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


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Update: Riluzole is no longer considered to be a promising avenue of research; it failed a phase III clinical trial in 2007. The trial ran for 3 years and included 537 adult HD patients, who were randomly assigned to either the treatment group (receiving 50 mg of riluzole twice a day) or the control group (which received a placebo instead). The 379 patients who completed the study were measured with the Unified Huntington’s Disease Rating Scale (UHDRS), a test commonly used in clinical trials to measures factors such as motor control, independence, and mental function. The scientists performing the study concluded that riluzole has no benefit for the treatment of HD, as it was not significantly better than the placebo; it does not slow the progression of HD, nor does it improve symptoms.

Previous studies found some improvement in motor control for patients who took riluzole. However, these studies were complicated by the fact that other drugs, such as antipsychotics, were taken at the same time to control chorea. Therefore, this study was careful to look at the effects of riluzole separate from all other treatments; patients who participated in the study exclusively used drugs prescribed for the study.

For more information, click here.

Drug Summary: Riluzole has been shown to have energy-buffering and anti-glutamate properties. It has been associated with increased energy metabolism efficiency and inhibition of glutamate activity, and is currently used as a treatment for Amyotrophic Lateral Sclerosis (ALS), a disease that is also hypothesized to involve glutamate toxicity. Huntington’s disease is associated with these both problems in energy metabolism and glutamate toxicity; let us discuss some of these problems and the ways in which riluzole might alleviate them.

Problem: Aerobic inefficiency^

Energy metabolism is the process by which cells produce energy. Normally, cells prefer a form of energy metabolism called aerobic respiration due to its efficiency and high-energy yield. The altered huntingtin protein in people with HD is believed to interfere with aerobic respiration, resulting in the inability of HD cells to perform aerobic respiration efficiently. Instead, HD cells must resort to anaerobic respiration, another form of energy metabolism that is less efficient. This impairment in energy metabolism results in various negative effects that eventually lead to cell death.

Studies have reported that riluzole treatment improves motor abnormalities associated with administration of a toxin that blocks energy metabolism. The improvements indicate that riluzole may have positive effects on cells with defective metabolism. However, the mechanism by which riluzole improves energy metabolism is still unknown.

Problem: Glutamate Sensitivity^

One of the effects of the impairment in energy metabolism in HD cells is an increased sensitivity to glutamate. Glutamate is one of the major neurotransmitters in the nervous system, used to transmit messages from nerve cell to another. (For more on glutamate, click here.) Increased activation of receptors that receive glutamate has been observed in people with HD. Increased glutamate activity, in turn, has been associated with nerve cell death.

Studies have demonstrated that riluzole may act as an anti-glutamate drug in two ways: 1) by inhibiting the release of glutamate and 2) by interfering with the effects of glutamate on nerve cells.

Fig L-3: Riluzole Inhibits Glutamate Release

It is thought that riluzole inhibits the release of glutamate by interfering with sodium (Na+) channels that are required for normal glutamate release. Figure L-3 shows how riluzole inhibits glutamate release.

The mechanism by which riluzole disrupts the effects of glutamate on target cells is slightly more complicated. Let us first go over what happens in a normal glutamate-receiving cell in order to understand the effects of riluzole on these cells in a patient with HD.

Various types of glutamate receptors are found in nerve cells. One type of glutamate receptor allows the entry of ions into the cell upon glutamate binding, resulting in various changes inside the cell. Among these receptors are NMDA receptors, discussed in the section HD and Glutamate. A second type of glutamate receptors causes cellular changes by initiating a messenger cascade, which involves the activation and deactivation of various molecules and pathways that can cause changes inside the nerve cell.

In a messenger cascade, the binding of glutamate is a “message” that is being sent to the nerve cell. This message is passed on from one molecule to another, until it reaches its final destination. Scientists have discovered that glutamate binding “tells” the cell to release calcium from its stores.

Fig L-4: Messenger Cascades

In HD cells, the overactivation of the glutamate receptors results in overactivation of the messenger cascades and consequently, increased calcium release. High amounts of calcium in the nerve cells are known to cause cell death, which is one possible explanation of how HD nerve cells die. Figure L-4 shows a diagram depicting the molecules involved in the messenger cascade as well as the final effects of the cascade.

Riluzole may disrupt glutamate activity by interfering with the activity of certain proteins involved in the messenger cascade. Once the cascade is inhibited, changes induced by glutamate such as calcium release and the associated cell death might eventually be delayed.

Research on Riluzole^

Bensimon, et al. (1994) hypothesized that riluzole may have beneficial effects on people with diseases such as amyotrophic lateral sclerosis (ALS) which involve overactivation of glutamate receptors. ALS is a progressive and fatal disorder affecting nerve cells. The cause of the disease is unknown, and no treatment is available that influences survival.

Many hypotheses about the cause of the disease are currently being studied. One of these hypotheses involves glutamate. Studies have reported that increased glutamate concentrations in the brain result in nerve cell death. Given this possible role of glutamate in ALS progression, the researchers sought to assess the effects of riluzole in people with ALS.

The researchers conducted a trial in 155 participants with ALS in France for one year. The participants were given either 50-mg of riluzole twice a day or a placebo. Survival and changes in ability to function were used as tests for the drug’s effectiveness. A secondary test used to examine the drug’s effectiveness was change in muscle strength.

After 12 months, 58 percent in the placebo group were still alive, compared with 74 percent in the riluzole group. The deterioration of muscle strength and functional ability was significantly slower in the riluzole group than in the placebo group.

Side effects of riluzole included stiffness, mild increase in blood pressure, and increase in the levels of the enzyme aminotransferase, which sometimes result in elevations of toxic ammonia. High levels of ammonia have been associated with brain damage, although the reason for ammonia toxicity is still unknown. While aminotransferase elevations were more frequent with riluzole treatment, the elevations were well tolerated and did not cause severe adverse effects in most of the participants in this study. More studies need to be conducted to understand this side effect of riluzole.

On the whole, it appears that these reported side effects may worsen the quality of life, but such consequences may be outweighed by the effect of the drug in improving muscle function and survival rates. The mechanism by which riluzole improves muscle function and survival rates is still unknown. However, the results of this study indicate that riluzole may have a beneficial effect in people with diseases that involve glutamate toxicity such as ALS and HD.

Rosas, et al. (1999) hypothesized that riluzole treatment may have beneficial effects in people with HD. The researchers conducted a 6-week trial of riluzole in eight participants with HD. The participants were treated with 50 mg of riluzole twice a day and were observed for changes in chorea (involuntary dance-like movements), dystonia (prolonged muscle contractions), and total functional capacity (TFC) scores. TFC is a standardized scale used to assess the capacity to work, handle finances, perform domestic chores and self-care tasks, and live independently. The brain lactate evels of the participants were also studied. Lactate is a by-product of anaerobic metabolism that is often used as a measure of energy metabolism efficiency in cells. Low lactate levels would indicated high aerobic respiration and high energy yields. High lactate levels on the other hand, would indicate that cells are unable to perform aerobic respiration and had to resort to the less-efficient anaerobic respiration instead. Changes in lactate levels were then used by the researchers to test the effects of riluzole on energy metabolism.

The researchers found that the chorea rating score of the participants who took riluzole improved by 35% compared to their scores before treatment. Discontinuation of treatment resulted in worsened chorea, indicating that riluzole was indeed associated with the improved chorea. No significant changes were seen on the dystonia or TFC scores.

Lactate levels were lower in the riluzole-treated participants compared to their levels before treatment. However, the researchers reported concerns about inaccuracies in lactate measurements due to limitations in their instruments and measuring methods. Whether or not the decreased lactate levels associated with riluzole indicate improved energy metabolism remains to be determined.

In this study, no significant adverse effects were observed after 6 weeks of treatment. The most frequent side effect was diarrhea; other symptoms quickly resolved without the need for medical intervention.

The results of this study also suggest a possible role for riluzole in the treatment of chorea in people with HD. However, the mechanism by which riluzole might alter or prevent disease progression is still ambiguous. More studies need to be conducted to determine whether and how riluzole can slow the progression of HD and protect nerve cells.

For further reading^

  1. Bensimon, et al. “A Controlled Trial of Riluzole in Amyotrophic Lateral Sclerosis (ALS).” The New England Journal of Medicine. 1994; 330(9): 585-591. Online.
    This study reported that riluzole treatment resulted in increased survival rates and improved muscle function in people with ALS.
  2. Rosas, et al. “Riluzole Therapy in Huntington’s Disease (HD).” Movement Disorders. 1999; 14(2): 326-330.
    This study reproted that riluzole treatment resulted in decreased chorea and lactate levels in people with HD.
  3. Landwehrmeyer GB, Dubois B, de Yébenes JG, Kremer B, Gaus W, Kraus PH, Przuntek H, Dib M, Doble A, Fischer W, Ludolph AC; European Huntington’s Disease Initiative Study Group. Riluzole in Huntington’s disease: a 3-year, randomized controlled study. Ann Neurol. 2007 Sep;62(3):262-72.

This study concluded that Riluzole has no benefit for HD.

-E. Tan, 1-15-02, updated by M. Hedlin 7-1-11