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

Omega-3 Fatty Acids

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 need for more glutamate molecules before excitation occurs also meant that cells treated with EPA become less sensitive to the potential toxic effects of glutamate.

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.

In conclusion, protection from omega-3 may be due to their ability to block ion channels, increase nerve impulse thresholds, and/or stabilize cell membranes.

For further reading^

  1. 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.
  2. 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.
  3. 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.
  4. 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.
  5. 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.
  6. 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.
  7. 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, 5/6/03