Lithium is a soft, light metal that is used in various industries, including in the production of ceramics, glass, and batteries. It is found in trace amounts in all living organisms. While it is not necessary for survival, lithium does play some role in the human body since the lithium ion (Li+ ) has neurological effects. In medicine, Li+ is used to treat psychiatric disorders, specifically to stabilize mood and treat mania symptoms of bipolar disorder, a mood disorder characterized by alternating episodes of depression and mania.
The method by which lithium affects the brain to influence mood remains unclear but several mechanisms have been suggested. Scientists believe that lithium could stabilize mood by regulating levels of glutamate, the main excitatory neurotransmitter in the brain (For more on glutamate, click here.), or by interacting with nitric oxide, a gaseous signaling molecule. It could also work by altering the body’s circadian rhythm (biological clock).
HD and Lithium^
In recent years, researchers have investigated lithium as a potential treatment for HD because of its ability to regulate glutamate levels. Several studies have evaluated the effects of lithium on rat models of HD.
In the Wei et al. (2001) study, rats were injected with a lithium solution or with a control saline solution daily. After 16 days, the researchers infused the rats’ brains with quinolinic acid (QA), a chemical that has neurotoxic effects and is an agonist that activates the glutamate NMDA receptors. QA injections produce rats with lesions that lead to HD-like symptoms because one potential cause of HD pathology is over-activation of NMDA receptors due to high concentrations of glutamate. This over-activation can cause neuron death. Results showed that the brains of rats that received pre-treatment with lithium contained significantly smaller lesions (40-50%) than those treated with the control solution. Since lithium inhibits excessive NMDA receptor function, it could potentially counteract over-activation of NMDA receptors that occurs in the HD brain (For more on NMDA receptors and its role in HD, click here.). Nevertheless, it remains unclear how long the rats must be treated with lithium in order to sustain these positive effects. Future studies need to be conducted to answer this question.
Another study by Senatorov et al. (2004) used a similar QA-infused rat model of HD but instead injected rats with either lithium or saline control twice, once 24 hours prior to, and 1 hour after, QA infusion. Seven days later, lithium treatment again decreased lesions by 40% as compared to the control. In addition to its role in preventing neuronal death, the researchers believe lithium also has ability to produce new neurons in the hippocampus, a brain area involved in learning and memory.
Lithium has numerous side effects and can be toxic at high doses. The most common side effects are nausea, headaches, and hand tremor. Because lithium is a salt, it can also cause electrolyte imbalance and dehydration.
Research on lithium and HD is still in its early stages, as studies with HD patients have yet to be conducted. However, research on lithium in rat models of HD has yielded promising results so far.
For further reading:^
2. Senatorov et al. “Short-term lithium treatment promotes neuronal survival and proliferation in rat striatum infused with quinolinic acid, an excitotoxic model of Huntington’s disease.” Molecular Psychiatry (2004) 9, 371–385.
– A. Zhang, 08-21-12
Glutamate is a powerful excitatory neurotransmitter that is released by nerve cells in the brain. It is responsible for sending signals between nerve cells, and under normal conditions it plays an important role in learning and memoryMore
Drug Summary: Memantine is an anti-glutamate and energy-buffering drug. As an NMDA antagonist, memantine prevents the neurotransmitter glutamate from leading to nerve cell degeneration by inhibiting glutamate´s binding to the receptor. Memantine has been clinically used to treat dementia and Alzheimer´s disease. Current research on its effects in other diseases of the central nervous system (CNS), including HD, looks promising because memantine appears to be well-tolerated, and may help learning. It is possible that memantine may even be able to disrupt the progression of HD.
Mechanism of Action^
According to a theory known as the excitotoxicity theory, lower energy levels in the nerve cells of people with HD cause them to be overly sensitive to glutamate. As a result, even normal levels of glutamate can overactivate the glutamate receptors on the nerve cells. When these receptors (also known as NMDA receptors) are activated, calcium ions enter the nerve cells. Excessive activation causes a buildup of these calcium ions, which then leads to the death of the nerve cell. (For more on the excitotoxicity theory, click here.)
HD researchers believe that memantine may have strong potential to slow the progression of HD by decreasing the NMDA receptor´s sensitivity to glutamate. Memantine is an NMDA antagonist. As an antagonist, memantine prevents the excessive binding of glutamate to NMDA receptors, inhibiting the pathway to excessive NMDA activation and nerve cell death. Memantine is also a non-competitive antagonist. “Non-competitive” means that memantine binds to a site on the NMDA receptor that is different from glutamate´s binding site. By binding to one portion of the NMDA receptor, memantine changes the overall shape of the receptor, making it more difficult for glutamate to bind to the other portion of the receptor.
Memantine differs from other NMDA non-competitive antagonists in that it allows the NMDA receptor to undergo physiological activity required for normal nerve cell functioning, while at the same time preventing the receptor from the over-activation that leads to nerve cell death. This is important because NMDA receptors still need to be activated to allow the entry of calcium ions, which facilitate learning and memory. But once again, too much activation of the receptor can lead to nerve cell death. Two properties of memantine allow the NMDA receptors to be activated to the optimal level, which allows learning but prevents nerve cell death.
The first property of memantine prevents nerve cell death by decreasing the NMDA receptor´s sensitivity to glutamate. When glutamate binds to the receptor, it increases the cell´s electrical charge. The electrical charge inside the cell first needs to rise to a specific value before the magnesium ion leaves the receptor so that calcium can now enter. In people with HD, the over-excitation by glutamate causes the magnesium ion to leave too easily, allowing the influx of calcium ions responsible for nerve cell death. On the other hand, memantine is not as sensitive as the magnesium ion towards an electrical charge. That is, more glutamate needs to bind to the receptor before memantine will leave the receptor, thereby allowing calcium ions to enter. This is an advantage for those with HD, because memantine can block the pathological pathway by not responding as easily to an excessive amount of glutamate.
Besides inhibiting over-activation by glutamate, the second property of memantine still enables the physiological pathway to learning and memory. Memantine has “fast blocking/unblocking kinetics.” This means that, after glutamate strongly activates the receptor, memantine is still capable of quickly unbinding the receptor, thereby allowing calcium to enter the nerve cell. The fast kinetics of memantine is what allows an appropriate amount of calcium to enter the nerve cell, a process necessary for learning and memory.
Memantine has been clinically used in the treatment of dementia and Alzheimer´s disease. In studies general to all chronic neurodegenerative diseases, therapeutic doses of memantine inhibit disruption of spatial learning and aid learning in general through prevention of the pathological pathway discussed earlier. Researchers are currently testing its efficacy in treating other CNS disorders, including HD. Discussed later in this article, a clinical study on treatment of HD with memantine has also discovered benefits in its ability to slow the progression of HD.
Clinicians have used memantine to treat over 200,000 patients for mostly dementia over the last fifteen years. Although memantine has been well-tolerated in humans, in animals it has produced side effects characteristic of other NMDA receptor antagonists. For instance, memantine can impair the ability to control muscular movements (ataxia), muscle relaxation (myorelaxation), and is sometimes known to cause amnesia. However, these side effects were only seen at high dosages (greater than or equal to 20mg/kg per day)-dosages far higher than the usual 5mg/kg per day used in humans for therapy. In humans, high doses of memantine have been known to result in psychosis in some rare instances. At therapeutic (low-level) doses, memantine does not display the negative side effects found in other NMDA receptor antagonists.
Other tested side effects are drug dependency and abuse. There is some evidence to show that memantine can lead to dependence in animals. A dependency on memantine appeared in rats and monkeys but only at high doses. However, researchers have widely agreed that memantine has little abuse potential based on the many years it has been clinically used, recent clinical studies, and zero reports of abuse in humans.
Research on Memantine^
Beister, et al. (2004) conducted a two-year-long study with twenty-seven HD patients recruited from two different clinics. Each patient took up to a maximum of 30mg of memantine per day, depending on his/her individual tolerance for the drug. (Note: mg/day should not be confused with the units mg/kg per day that was used to specify therapeutic-level doses.)
Rating scales established in the HD medical literature measured the progression of HD. The Scale of Abnormal Involuntary Movements, the HD Rating Scale, and standardized video recordings evaluated chorea. For instance, in the videotapes, chorea was measured for the arms, legs, head, and trunk each on a three point scale, with 1 = slight, 2 = moderate, 3 = severe, and half-points possibly assigned. The scores for the different body parts were then averaged together.
The Clinical Global Impression (CGI) scale, the HD Activities of Daily Living (HD-ADL) scale, and the Total Functioning Capacity (TFC) of the HD Functional Capacity Scale were used to measure deteriorations. For example, HD-ADL consists of seventeen items that track the progress of HD through assessing a person with HD´s capabilities in taking care of him/herself in various areas, such as eating, dressing, taking medicine, and maintaining relationships. The person´s capability in each area is evaluated on a 3 point scale, with 0 indicating normal ability and 3 indicating necessary help from others required. The points for each area are summed to get the total HD-ADL score.
The Total Motor Score of the Unified HD Rating Scale (UHDRS) measured motor functioning. The Total Motor Score is reached by summing up points for certain movements, such as being able to carry out a sequence of hand movements or the velocity in moving a certain way. Scores for each movement are graded on a 4 point scale, with 0 being normal and 4 being unable to execute.
Psychometric tests, such as the Short Syndrome Test (SKT), the Brief Test of General Intelligence (KAI), and the Trail-making test were used to measure cognitive abilities.
The results following a two year treatment with memantine suggest that memantine has the ability to slow the progression of HD. Untreated people with HD in the Huntington Study Group (1996) experienced a 21.2% decrease in motor function over two years according to the Total Motor Score of the UHDRS. In comparison, treated patients experienced a decline of only 4.3%.
The scores on competence in daily living tasks also show memantine´s benefits. Researchers compared their results measured by HD-ADL with results measured by TFC of the HD Functional Capacity Scale because the two are similar enough to produce comparable outcomes. Untreated people with HD had a decrease in ability of daily living tasks, demonstrated by their average decline of 0.5 points over six months on the TFC scale. On the other hand, people with HD who received memantine treatment actually gained ability in daily living tasks, with an average increase of 0.28 points. These results translate to a 15.4% decrease in competency of daily living tasks over two years in untreated people with HD but a 9.3% reduction in progression of incompetence in daily living tasks in treated people with HD.
Furthermore, in the second year of treatment (between 12 and 24 months), there were no significant changes in CGI and HD-ADL scores. This score stability indicates a reduction in progression of deterioration. It also interestingly suggests that memantine´s ability to prevent HD progression is expressed only after long treatment with memantine.
Overall, the researchers concluded that memantine has good potential to slow the progression of HD. However, more studies need to be conducted with control groups to serve as a comparison (control groups do not get treatment, they take a placebo) in order to verify the study´s findings.
Forest Pharmaceuticals, Inc. (2010) ran a phase II clinical trial in which 50 people with mild to moderate Huntington’s disease received either 10 mg of memantine or a placebo twice daily for 12 weeks. Then, for the next 12 weeks, all participants took memantine. When compared to patients taking placebo, patients taking memantine showed improvements on tests of memory and attention, but performed worse on tests measuring motor symptoms. Larger studies will be necessary to confirm these findings.
For further reading^
- Beister, et al. “The N-methyl-D-asparate antagonist memantine retards progression of Huntington´s disease.” Journal of Neural Transmission Supplement. 2004 Supplement; (68): 117-22.
This fairly technical article presents the complete details of the study conducted by Beister, et al. The article concludes that memantine has good potential to slow the progression of HD, but more studies still need to be conducted to confirm results.
- Parsons, et al. “Memantine is a clinically well tolerated N-methyl-D-asparate (NMDA) receptor antagonist-a review of preclinical data.” Neuropharmacology. 1999, Jun; 38(6): 735-67. Review.
This is a highly technical article that summarizes the findings on memantine in its usage for a variety of diseases, including HD. The article also explains in detail memantine´s mechanism and tolerability.
This website is easy to understand but centers on memantine´s use for Alzheimer´s disease. However, the website clearly explains memantine´s mechanism as well as provides many research studies. The research posted under “Studies & Literature” is helpful in understanding more about memantine´s effects and good tolerability.
- Palmer GC. “Neuroprotection by NMDA receptor antagonists in a variety of neuropathologies.” Current Drug Targets. 2001 Sep; 2(3): 241-71. Review.
This is a highly technical article that reviews memantine´s mechanism against glutamate toxicity. It is not very useful in understanding memantine´s effects on HD in particular.
- Proc. of Fourth Annual Huntington Disease Clinical Research Symposium, San Pavilion Ballroom at the Hyatt Regency La Jolla at Aventine, San Diego. This technical report describes the results of the phase II clinical trial on memantine
– C. A. Chen, 05.02.05, Updated by M. Hedlin on 9.13.11More
Drug Summary: Lamotrigine belongs to a group of medications called anticonvulsants, which are used to control seizure disorders. Lamotrigine acts on the central nervous system to control the number and severity of seizures. It is thought to suppress the activity of certain parts of the brain and the abnormal firing of nerve cells that cause seizures. In psychiatry, lamotrigine may be used as a mood stabilizer. In the laboratory, researchers have found that lamotrigine also inhibits release of the neurotransmitter glutamate. This is important because glutamate may play a role in nerve cell degeneration in the brains of people with HD, so reducing the amount of glutamate released makes lamotrigine a potential treatment for HD.
Problem: Glutamate sensitivity^
Many factors contribute to the degeneration and death of nerve cells in people with HD. One aspect of HD is that nerve cells are particularly sensitive to glutamate. Glutamate is a neurotransmitter that is used to pass messages along from one nerve cell to another. (For more information on glutamate and HD click here.) Researchers have observed that because glutamate receptors in some nerve cells of people with HD are more sensitive than in people without HD, they are activated more frequently than normal receptors. This increased activity and sensitivity to glutamate has been associated with nerve cell death.
One way to prevent the overstimulation of a nerve cell by glutamate is to inhibit glutamate release from the nerve cells that communicate with it. In order to understand this kind of treatment, we must first understand the steps involved in the nerve impulse. (For more information on how nerve impulses work, click here.) It is important that we understand the steps of the nerve impulse because different treatments can be used to inhibit glutamate release by interfering at different steps. A nerve impulse involves receiving a message at one end of a cell and transmitting it via an electric signal to the other end of the cell. Neurotransmitters such as glutamate are stored at the end of the cell and are released in the last step. They act as a chemical signal, transmitting the message to a neighboring cell.
An important step in the electrical transmission of the nerve impulse involves sodium (Na+) channels. Most of the time, charged particles called ions line up along the inside and outside of the nerve cell membrane, giving the membrane a small electric voltage. Many different types of channels are located in the membrane, acting like guards at an exclusive community, only letting certain molecules in and out. Some of these channels open or close depending on what the membrane voltage is. One of these voltage-gated channels is the sodium channel, and it opens when the inside of the membrane becomes more electrically positive than usual. When the channel opens, sodium ions are free to enter the cell and continue the messaging cascade that ultimately leads to the release of neurotransmitters such as glutamate.
After the sodium channel lets enough sodium into the cell so that it reaches a maximum voltage, the channel temporarily becomes inactivated. An inactivated channel means that not only can no more sodium get through to relay the current message, but also the channel cannot be immediately reset, and thus will let no new messages be relayed. This intermediate stage between open and closed is called the refractory period. The sodium channel returns to the closed position only after the membrane voltage returns to a normal level (restoring the normal voltage involves the exit and entry of different ions). Once the channel is back in the closed position it can be opened again when the voltage rises enough. (See figure L-5 for a representation of the different sodium channel positions.)
How can lamotrigine reduce glutamate release?^
Studies have shown that lamotrigine may inhibit the release of glutamate. While lamotrigine may act in several different ways, it is primarily thought to act as an anti-glutamate drug by interfering with sodium channels. These channels are a necessary step in the nerve impulse and for normal release of glutamate by a nerve cell. In this way, lamotrigine’s inhibition of glutamate release is similar to that of the drug riluzole. (For more information on riluzole click here.)
Lamotrigine exerts its effects during the refractory period by binding to sodium channels. In overactive nerve cells such as in people with seizure disorders or HD, it takes longer for sodium channels to transition from the open period to the inactivated refractory period. An extended open period is what allows so much glutamate to be released in overactive cells. Lamotrigine targets these overactive cells that are slow to inactivate, leaving normal areas of the brain unaffected. Lamotrigine acts by prolonging the inactive refractory period so that sodium channels cannot return to the closed position. Since the channel must first be closed before it can be re-opened, prolonging the inactive period decreases the time of the open period, thus decreasing glutamate release. To put it another way, during the inactive refractory period, no more sodium can get in, so the membrane’s voltage is stabilized. When sodium is kept out, no more messages can be relayed, and thus no more glutamate is released. Therefore, lamotrigine inhibits glutamate release by interfering with sodium channels.
Research on lamotrigine^
Kremer, et al. (1999) recognized that prolonged exposure to glutamate leads to the gradual decline and death of nerve cells in diseases such as HD. They therefore hypothesized that inhibiting the release of glutamate would prevent or at least slow the progression of HD. Lamotrigine is known to inhibit glutamine release in vitro, and has been successfully applied to protect nerve cells in other experiments using animal models. Building on these results, the researchers ran a clinical trial on humans lasting 30 months to see if lamotrigine would slow the progression of HD in people who had experienced physical symptoms for less than five years.
The researchers studied the effects of lamotrigine on 28 people with HD; they also gave a placebo to 27 people with HD to control for psychological effects of treatment as well as to have a comparison group. This was a double-blind study, meaning neither the researchers nor the patients knew which group received the lamotrigine and which received the placebo. (The purpose of a double-blind study is to remove any experimenter or patient bias in evaluating the treatment.) The efficacy of the drug was primarily measured using the total functional capacity (TFC) scale. Patients were also assessed using a variety of cognitive and physical tests.
Over the course of the 30 months of the study, both groups significantly declined in their TFC scores, without any significant difference between the group receiving lamotrigine treatment and the group receiving a placebo pill. This led the researchers to conclude that lamotrigine is not effective in slowing the progression of HD. However, there was slightly less deterioration in terms of the physical symptoms known as chorea in the group receiving lamotrigine. Also, when asked about their various symptoms (mood, physical, etc.), a larger percentage of patients in the group receiving lamotrigine reported an improvement. Despite this perception, both groups declined in their performance on physical tasks. In addition, not much change was observed in the cognitive tests, although the placebo group performed better than the lamotrigine group on one test due to better learning.
Sixteen (of 28) people receiving lamotrigine treatment reported several side effects, including nausea, skin rash, insomnia, and severe depression. Eight (of 27) people receiving a placebo reported mild side effects.
While the study reported the overall inefficacy of lamotrigine, it is important to consider the relatively small sample size and the fact that deterioration varied widely among participants. This is why the researchers have not fully ruled out lamotrigine’s ability to treat early HD. The positive results of the study (decreased chorea and improved symptoms such as mood) may be a result of what lamotrigine is already used for – as an anticonvulsant and mood elevator. A possible reason why the clinical results on humans were not as favorable as those on animals is because the effective dose in animals is much too high for humans to tolerate. Increasing the dose in people is not an option because of the harmful side effects associated with the drug.
Higgins, et al. (2002) also focused on decreasing the amount of glutamate released in nerve cells. Since lamotrigine is known to inhibit the release of glutamate, this group tested the safety of various doses of the drug and how well it was tolerated in HD patients. They conducted an open-label study, meaning that the patients knew they were receiving an actual drug and not a placebo. Over the course of seven weeks the researchers increased the amount of lamotrigine given and then continued giving the maximum dose up to six months. The effects of the drug were tested using the Unified Huntington’s disease Rating Scale (UHDRS) and cognitive tests.
The researchers studied only twenty people with HD and ended up collecting data from fifteen (two people’s symptoms got worse while three people did not report back). The researchers did not find any changes in the UHDRS (this includes motor, functional, and behavioral aspects of HD). However, significant improvements were seen in two parts of the cognitive tests, Verbal Fluency and Symbol Digit Modalities.
Overall, the researchers found that the patients were able to tolerate the drug well and that it was safe to use. They were not able to reproduce the results seen in a previous study that found lamotrigine could reduce chorea. Researchers will need to follow up on this study with a longer lasting investigation that is not open-label and includes more patients.
For further reading^
- Kremer, et al. Influence of lamotrigine on progression of early Huntington’s disease. 1999. Neurology 53(5): 1000. Online.
This is a research article about a clinical trial of lamotrigine and HD. It describes the study’s methods and results in great detail and is directed toward a scientific audience.
- Higgins, et al. Safety and tolerability of lamotrigine in Huntington’s disease. 2002. Movement Disorders 17(S5): S324.
This is a short description of medium difficulty of a clinical trial using lamotrigine as presented at the 7th international congress of Parkinson’s disease and movement disorders.
- Hurley, Stephen C. Lamotrigine update and its use in mood disorders. 2002. The Annals of Pharmacotherapy 36(5): 860-873. Online.
This article reviews known information about lamotrigine and evaluates its use in treating mood disorders. It is not directly related to HD, but the section on pharmacology on page 861 is helpful in understanding how lamotrigine works on nerve cells.
-K. Taub, 11/21/04More
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.
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.
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^
- 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.
- 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.
- 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 7-1-11More
Drug Summary: Remacemide (RMC) is a drug that HD researchers hope can alleviate glutamate toxicity in the brains of HD patients. Remacemide is an NMDA antagonist – it inhibits the binding of glutamate to NMDA receptors, preventing glutamate from exerting its toxic effects on the nerve cell. Although, it has been shown to transiently improve motor performance in mouse models of HD, the few human clinical trials that have been performed have not produced statistically significant improvements in brain or motor function. Patients have also experienced side effects such as lightheadedness, dizziness, vomiting, nausea, and gastrointestinal disturbance.
The lowered amount of energy available in the nerve cells of patients with HD is thought to cause NMDA receptors to be oversensitive to glutamate. Therefore, normal physiological levels of glutamate can cause overexcitation of the NMDA receptor, leading to the influx of calcium ions into the cell. Excess calcium ion entry can lead to cell death through a combination of events. (For more information, click here.)
Remacemide, sometimes referred to as Remacemide Hydrochloride, is under investigation as a treatment for HD because it acts as a non-competitive inhibitor of the NMDA receptor. This means that remacemide decreases the receptor’s ability to bind glutamate by docking to a site on the receptor other than the glutamate binding site, and changing the shape of the receptor such that glutamate has a difficult time binding. Researchers hope that by inhibiting the NMDA receptor, the toxic effects of glutamate in the neurons of patients with HD can be lessened.
Clinical trials have examined the effectiveness of remacemide in curbing or stopping the neurodegenerative effects of HD in humans. Although remacemide treatment has not produced statistically significant improvement in these trials, in some patients it seems to transiently improve certain motor symptoms caused by HD such as chorea. Side effects such as dizziness, nausea, vomiting, lightheadedness, and gastrointestinal disturbances tended to accompany treatment.
Experiments done on mouse models of HD have been more positive.
Research on Remacemide^
Kieburtz, et al. (1996) conducted a study on the effects of remacemide in 31 participants in the early-stages of HD. The study was conducted over a 5-week period and the participants were divided into three treatment groups:
The total functional capacity (TFC) of the participants was used as the criteria of the drug’s effectiveness. TFC is a standardized scale used to assess capacity to work, handle finances, perform domestic chores and self-care tasks, and live independently. The TFC scale ranges from 13 (normal) to 0 (severe disability). The HD Motor Rating Scale (HDMRS) was also used to assess the motor capabilities of the participants. The HDMRS consists of 14 items that assess the relevant motor features of HD including chorea and other motor functions. Other psychological tests were also conducted to measure the effectiveness of the drug in improving cognitive function.
Following treatment, the researchers concluded that there was no statistically significant difference between the three treatment groups. However, a trend towards improvement in chorea was observed among the participants who received 200 mg of remacemide per day. No major side effects were observed in most of the participants. However, one of the participants who received 600 mg/day did not complete the study due to persistent nausea and vomiting, which was believed to be a result of the medication.
The researchers concluded that remacemide could have short-term effects in improving chorea experienced by people in the early stages of HD. No statistically significant changes in cognitive performances were seen in the treatment groups. Larger, long-term controlled studies of remacemide are needed to determine the duration of tolerability and potential benefits of remacemide and other NMDA blockers.
The Huntington Study Group (2001) conducted a clinical trial involving 347 early-stage HD patients at 23 sites in the United States and Canada, monitored between July 1997 and June 1998. Participants in the study were assigned to four different treatments:
The primary measure of the drug’s effectiveness was change in total functional capacity (TFC) of the people with HD. A score of 13 represents a normal degree of function and a score of 0 represents a severely disabled state. The average TFC score of the participants before the study was 10.2. None of the treatments significantly altered the decline in TFC.
The condition of the participants who were treated with remacemide worsened by 2.3 points on the TFC scale, showing that the drug had no beneficial effect on slowing the functional decline experienced by people with HD. However, there was a trend toward an improvement in the degree of chorea in the participants treated with remacemide. Although this effect was not statistically significant, the effect was seen during the patient’s first visit after treatment began, suggesting that remacemide may decrease chorea. These findings suggest that antiglutamate therapies could be useful in controlling chorea even if they have no impact on slowing functional decline. However, remacemide was associated with side effects that included dizziness, lightheadedness and nausea. A trend towards a decrease in TFC decline was seen in the participants treated with CoQ10. (For information on CoQ10, click here.)
Ferrante et al. (2002) studied the potential therapeutic effects of remacemide, coenzyme Q10, and the combination of the two drugs on transgenic mouse models of Huntington’s Disease. They found that oral administration of either coenzyme Q10 or remacemide significantly extended survival and delayed the development of motor deficits, weight loss, cerebral atrophy, and neuronal intranuclear inclusions in the R6/2 transgenic mouse model of HD. The combined treatment, using CoQ10 and remacemide together, was even more effective than either compound alone.
For further reading^
- Kieburtz, et al. “A controlled trial of remacemide hydrochloride in Huntington’s disease.” Movement Disorders. 1996, May; 11(3): 273-7.
This article contains the full details on the study by Kieburtz, et al.
- The Huntington Study Group. “A randomized, placebo-controlled trial of coenzyme Q10 and remacemide in Huntington’s disease.” Neurology. 2001, Aug 14; 57(3): 397-404.
This article contains details on the study done by The Huntington Study Group.
- Schilling, et al. “Coenzyme Q10 and remacemide hydrochloride ameliorate motor deficits in a Huntington’s disease transgenic mouse model.” Neuroscience Letters. 2001, Nov 27; 315(3): 149-153.
- Ferrante, et al. “Therapeutic Effects of Coenzyme Q10 and Remacemide in Transgenic Mouse Models of Huntington’s Disease.” Journal of Neurosience. 2002, Mar 1; 22(5): 1592-1598.
-P. Chang, 7/5/04More
Update: According to a press release on 4/11/11, dimebon did NOT pass the Horizon trial and is not effective in treating HD. There was no statistically significant difference in symptoms between the experimental (received dimebon) and placebo (did not receive dimebon) groups. According to the president and chief executive officer of Medivation, development of dimebon in HD will be discontinued. However, dimebon trials for treatment of Alzheimer’s disease will continue.
The press release can be viewed here.
Drug Summary: Dimebon (pronounced deh-mah-bonn) is an anti-histamine drug with a 20-year history of use in Russia. Its potential as a neuroprotective agent was recently recognized when a large chemical library screen found that the class of molecules it belongs to, gamma-carbolines was likely to be effective in blocking nerve-cell receptors for glutamate (see Glutamate excitotoxicity below) and in blocking cholinesterases (see Low levels of Acetylcholine below). Studies are now being undertaken to assess its efficacy.
Currently, Dimebon is being developed by pharmaceutical company Medivation, in collaboration with Pfizer, for use in treating Huntington’s Disease (HD) and Alzheimer’s Disease. Lab studies (using rats and human nerve cells in culture) have shown that Dimebon may be helpful in treating problems common to the two diseases, including glutamate excitotoxicity and low levels of acetylcholine. Clinical studies with both Huntington’s and Alzheimer’s patients have also had encouraging results. Dimebon’s protective effects in these cases may make a significant difference in alleviating cognitive symptoms and improving overall quality of life. Dimebon is currently in Phase III clinical trials for both diseases.
The chemical glutamate is an excitatory neurotransmitter in the brain, and a routine part of nerve impulse transmission. When present in excessive amounts though, glutamate can cause a chain of reactions that ultimately leads to nerve cell death. This process is called “excitotoxicity” because glutamate over-excites the nerve cell and becomes bad for it, or toxic. Cell death can also occur at normal glutamate levels if nerve cells become “hypersensitive” to glutamate. This hypersensitivity is thought to be the reason glutamate excitotoxicity exists in HD. For a more detailed explanation of this process, please see Glutamate Toxicity: Disease Mechanism V.
In rat studies, Dimebon has been shown to work against glutamate excitotoxicity in two main ways. First, Dimebon acts as an antagonist to glutamate by binding to glutamate receptors, called NMDA receptors, on the surface of nerve cells. If glutamate can’t bind to the NMDA receptors because Dimebon is in the way, then glutamate cannot send its message to the cell. This process is similar to the situation that would arise if you needed to send an e-mail, but someone was sitting in your chair. If the other person sits there and doesn’t send a message, then you can’t sit down to send a message and no message gets sent at all. This activity has the potential to prevent cell death if there are abnormally high levels of glutamate in the brain but also, as is most likely in Huntington’s, if nerve cells are hypersensitive to normal levels of glutamate.
Dimebon also counters excitotoxicity by blocking calcium ion (Ca2+) channels located on the surface of nerve cells. This activity prevents the influx of Ca2+ ions, a consequence of glutamate excitotoxicity. (For more information about this process please see Glutamate Toxicity: Disease Mechanism V.) When blocked, Ca2+ cannot get into the cell to activate free radicals and other damaging molecules that ultimately lead to cell death. In this way, Dimebon may be able to stop a cell from progressing towards cell death even if glutamate is able to over-excite it.
So Dimebon may help prevent nerve cell death by preventing glutamate from over-stimulating nerve cells and preventing over-excited cells from taking in large amounts of Ca2+. How else might Dimebon help treat HD?
Low levels of Acetylcholine
Acetylcholine is a neurotransmitter that is vital to proper memory function. Current research suggests that, in HD, degeneration of the basal ganglia involves the death of a great number of cholinergic nerve cells, which are the nerve cells that produce acetylcholine. This loss of cholinergic nerve cells results in low levels of acetylcholine, which likely contribute to the cognitive impairment associated with HD. Replacing acetylcholine by way of dietary supplements is sometimes suggested as a treatment for memory deficiency in neurodegenerative diseases.
Studies have suggested two ways that Dimebon might enhance cognition (memory and learning ability) in HD patients. The first of these is that Dimebon’s has been shown to protect nerve cells in culture from neurotoxins. The simple prevention of nerve cell death is surely beneficial to memory. Additionally, a high number of surviving cells can produce close to normal levels of acetylcholine. However, even if acetylcholine is only produced in small amounts, Dimebon can keep this neurotransmitter at normal levels by inhibiting two enzymes that normally break it down. This activity by Dimebon helps keep each molecule of acetylcholine around longer, allowing small amounts to accumulate and reach normal levels.
So we know that Dimebon can decrease cell death from excitotoxicity and that it can increase levels of acetylcholine. The question then becomes: how well might Dimebon work as a treatment for HD? The three studies outlined below—one on rats and two in humans—test Dimebon’s effect on the entire organism. These studies were designed and evaluated with Alzheimer’s disease in mind, but the results are still useful to HD research.
1) In a 2001 study by Bachurin, S. et al. (see “For further reading” below), rats were given a neurotoxin that selectively kills cholinergic nerve cells. Then one group of rats was treated with Dimebon and a second group was not. The group of rats that was given no treatment had severely reduced cognition. In comparison, rats that were treated with Dimebon showed significantly better memory and learning ability.
2) The second study was a preliminary clinical trial with 14 participants exhibiting mild to moderate Alzheimer’s disease. The study lasted 8 weeks but participants showed marked improvements in cognition and independence as early as 2-4 weeks. A variety of common conditions were alleviated including depression, anxiety, tearfulness, headache and psychopathic symptoms. These improvements tended to be gradual but significant; for example, 50% of patients with headaches showed improvement at 4 weeks and 80% showed improvement at 8 weeks. This trial was also part of the Bachurin, S. et al 2001 study mentioned above.
3) In September 2006, results of a phase II study of Dimebon were reported by a company called Medivation. According to standard procedures, phase II testing uses a medium-sized group of patients to test a drug’s usefulness and look for side effects. In this study, 183 individuals with mild to moderate Alzheimer’s disease were treated with either Dimebon or a placebo for six months. Five different tests were used to evaluate progression of the disease and Dimebon-treated participants showed “highly statistically significant improvement” on all of them. This means that it is very likely that patients treated with Dimebon improved because of the drug and not because of a placebo effect. Patients taking Dimebon not only did better than placebo patients throughout the trial but also actually improved from their original, or baseline, condition.
Dimebon was also well tolerated – more serious adverse events occurred in the placebo group. This is certainly an advantage of using a drug with a previous history of use in humans. A large percentage of individuals (86%) chose to participate in a continuation study that brought treatment to a full year. Results from this study were announced in June 2007 and demonstrated that at one year, the benefits of Dimebon over placebo on all five efficacy endpoints were stable or greater when compared to the benefits at six months.
Medivation is currently undertaking The Connection Study, a Phase 3 Clinical Trial of Dimebon in patients with mild to moderate Alzheimer’s Disease, and The Concert Study, a similar trial in Alzheimer’s patients who are also taking Aricept (donepezil).
So what about Huntington’s?
In July 2008, Medivation published the results of their Phase II trial of Dimebon in persons with HD. The trial was done in cooperation with the Huntington Study Group and enrolled 90 participants with mild to moderate HD for three months. The results showed statistically significant improvement in cognition as measured by the Mini-Mental State Examination (MMSE). This is a very exciting result because there is currently no treatment that has been shown to improve cognition in HD. Additionally, Dimebon was well-tolerated, showing very few side effects.
In July 2009, Medivation, teamed with a larger pharmaceutical company called Pfizer, announced their Phase III clinical trial, Horizon. Horizon will enroll 350 HD patients suffering from cognitive impairment, and will last for six months. As a Phase III trial, Horizon will focus on trying to determine whether or not Dimebon significantly improves cognition in HD patients and can be approved to treat cognitive symptoms of HD, such as memory and decision making.
To learn more about the Horizon study, including how to participate, see http://www.horizontrial.com/
You can stay updated on the progress of both Alzheimer’s and Huntington’s trials by checking press releases on the Medivation website or by returning to the HOPES site in the future when new results are published. We’ll do our best to keep you posted!
For further reading
- Bachurin S., Bukatina, E., Lermontova, N., Tkachenko, S., Afanasiev, A., Grigoriev, V., Grigorieva, I., Ivanov, YU., Sablin, S. & Zefirov, N.: Antihistamine Agent Dimebon As a Novel Neuroprotector and a Cognition Enhancer. Annals of the New York Academy of Sciences 939: 425-435, 2001
- This scientific study includes information on many aspects of Dimebon’s potential use in Alzheimer’s disease. It is easy to get bogged down in details and scientific language but if you stick to the introduction, results, and discussion you will find it informative.
- Medivation (September 21, 2006). Medivation’s Dimebon Meets All Five Efficacy Endpoints in Phase 2 Alzheimer’s Disease Study. Press Release. Click here to read this article.
- This is an easy-to-read press release by the company that owns rights to develop and test Dimebon as a neuroprotective drug in the US.
- Medivation (October 19, 2006). Medivation Begins Phase 1-2a Trial of Dimebon in Huntington’s Disease. Press Release. Click here to read this article.
- Another easy-to-read press release from Medivation announcing the beginning of the Dimebon trial for Huntington’s Disease.
- Medivation (June 11, 2007). Medivation’s Dimebon(TM) Maintains Statistically Significant Benefit on All Five Efficacy Endpoints in Alzheimer’s Disease Trial After One Year of Therapy. Press Release.
- Click here to read this article.
- The Medivation press release announcing results of the year-long Dimebon trial for Alzheimer’s.
- Medivation (July 7, 2008) Medivation Announces Positive Top-Line Results From Phase 2 Dimebon Study in Huntington’s Disease. Press Release. Click here to read this article.
- The Medivation press release announcing results of the Phase II trial in Huntington’s Disease (HD)
-F. Clum, 4-19-10
-updated A. Zhang, 4-25-11More