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.
This section will discuss the following inflammatory mediators: Free Radicals, Excitotoxins, Complement, Cytokines, Prostaglandins.
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 MAC creates a pore that allows the movement of various ions and substances into and out of the cell, resulting in cell damage.
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^
- 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, 5/6/03