Arches. Photo by Daniel Chia
Jun
29
2010

Vitamin C

Drug summary: Vitamin C, also known as ascorbic acid, has been shown to have antioxidant properties. Research shows that in nerve cells, vitamin C has the ability to directly react with free radicals to prevent oxidative stress, which contributes to the progression of the HD disease process. (For more information on free radicals and antioxidants, click here.) Vitamin C may also have the potential to prevent toxicity caused by a neurotransmitter called glutamate. (For more information on glutamate toxicity, click here.)

What is vitamin C?^

In the 1970’s, famous Nobel Prize-winning scientist Linus Pauling advocated Vitamin C use to prevent and cure anything from the common cold to heart disease and cancer. While the recommended daily intake of vitamin C is around 60-75 mg, Pauling himself supposedly took 12,000 mg daily and increased that value to 40,000 mg if he felt a cold coming on! While most doctors and researchers have never agreed with Pauling about the wonders vitamin C could work, there is now evidence that vitamin C actually plays an important role in protecting nerve cells from oxidative damage, which may prove vitamin C supplementation to be a promising treatment for people with HD.

Vitamin C, or ascorbic acid, is a water-soluble vitamin. While most animals can make their own vitamin C, humans and a few closely related animals have lost this ability because of a mutation in their DNA that occurred earlier in their evolution. This means that we have to supply the body with small daily amounts of vitamin C through our diet. In the body, vitamins work as coenzymes, meaning that they help enzymes facilitate necessary reactions. Vitamin C’s job is to help in the reactions by which the body makes necessary molecules. One of these is collagen, which makes up connective tissue throughout the body. Another is the molecule carnitine, which shuttles fats into the mitochondria, where they are converted into energy. (For more information on how carnitine can help treat HD, click here.) Vitamin C is also necessary in the synthesis of the excitatory neurotransmitter noradrenaline (also called norepinephrine).

Vitamin C also has antioxidant properties that may prove to be helpful in treating HD. Inside the body, ascorbic acid (vitamin C) changes form to become the negatively charged ascorbate. Ascorbate can then directly neutralize very reactive free radicals by donating its own electrons to them. In this way ascorbate can protect other cell components from oxidation by free radicals. Oxidation can cause cell components to lose their ability to function normally, and excessive oxidative damage may eventually lead to nerve cell death. It has even been found that ascorbate prevents free radicals from oxidizing its fellow vitamin, vitamin E! (For more information on vitamin E, click here .)

How are ascorbate and HD related?^

In humans, there is normally a very high concentration of ascorbate in the part of the brain called the striatum. Interestingly, the striatum is the same part of the brain that is most affected by HD. (For more information about the brain and HD, click here.) Most of the ascorbate in this part of the brain exists in the extracellular fluid, or in the spaces between the nerve cells. Scientists now know that ascorbate is actually released from the nerve cells into the extracellular space during times of motor activity. Researchers recently found that in HD mice, this releasing mechanism does not work as well as it does in normal mice. This finding suggests that a decline in motor functions in HD could be tied to lowered levels of ascorbate in specific areas of the brain.

How can ascorbate protect nerve cells in HD?^

The release of ascorbate from nerve cells is actually linked to the uptake of another molecule into the nerve cells. This molecule is glutamate, an excitatory neurotransmitter that can be toxic to nerve cells. It can exert toxic effects either when it is present in large amounts or when the nerve cells are overly sensitive to it, as are nerve cells in many people with HD. Because glutamate is excitatory, it is often released by nerve cells during times of motor activity. When it is released by one nerve cell, it travels to the next nerve cell to stimulate it. (For more information on nerve cells, click here.) When glutamate has done its job as messenger, it can either be broken down or taken back up by the nerve cells that released it.

Fig K-4: Release of Ascorbate in the Brain

Researchers found that when glutamate is taken back up by the nerve cells, these cells simultaneously release ascorbate. Because glutamate release is tied to increased production of free radicals, this ascorbate release mechanism might have evolved in order to protect nerve cells. The more glutamate that is released by the nerve cell, the more is taken back up later. Because glutamate is “exchanged” with ascorbate when it goes back into the nerve cell, the cell can regulate how much ascorbate it releases based on how much glutamate was originally released. This mechanism allows the cell to release appropriate amounts of ascorbate because it can measure how much free radical production may have been stimulated by the glutamate release. But glutamate is not the only factor responsible for increasing free-radical formation during this time. When a cell is more active, it has to carry out more metabolic processes, and at a faster rate, which also increases the natural production of free radicals. Therefore, the levels of extracellular ascorbate should be highest during times of motor activity: this is a time when the cells are most likely producing increased levels of free radicals themselves and may need extra protection from glutamate toxicity.

Researchers recently found that nerve cells in the striatum of HD mice release much less ascorbate during motor activity than do the nerve cells of normal mice. Because it is also known that loss of ascorbate in the striatum can impair motor behavior, they decided to test whether injections of ascorbate could improve the motor symptoms of HD mice. They found that injections of ascorbate allowed the nerve cells of HD mice to release normal amounts of ascorbate when they were active. The researchers also found that HD mice treated with ascorbate performed better on two out of three motor tests than did untreated HD mice. These studies show that an inadequate amount of ascorbate in the striatum of HD mice may play a role in worsening their symptoms. While some studies have also shown a connection between increased vitamin C intake and decreased risk of developing Alzheimer’s disease, there are still no studies on the effect of the vitamin on people with HD. Researchers first need to find out if these animal model findings translate to humans with HD before considering ascorbate as a possible treatment.

Research on vitamin C and HD:^

Rebec, et al. (2002) discovered that the nerve cells in the striatum of HD mice release much lower quantities of ascorbate than do nerve cells of normal mice. The researchers used two groups of mice: one group was composed of HD mice, and the other was the control group (composed of normal mice). They first put both groups of mice under anesthesia so that they could place electrodes into the striatum of the brain that would measure ascorbate levels. When the mice were under anesthesia, the levels of ascorbate in the striatum were the same in both groups. As the normal mice woke up, their ascorbate levels increased and continued increasing as they became more active. As the HD mice woke up, their ascorbate levels actually decreased by up to 50% below the anesthesia level. The HD mice also went on to engage in less motor behavior and spent more time resting than the control mice. These findings suggest that the brains of HD mice are unable to release the normal amounts of ascorbate when necessary.

Rebec, et al. (2003) went on to test whether treatment with ascorbate would help alleviate motor symptoms in HD mice. This time there were four groups of mice: two groups of HD mice and two groups of normal mice; only one group of HD mice and one group of normal mice was treated with ascorbate. These groups received injections of ascorbate 4 days of the week and then were allowed 3 days of recovery. The two groups that were not treated (one of the HD mice, the other, normal mice) got injections of a placebo to control for any effects that the actual injections and handling may have had on the mice. Treatment and observation went on for three weeks and ascorbate levels in the striatum of the mice were measured twice during the study.

In order to measure the ascorbate levels, the mice were once again put under anesthesia. When they were in this state, mice in all four groups had similar levels of extracellular ascorbate. As they woke up, both groups of normal mice, whether they had been treated with ascorbate or not, showed the expected increase in ascorbate. HD mice that had not been treated with ascorbate showed the same decrease in extracellular ascorbate that had been seen in Rebec, et al.’s previous study (2002, see above). However, HD mice that had been treated showed an increase in ascorbate levels that was similar to the increase seen in both groups of normal mice. These findings are important because they show that treatment with ascorbate can help restore the ascorbate-releasing ability to active nerve cells in HD mice. They also show that treatment with ascorbate only affected the HD mice, since normal mice that were treated did not show a greater increase in ascorbate release than was expected.

Next, the behavior of the mice was observed to determine whether ascorbate treatment actually helped improve motor symptoms. The researchers used three motor tests and behaviors as their criteria. The first was the performance of a repetitive grooming movement that is a sign of nerve cell damage in the HD mice. The next was a test of motor flexibility that recorded how often the mice would choose to turn left or right instead of going straight through a maze, with more turns indicating more flexibility. The final test measured general movement in an open area. The researchers found that HD mice treated with ascorbate performed the repetitive grooming movement less often and had increased flexibility in the maze than did untreated HD mice, suggesting that ascorbate treatment is beneficial to these mice (specifically, by acting as an antioxidant in the striatum). Despite the fact that there was no significant difference between the two groups in the third overall movement test, the researchers still believe that continued study of ascorbate (and vitamin C) may be helpful in understanding more about nerve cell damage in HD.

For further reading^

  1. Rebec, et al. “Ascorbate treatment attenuates the Huntington behavioral phenotype in mice.” Neuroreport. 2003 Jul 1; 14(9): 1263-5.
    This is the original article that documents the results of ascorbate treatment in HD mice. It is very technical and meant for a scientific audience.
  2. Rebec, et al. “Dysregulation of ascorbate release in the striatum of behaving mice expressing the Huntington’s disease gene.” The Journal of Neuroscience. 2002 Jan 15; 22(2): RC202.
    This highly technical article explains the differences in ascorbate release between normal and HD mice.
  3. Rice, Margaret E. “Ascorbate regulation and its neuroprotective role in the brain.” Trends in Neuroscience. 2000 May; 23(5): 209-16.
    This is a very technical article that explains the many roles ascorbate plays in the brain as well as the mechanism by which ascorbate moves into and out of nerve cells.

A. Milczarek, 12/24/04