve cells to oxidative and excitotoxic injury, and activates PARP.
- Kruman et al. “Folate deficiency inhibits proliferation of adult hippocampal progenitors.” Neuroreport. 2005 Jul 13;16(10):1055-1059.
This technical but concise paper reports that adult mice with a folate deficient diet had significantly higher blood tHcy levels and significantly inhibited proliferation of neuroprogenitor cells in the hippocampus.
-M. Morici, 8-30-05
-Updated A. Zhang, 1-23-12More
Update: a 2010 study of Minocycline, called DOMINO, concluded that minocycline does not warrant further study for the treatment of HD. 114 patients who had mild to moderate HD were treated with either 200 mg of minocycline or a placebo every day for 18 months. The study measured patient’s improvement in the Total Functional Capacity (TFC), a test that measures an HD patient’s ability to function in day-to-day life. The conclusion – that minocycline is not worth studying further – is unfortunate, but clears up resources for the study of other drugs.
DOMINO was a futility study, which is a small trial that is designed to show whether a drug is worth the expense of a full clinical trial. The standards for a futility study are low; the study only needs to show that there is a reasonable chance that the drug is more effective than a placebo. The scientists performing the study attempted to show that minocycline could be 25% better than placebo – a modest goal – but concluded that there is only a small chance that minocycline can reach even that threshold. Therefore, minocycline is unlikely to be considered for further trials. For more information, click here.
The study: Huntington Study Group DOMINO Investigators. A futility study of minocycline in Huntington’s disease. Mov Disord. 2010 Oct 15;25(13):2219-24.
Drug Summary: Studies have discovered that minocycline is able to inhibit the activation of cells involved in inflammation as well as decrease the production of free radicals. Because long-term inflammation as well as increased free radical production are believed to contribute to the progression of HD, minocycline treatment may aid in delaying HD progression.
Minocycline and Inflammation^
Minocycline, an antibiotic commonly used to treat acne and some forms of arthritis, has been found to delay disease progression and mortality in mice with Huntington’s disease (HD). Minocycline is able to cross the blood-brain barrier and exhibit anti-inflammatory effects. The blood-brain barrier is a group of cells that form a special, selectively permeable lining in the blood vessels of the brain. This lining serves to prevent toxic substances in the blood from entering the brain.
The anti-inflammatory effects of minocycline include inhibition of microglial activation. Microglia are cells found in the brain that are involved in the immune response. By inhibiting the activation of microglia, minocycline inhibits inflammation. (For more on microglia cells and HD, click here)
Minocycline and Free Radical Formation^
In addition, minocycline has been found to decrease free radical formation. Free radicals are very reactive molecules that are capable of inducing various biological damage. Studies have reported that free radicals play a role in the progression of HD. Minocycline decreases free radical formation by inhibiting the production of inducible nitric oxide synthetase (iNOS), an enzyme responsible for the formation of nitric oxide (NO), which acts as a free radical in the cell. Increased iNOS activity is present in activated glial cells of the HD brain. As iNOS activity increases, more nitric oxide molecules are produced, resulting in greater damage from free radicals. Figure 1 shows an illustration of how minocycline decreases free radical production.
Minocycline and Protein Aggregation^
Minocycline also inhibits the production of caspases, a family of enzymes involved in HD progression. Evidence suggests that caspases are important mediators of inflammation and apoptosis. Caspases are activated in the brains of humans with HD and certain mouse models of HD. Once activated, caspases cleave the altered huntingtin protein. Studies have shown that the cleaved huntingtin fragments easily aggregate to form aggregations called neuronal inclusions (NIs) that are toxic to the cell.
Caspases are also required for the processing of mature Interleukin-1 (IL-1), one of the cytokines involved in the inflammatory response. Cytokines are one of the “weapons” by which the immune system removes and kills foreign substances. Mature cytokines such as IL-1 then go on to initiate various pathways that further increase cellular damage. By inhibiting caspases, minocycline could potentially decrease formation of neuronal inclusions as well as inflammation in the brain.
Because inflammation, free radicals, and neuronal inclusions are all believed to contribute to the progression of HD, it is possible that minocycline may work on these various pathways and decrease or delay nerve cell death in people with HD. The success of minocycline as a treatment for HD in animal models has not yet been applied to clinical trials on humans, but pilot studies to test the safety/tolerability and efficacy of minocycline in patients with early HD are currently underway.
Research on Minocycline^
Chen, et al. (2000) investigated the overall effects of minocycline on HD progression. They hypothesized that minocycline should act on the various disease mechanisms associated with HD and cause a delay or improvement in the condition of treated mice.
To assess the efficacy of minocycline, the researchers looked at changes in motor performance, survival rates, and amount of huntingtin fragments and neuronal inclusions.
The investigators gave injections of minocycline to 6-week old mice that expressed the symptoms of HD. At 6 weeks of age, the mice were in the early stages of HD and showed some of the pathological characteristics associated with HD, such as NI formation and declined motor performance. The researchers found that minocycline significantly delayed the decline in motor performance. Furthermore, the treated mice lived 14% longer than untreated mice. This extended period of survival is roughly equivalent to one to five years in people with HD.
As a means of comparison with minocycline, the researchers also injected tetracycline to another group of mice. Tetracycline is a drug similar in effects to HD but is not known to cross the blood-brain barrier. Mice treated with tetracycline showed no improvements in performance or survival.
Minocycline-treated mice were also found to have significantly lower levels of the huntingtin fragments. However, minocycline did not inhibit formation of neuronal inclusions (NIs) despite the fact that lower levels of huntingtin fragments are present in the brains of minocycline-treated mice. (For more on neuronal inclusions, click here)
These results indicate that minocycline-mediated neuroprotection is not related to the effect that NIs have on the disease. The researchers believe that NI formation is dependent on caspase activation only during the initial stages of huntingtin aggregation. Specifically, the cleavage of the full-length huntingtin may be the caspase-dependent step. Once cleavage occurs, aggregation of the fragments and consequent formation of NIs follows.
Once NIs begin to form, their growth is no longer dependent on caspase activity since the formation of aggregates no longer require caspase cleavage. In short, caspases produce the fragments needed to form NIs but are not needed in the aggregation process of these fragments. NIs have been detected in HD mice as early as three weeks of age. The minocycline administered in this study probably did not inhibit NI formation because it was administered when the mice were already six weeks old. At that time, the early caspase-dependent step was likely to have passed and aggregates were already able to form without the need for caspase-activity.
Minocycline treatment also resulted in a 72% inhibition of iNOS activity in brains of HD mice when compared to untreated HD mice. These results indicate that neuroprotection from minocycline treatment results in part from inhibition of iNOS activity, which leads to decreased free-radical damage.
Researchers are not exactly sure how caspases are activated or inhibited. They do know that caspases are not always present in the cells and are produced only during specific times such as inflammation or apoptosis. Beginning in the early stages of HD, the altered huntingtin induces caspase production and activation, resulting in mature IL-1 production and huntingtin cleavage. As activated caspases play a role in HD progression, an effective therapeutic intervention would require inhibition of these various caspases.
Minocycline has been shown to inhibit caspase production, though the mechanism by which inhibition occurs is still not known. Minocycline also inhibits the formation of nitric oxide, making it an important neuroprotective compound. Few side effects have been reported by people treated with minocycline, as it is a fairly safe and common antibiotic used to treat diseases such as acne and arthritis. With the results of this study and its low toxicity, minocycline represents a new potential therapeutic agent for HD treatment.
Tikka, et al. (2001) studied the effects of minocycline on microglial proliferation due to NMDA receptor activation. (For more on NMDA receptors, click here.) The researchers hypothesized that minocycline treatment to cells exposed to excitatory molecules such as NMDA can protect nerve cells from death.
NMDA receptors are activated by various excitatory molecules such as NMDA and glutamate. Activation of these receptors leads to entry of calcium ions (Ca2+) into the cell. Ca2+ entry then activates various calcium-dependent proteins and molecules that can initiate activities promoting cell death. The researchers believe that NMDA receptor activation also leads to microglial proliferation and activation of the inflammatory response. In the rat brain, the microglia cells are known to have various NMDA receptors on their surfaces, explaining why increased glutamate levels trigger microglial proliferation and activation. Increased glutamate levels or NMDA activation (as known to happen in HD cells) can therefore induce microglial proliferation and activation.
Minocyline, a compound known to decrease the activation of microglia, was used to study whether it will have any beneficial effects on cells exposed to NMDA. To test the efficacy of minocycline, the researchers looked at the amount of activated microglia and the survival rates of nerve cells.
The researchers exposed a group of nerve cells to NMDA. They then added minocycline to one group of nerve cells while left another group untreated. Following NMDA administration, the researchers saw an increase in microglial proliferation, followed by an increase in nerve cell loss. These changes were also associated with increased release of cytokines and nitric oxide free radicals. Minocycline administration was found to reduce microglial proliferation and nerve cell loss.
The researchers also discovered that increased microglial activation enhances the neurotoxicity of NMDA. They believe that the enhanced toxicity arose due to the increased release of cytokines and free radicals from the activated microglia. Increased cytokine production has been known to result in delayed removal of glutamate molecules, enhancing NMDA receptor activation.
One way by which the researchers believe that minocycline was able to reduce nerve cell loss was by its ability to inhibit caspases. Because caspases are needed for the maturation of certain cytokines, inhibiting the caspases could have decreased damage due to the cytokines. Decreased production of the mature cytokines would have enabled the normal removal of glutamate and excitatory molecules, thereby decreasing NMDA receptor activation. However, the researchers are still uncertain as to how minocycline was able to reduce the proliferation of microglia.
In conclusion, the study showed that minocycline treatment results in the inhibition of microglial activation and decreased release of cytokines and certain free radicals. Minocycline may therefore be beneficial to people with diseases such as HD that involve toxicity due to excitatory molecules, although more research is needed.
For further reading^
- Chen, et al. “Minocycline Inhibits Caspase-1 and Caspase-3 Expression and Delays Mortality in a Transgenic Mouse Model of Huntington Disease.” Nature Medicine. 2000; 6:797-801.
This study reported that minocycline was able to reduce huntingtin fragments and nitric oxide formation, but had no effect on neuronal inclusion formation.
- Tikka, et al. “Minocycline Provides Neuroprotection Against N-Methyl-D-aspartate Neurotoxicity by Inhibiting Microglia.” The Journal of Immunology. 2001; 166: 7527-7533.
This study reported that minocycline treatment is associated with reduced inflammation and nerve cell loss due to NMDA activation.
-P. Chang, 5/6/03, updated by M. Hedlin on 6/29/11More
Drug Summary: Omega-3 fatty acids are a form of fatty acids that our body derives from food. Studies have discovered that omega-3 fatty acids have anti-inflammatory effects due to their ability to convert into anti-inflammatory prostaglandins. In addition, omega-3 fatty acids can decrease the production of inflammatory prostaglandins, resulting in a greater decrease in inflammation.
What Are Omega-3 Fatty Acids?^
Omega-3 fatty acids are essential fatty acids necessary for human health. There are two families of essential fatty acids: Omega-3 fatty acids and Omega-6 fatty acids. They are termed “essential” because they cannot be produced by the body, and must therefore be obtained from the diet.
Both omega-6 and omega-3 fatty acids are stored in the cell membranes of tissues and have two primary functions. First, they are structural components of cell membranes where they ensure fluidity, stability, and act as gate-keepers in the cell. Second, both omega-6 and omega-3 fatty acids are converted into a number of important, active molecules called prostaglandins. There are three types of prostaglandins: PG1, PG2, and PG3.
PG1 have many beneficial effects, including reducing inflammation, inhibiting blood clotting, and maintaining various regulatory states in the body. The strong anti-inflammatory properties help the body recover from injury by reducing pain, swelling and redness.
PG2 have the opposite effects of PG1. They have been found to strongly increase inflammation, constrict blood vessels, and encourage blood clotting. These properties come into play when the body suffers a wound or injury, for without these prostaglandins, a person could bleed to death from the slightest of cuts. However, in excess, these prostaglandins may be harmful.
PG3 have a mixture of functions in the body. In general, they are important in protecting the body from various modes of injury. One of their most important functions however, is their role in decreasing the rate at which PG2 are formed. Because of their role in reducing inflammation caused by PG2, PG3 are often described as having anti-inflammatory properties.
In people with HD, inhibition of PG2 is desirable due to the role of inflammation in the progression of the disease. Studies have found that high omega-3 intake can decrease the production of PG2. To understand how omega-3 inhibits inflammation due to PG2, we need to go over the pathways by which the omega-3 and omega-6 fatty acids are processed in the body.
Essential Fatty Acids Pathways^
Although most omega-3 and omega-6 fatty acids are generally referred to as “essential” fatty acids, only linoleic acid (LA) of the omega-6 family and alpha-linolenic acid (ALA) of the omega-3 family are truly “essential”. Once we have either LA or ALA, our body has enzymes that can convert these fatty acids into all the other different types of omega-6 and omega-3 fatty acids.
It turns out that both the omega-3 and omega-6 pathway utilize the same enzymes, and both omega-6 and omega-3 fatty acids have to compete for these enzymes in order to produce their final product. Studies have reported that the enzymes used in these pathways were found to prefer the omega-3 pathway. It turns out then that in diets high in omega-3 fatty acids, most of the enzymes will be “busy” converting the omega-3 acids.
The omega-6 fatty acids, Dihommogamma-Linoleic Acid (DGLA) in particular, can be converted to either the anti-inflammatory PG1 or into arachidonic acid (AA), a precursor of PG2. Conversion of DGLA into PG1 does not require any enzymes, but conversion of DGLA into AA requires the enzyme delta-5 desaturase. In diets high in omega-3, most of the delta-5 desaturase will be used in the omega-3 pathway; few delta-5 desaturase will be available to convert DGLA into arachidonic acid, and subsequently, PG2. DGLA ends up being converted into the anti-inflammatory PG1 and inflammation is therefore decreased.
In a diet low in omega-3 fatty acids, large quantities of delta-5 desaturase enzymes are available to convert DGLA into AA. The available AA is then converted into the inflammatory PG2. Thus, the more omega-3 fatty acids present in our body, the fewer enzymes are available for converting omega-6 fatty acids into the inflammatory prostaglandins. A balance of omega-6 and omega-3 fatty acids is therefore essential for proper health. However, the typical Western diet has evolved to be high in omega-6 and low in omega-3 fatty acids. While omega-6 fatty acids are not necessarily bad, a skewed ratio in favor of too much omega-6 can be detrimental to one’s health.
One last note about essential fatty acids concerns their relationship with vitamin E. Some studies have reported that there is a significant correlation between vitamin E and omega-3 fatty acid supplementation. Findings suggest that an inadequate intake of vitamin E results in a decreased absorption of omega-3. Hence, some experts suggest that vitamin E supplementation may be helpful in conjunction with omega-3 supplementation. (Wander, et al.)
Effects on HD^
Omega-3 fatty acids may be relevant to the treatment of people with HD due to the fact that inflammation is believed to play a role in HD progression. By increasing the amounts of omega-3 fatty acids in the diets of people with HD, the rate of inflammation may decrease, and disease progression could possibly be delayed.
The drug LAX-101, produced by Amarin Corp., is a purified form of eicosapentaenoic acid (EPA). This drug has shown positive preliminary results in a phase III clinical trial, and is currently undergoing additional phase III clinical trials to further determine its efficacy. For more information on LAX-101, click here.
Research on Omega-3 Fatty Acids^
Katsumata, et al. (1999) investigated whether the delayed administration of the omega-3 fatty acid eicosapentaenoic acid (EPA) has a favorable effect on blood flow and metabolism in the brains of rats suffering from cell death due to an interruption in blood flow. The researchers hypothesized that omega-3 fatty acids may improve blood flow, and consequently, metabolism in cells.
Previous studies have reported that long-term treatment of EPA improved an age-related reduction in blood flow in the brain and increased glucose metabolism. Other studies have also reported that pre-treatment with EPA contributed to reduced brain damage and improved metabolism in rats whose blood flow to their brains have been interrupted. The researchers then wondered whether EPA treatment after the attack would have similar beneficial results.
Blood flow to the nerve cells of adult male rats were interrupted for 2 hours through surgery. After the interruption, the rats were divided into two groups. One group was treated with 100 mg/kg of body weight of EPA while another group was left untreated. After four weeks, blood flow, glucose metabolism, and brain lesion size was measured.
The researchers found no difference in lesion size between the group treated with EPA and the group that received no treatment. The delayed treatment was not effective in decreasing the number of shrunken neurons typically found in brains that have been subjected to inadequate blood flow for quite some time. However, EPA treatment was able to increase glucose utilization, suggesting possible improvement of energy metabolism.
Xiao, et al. (1999) studied the effects of omega-3 fatty acids on membrane excitability and stability. The researchers hypothesized that omega-3 fatty acids may reduce membrane excitability caused by exposure to excitatory amino acids such as glutamate. (For more on glutamate, click here.)
To test the role of omega-3 fatty acids in regulating membrane excitability, the researchers first exposed the cells to glutamate. The frequency of nerve impulses significantly increased after exposure to glutamate.
Treatment with the omega-3 fatty acid eicosapentaenoic acid (EPA), decreased the frequency of nerve impulses. The frequency returned to pretreatment levels after EPA was washed out of the cells. In addition, EPA was found to raise the threshold of nerve impulses in the nerve cells. The raised threshold meant that cells had to be subjected to more glutamate molecules before they became excited and transmitted nerve impulses.
The researchers have proposed a variety of hypotheses on how omega-3 fatty acids decrease the toxic effects of glutamate.
One hypothesis is that omega-3 fatty acids may have a suppressive effect on ion channels involved in cell death. Omega-3 fatty acids may reduce membrane excitability by blocking ion channels that are responsible for nerve cell excitation. Excessive excitatory activity due to glutamate increases overall intracellular calcium ion (Ca2+) concentrations. Increased Ca2+ concentration results in the activation of Ca2+ dependent proteins and molecules that contribute to cell death. However, the mechanisms by which omega-3 fatty acids block these ion channels are not yet known.
Another hypothesis is that omega-3 fatty acids could also be acting to stabilize cell membranes by inhibiting the release of arachidonic acid (AA) from cell membranes. Aside from its anti-inflammatory effects, PG3 synthesized from omega-3 fatty acids also inhibit the release of free AA from the cell membrane. Inhibition of AA release from cell membranes may stabilize the cell and protect it from damage.
Overactivation of glutamate receptors has been implicated in the pathology of HD nerve cells. The increased glutamate activation is thought to contribute to nerve cell death through a variety of mechanisms. By decreasing membrane excitabilty, the omega-3 fatty acids may therefore protect the brain from damage caused by excitotoxins such as glutamate.
For further reading^
- Katsumata, et al. “Delayed Administration of Ethyl Eicosapentate Improves Local Cerebral Blood Flow and Metabolism Without Affecting Infarct Volumes in the Rat Focal ischemic Model.” European Journal of Pharmacology. 1998; 372: 187-74.
This study investigated the effects of EPA on blood flow and glucose metabolism.
- Xiao, et al. “Polyunsaturated Fatty Acids Modify Mouse Hippocampal Neuronal Excitability During Excitotoxic or Convulsant Stimulation.” Brain Research. 1999; 846: 112-21.
This study investigated the effects of EPA on nerve cell excitation caused by glutamate.
- Hughes, et al. “n-3 Polyunsaturated Fatty Acids Inhibit the Antigen-presenting Function of Human Monocytes.” The American Journal of Clinical Nutrition. 2000; 71(1): 357S-360S.
This study investigated the effects of EPA on the expression of MHC II molecules.
- James, et al. “Dietary Polyunsaturated Fatty Acids and Inflammatory Mediator Production.” The American Journal of Clinical Nutrition. 2000; 71(1): 343S-348S.
This article contains details on the relationship between essential fatty acids and mediators of the inflammatory response.
- Wander RC, et al. “The ratio of Dietary (n-6) to (n-3) Fatty Acids Influences Immune System Function, Eicosanoid Metabolism, Lipid Peroxidation and Vitamin E Status in Aged Dogs.” Journal of Nutrition. 1997; 127: 1198-1205.
This study investigated the relationship between essential fatty acids and Vitamin E.
- Omega-3 and Omega-6 pathways available online at: http://www.asthmaworld.org/OMEGA3.htm#Cyclo-oxygenase%20and%20oxygenase%20conversion%20of%20EPA
This page contains detailed, easy-to-understand information on the Omega-3 and Omega-6 Pathways. A must-read for those interested in the essential fatty acids and the reactions involved in their transformation.
- Fats for health.com: http://www.fatsforhealth.com/library/libitems/ancestors.php3
This page contains information on the effects of essential fatty acids on the body.
-E. Tan, 6/15/02; Revised and Updated by P. Chang, 5/6/03More
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^
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 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 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 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^
- 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.
- 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.
- 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 10/7/11More
Drug Summary: Glucocorticoids are powerful anti-inflammatory compounds that have the ability to inhibit all stages of the inflammatory response. Common glucocorticoids include prednisone, dexamethasone, and hydrocortisone. While glucocorticoids are widely used as drugs to treat various inflammatory conditions, prolonged glucocorticoid use may have adverse side effects such as immunosuppression, fluid shifts, brain changes, and psychological changes. Physicians are therefore very cautious about prescribing these medications, especially for long periods of time.
What are glucocorticoids?^
Natural glucocorticoids are steroid hormones with powerful anti-inflammatory effects produced by the human body. Glucocorticoid drugs are usually synthetic compounds that have anti-inflammatory effects similar to those of natural glucocorticoids.
Natural glucocorticoids are produced by the cortex of the adrenal gland. The adrenal glands are organs located immediately above our kidneys (ad = top of, renal = kidney). They are divided into two distinct regions:
- The adrenal medulla comprises the inner portion of the adrenal gland. It is the source of the body’s stress hormones: norepinephrine (noradrenaline) and epinephrine (adrenaline).
- The adrenal cortex comprises the outer portion of the adrenal gland. It secretes several types of steroid hormones collectively known as corticosteroids. There are two main types of corticosteroids: mineralcorticoids and glucocorticoids. Mineralcorticoids like aldosterone are responsible for the maintenance of salt and fluid balance in the body. Glucocorticoids like cortisol and cortisone affect metabolism and inhibit inflammation.
Drugs with glucocorticoid activity are compounds that have similar effects to the natural steroid hormones produced by the adrenal cortex. While glucocorticoid drugs are steroids, they are unlike the anabolic steroids that some athletes take to build up and increase their muscle mass. Glucocorticoids are catabolic steroids, which means that they are designed to break down the body’s stored resources through their various metabolic effects. As stated above, glucocorticoids have two principal effects in the body: metabolic and anti-inflammatory. It therefore follows that glucocorticoid drugs affect both metabolism and inflammation.
The name “glucocorticoid” derives from early observations that these hormones were involved in glucose (sugar) metabolism. During times when no food is being taken into the body, glucocorticoids stimulate several processes that serve to increase and maintain normal glucose concentrations in the blood. These processes include:
- Stimulation of glucose production in cells, particularly in the liver.
- Stimulation of fat breakdown in adipose (fat) tissues.
- Inhibition of glucose and fat storage in cells.
Glucocorticoids (both naturally produced and synthetic) are powerful anti-inflammatory compounds due to their ability to inhibit all stages of the inflammatory response, from redness to wound healing to cell proliferation. (For more on the relationship between inflammation and HD, click here). They affect all types of inflammatory responses, regardless of the mode of injury or type of disease-causing substance.
Glucocorticoids are steroid hormones, which can cross the cell membrane. Most of their effects involve interactions with intracellular receptors (receptors inside the cell). They bind to these receptors, and the hormone-receptor complex then enters the nucleus and acts as a transcription factor.
Transcription is the set of processes in the nucleus by which the base sequence “code” of DNA is converted to a sequence of complementary bases in mRNA. (For more on DNA, complementary and nitrogenous bases, click here.) Once mRNA is formed from transcription, it is transported into the cytoplasm where it is used as to help in the construction of a protein molecule. The process by which the protein molecule is formed from the mRNA blueprint is called translation.
Glucocorticoids bind to glucocorticoid receptors (GR) inside the cell and form a glucocorticoid-GR complex. This complex enters the nucleus and causes changes that alter the synthesis of mRNA from the DNA molecule, thereby altering the production of different proteins. Glucocorticoids can cause an increase in the production of certain proteins and a decrease in the production of other proteins by binding to key sites in the gene and enhancing or suppressing their transcription into mRNA. Glucocorticoids have also been found to cause changes in the mRNA molecule itself. Modifications to the mRNA can further alter the production of proteins in the cell.
Studies have shown that glucocorticoids can suppress the production of proteins involved in inflammation (resulting in their role as anti-inflammatory compounds). Aside from interfering with the transcription of enzymes involved in inflammation, glucocorticoids further suppress inflammation by activating a group of enzymes known as lipocortins. Lipocortins have been found to inhibit or slow the action of phospholipase A2 (PLA2), a key enzyme involved in the release of arachidonic acid (AA) from the cell membrane.
Arachidonic acids are a type of omega-6 fatty acid. The omega-6 fatty acids in our body often come from the vegetable oils and animal meats in our food. Once arachidonic acid is in our body, it is usually incorporated into our cell membranes. When a cell is damaged or under attack by foreign substances, arachidonic acid is released from the cell membrane and is converted into substances such as prostaglandins which mediate inflammation. Free arachidonic acid is converted into inflammatory prostaglandins by enzymes known as COX-2. (For more information on COX-2 enzymes, click here.)
Release of arachidonic acids require the activation of the enzyme PLA2. As stated previously, lipocortins inhibit PLA2 activity. By activating lipocortins, glucocorticoids cause the inhibition of PLA2, thereby inhibiting release of AA and consequent prostaglandin synthesis in the cell. Because lower amounts of inflammatory prostaglandins are synthesized, inflammation is suppressed and damage caused by chronic inflammation is decreased.
Problems with glucocorticoid drugs^
We have discussed how glucocorticoids can have both metabolic and anti-inflammatory effects. So far, it has been impossible to give glucocorticoid treatments that have only anti-inflammatory effects. Glucocorticoids have been found to increase blood glucose levels as well as suppress calcium absorption through their various metabolic affects. As such, long-term anti-inflammatory therapy with glucocorticoids can often lead to swelling, skin changes, decreased immunity, and psychological changes. More severe side effects such as diabetes or osteoporosis can also occur (even short-term glucocorticoid therapy tends to cause the patient to become temporarily diabetic.) Moreover, patients on long-term glucocorticoid therapy must be gradually tapered off their medications when discontinuing them in order to avoid rebound effects produced by the body.
In addition to the difficulty of separating the metabolic and anti-inflammatory effects of glucocorticoids, most synthetic drugs often referred to as glucocorticoids are actually synthetic corticosteroids. These synthetic drugs have both mineralcorticoid and glucocorticoid activity. However, in a particular compound, one type of activity will predominate over the other. Synthesis of pure glucocorticoid drugs has so far been elusive.
Commonly prescribed steroid drugs:^
- Prednisone and Prednisolone – Most commonly used glucocorticoid because of its high glucocorticoid activity. Prednisone is transformed by the liver into prednisolone. Prednisolone may be administered in tablet form or produced by the body from prednisone. These medications are often considered to be interchangeable.
- Dexamethasone – Has a particularly high glucocorticoid activity and low mineralcorticoid activity and can therefore be used in high doses. Often used to reduce nerve swelling following neurotrauma and neurosurgery.
- Hydrocortisone – Has much more mineralcorticoid activity than Prednisone and is therefore not suitable for long-term use internally. Externally, it is used extensively as a cream or lotion for skin conditions such as rashes or itches.
Newton, et al. (1998) conducted an experiment to try to explain the mechanism by which the glucocorticoid dexamethasone suppresses the production of mediators involved in inflammation. Previous studies indicate that synthetic drugs such as dexamethasone act by mimicking the natural glucocorticoid cortisol in binding to the glucocorticoid receptor (GR). The glucocorticoid-GR complex then moves to the nucleus, where it can activate transcription of anti-inflammatory genes.
This study investigated how glucocorticoids cause suppression of inflammatory mediators such as COX-2 and inflammatory prostaglandins, and proposed possible mechanisms to explain the suppressive effect of glucocorticoids and their inhibitory effects on various transcription factors.
Glucocorticoids have been found to interact with two transcription factors that help in the transcription of inflammatory genes. These factors, NF-kappa B and AP-1 are believed to interact with the GR complex. Scientists believe that the both the NF-kappa B/GR and AP-1/GR interactions result in the decreased transcription of COX-2 mRNAs.
The researchers in this study also discovered that aside from its interactions with various transcription factors, dexamethasone is capable of suppressing COX-2 production by another mechanism as well. The researchers exposed cells to molecules that induce the production of COX-2 proteins and the release of inflammatory prostaglandins. To the surprise of the researchers, they discovered that dexamethasone not only lowers the rate of COX-2 mRNA transcription by about 44%, but it also causes structural changes in the COX-2 mRNA, further lowering the amount of COX-2 enzymes produced.
Previous experiments have shown that the COX-2 mRNA is extremely stable; its slow rate of degradation enables increased production of COX-2 proteins. Dexamethasone administration causes a decrease in the amount of COX-2 mRNA by suppressing its transcription and modifying the mRNA molecule. Modification of the COX-2 mRNA destabilized it, causing it to degrade at a faster rate, which in turn, decreases the production of COX-2 proteins.
The researchers are still uncertain as to what specific changes are induced by dexamethasone to cause the modification found in the COX-2 mRNA. The results of this study indicate that glucocorticoids such as dexamethasone exert their anti-inflammatory effects through a variety of mechanisms: by interacting with transcription factors that slow COX-2 mRNA transcription and by modifying the COX-2 mRNA, destabilizing it, and increasing its rate of degradation.
Aisen, et al. (2000) hypothesized that glucocorticoid administration may have beneficial effects for people with Alzheimer’s Disease (AD). Their hypothesis was based on observations that the brains of people with AD showed increased inflammation. The researchers conducted a clinical trial to determine the usefulness of the glucocorticoid prednisone in slowing the rate of cognitive decline in people with AD.
The study enlisted 138 people with AD ages 50 or older. Half the participants were given a placebo and the other half were given prednisone. The treatment regimen consisted of an initial dose of 20 mg of prednisone daily for 4 weeks, lowered to a maintenance dose of 10 mg daily for one year, followed by a gradual tapering off of the drug for another 4 months.
Cognitive and behavioral assessments were done at specific intervals over the trial period to determine the efficacy of prednisone treatment. The researchers looked for changes over a one-year period as determined by the cognitive component of the Alzheimer’s Disease Assessment Scale (ADAS) and other tests. Safety tests were also performed to monitor how the participants tolerated the drug.
Overall, the testing showed that low-dose prednisone did not slow the rate of cognitive decline when the prednisone-treated group was compared to those taking the placebo. Participants treated with prednisone also showed greater behavioral decline than those in the placebo group.
The researchers suggested some reasons why prednisone may not have been successful in treating AD. It is possible that the dosage given may not have been sufficient to suppress the destructive brain inflammatory activity. Much higher doses are used to treat inflammatory diseases of the brain such as cerebral lupus, a chronic autoimmune disease that causes inflammation in the brain. However, higher doses may not be safe for long-term treatment, particularly in the elderly. In this study, the incidence of hyperglycemia (greater than normal levels of blood glucose) and significant decline in bone density suggest that higher doses may cause substantial side effects.
Despite the negative results, the researchers believe that the study does not refute the potential benefit of anti-inflammatory compounds as treatment for neurological diseases such as AD. Rather, the study suggests that testing of other anti-inflammatory compounds such as NSAIDs (examples include aspirin and ibuprofen) or selective COX-2 inhibitors (examples include rofecoxib and celecoxib) is critical in the search for the right combination of therapies for AD. (For more on NSAIDs and COX-2 inhibitors, click here) Both NSAIDs and COX-2 inhibitors have more limited anti-inflammatory effects in comparison to glucocorticoids and may be appropriate candidates for future trials. The study on prednisone serves as an important step in directing scientists toward what may or may not work at certain stages of AD, HD, and other neurological diseases that involve chronic inflammation.
Diamond, et al. (2000) investigated the role of glucocorticoid receptors (GR) in the aggregation of expanded polyglutamine proteins. Previous studies have shown that binding of the glucocorticoid dexamethasone to the GR receptor forms a glucocorticoid- GR complex that causes changes in the transcription of certain genes. The researchers in this study speculated that glucocorticoid may affect the transcription of certain proteins that could inhibit the aggregation of expanded polyglutamine proteins.
Studies indicate that several polyglutamine diseases, including HD, are caused by multiple C-A-G repeats within a unique gene. Other examples include spinobulbar muscular atrophy (SBMA), Huntington’s Disease (HD), dentatorubro-pallidoluysian atrophy, and several spinocerebellar ataxias (SCAs) (For more on the polyglutamine diseases, click here.)
The altered genes result in the production of altered proteins that cause selective nerve cell death within the nervous system. For example, polyglutamine expansion within the androgen receptor (AR) protein results in SBMA, a disease associated with selective death of motor nerve cells. In the case of Huntington’s disease, the altered huntington gene results in the production of an altered huntingtin protein that causes selective death of nerve cells found in the basal ganglia.
Studies indicate that the nerve cell death associated with these polyglutamine diseases may be linked to the formation of neuronal aggregates of the altered proteins. These altered proteins have been found to form aggregates called neuronal inclusions (NIs) in the nucleus of the nerve cell. (For more on NIs, click here.) Some studies have shown that reducing aggregate formation could improve conditions in animal models of the polyglutamine diseases.
The researchers in the current study attempted to discover ways on how these aggregations can be reduced. Based on the role of GRs as regulators of transcription, the researchers wondered whether they may have any role in the aggregation of polyglutamine proteins. The researchers found that the addition of dexamethasone to human kidney cells and mouse nerve cells expressing HD reduced the aggregation of the altered huntingtin protein. Similarly, dexamethasone administration to cells expressing SBMA showed decreased androgen receptor (AR) aggregation.
The results of the study indicate that aggregation of expanded polyglutamine proteins are regulated within the cell. The aggregation process can be manipulated through glucocorticoid-controlled gene expression. The researchers believe that the glucocorticoid-GR complex acts as a transcriptional regulator: in the nucleus, the complex binds to sites that can control and modulate the expression of nearby genes. It is possible that the transcriptional changes induced by the complex may result in the production of proteins that could inhibit polyglutamine aggregation. What proteins are produced is still currently unknown.
More studies need to be done to identify the genes and proteins involved in the pathways that determine polyglutamine aggregations and nerve cell dysfunction. However, the results of this study raise the possibility that glucocorticoids could reduce polyglutamine aggregations. By reducing these aggregations, glucocorticoids could play essential roles in delaying or inhibiting the progression of diseases such as HD, SBMA, and possibly other polyglutamine diseases as well.
For further reading^
- Newton, et al. “Repression of Cyclooxygenase-2 and Prostaglandin E2 Release by Dexamethasone Occurs by Transcriptional and Post-transcriptional Mechanisms Inolving Loss of Polyadenylated mRNA.” Journal of Biological Chemistry. 1998; 273(48): 32312-32321.
This study reports that the glucocorticoid dexamethasone acts to modify COX-2 mRNAs as well as regulate the transcription of some genes involved in inflammation.
- Diamond, et al. “Regulation of expanded polyglutamine protein aggregation and nuclear localization by the glucocorticoid receptor.” Proceedings of the National Academy of Sciences of the United States of America. 2000; 97(2): 657-661.
This study reports that glucocorticoids may reduce the aggregations found in polyglutamine diseases such as SBMA and HD.
- Aisen, et al. “A randomized controlled trial of prednisone in Alzheimer’s Disease.” Neurology. 2000; 54:588.
This study reports that prednisone was not effective in slowing the cognitive decline of people with AD.
- Information on immunomodulation available online at: http://www.users.dircon.co.uk/~rosebud/drugs/Immune.html
This page contains some information on the various pathways involved in the inflammatory response.
-E. Tan, 6/15/02; Revised by P. Chang, 5/7/03More