All posts in Abnormalities in energy metabolism

About Abnormalities in Energy Metabolism

The mutant huntingtin protein has been found to disrupt cellular metabolism, the process by which cells make energy. It interacts with key proteins needed to produce energy and causes damage to mitochondria, the ‘energy factory’ of the cell. Mitochondria produce energy in the form of molecules known as ATP (for “adenosine triphosphate”). The amount of ATP available to cells is lower in Huntington’s Disease (HD), which makes cells more susceptible to damage by toxic compounds. Scientists are looking into drugs and supplements that increase the amount of energy available in cells, as they might be possible candidates for treating HD. This article explains how huntingtin affects cellular metabolism, which is important for understanding how these drugs may improve energy production in the cell.

The Basics of Energy Metabolism

J-9: Steps in Metabolism

Energy metabolism is a process by which the food we eat is broken down by various enzymes in order to produce a molecule called ATP, the energy source of the cell. The pathway by which ATP is produced depends on the availability of oxygen in cells. If there is a sufficient amount of oxygen, aerobic respiration takes place in the mitochondria and large amounts of ATP are produced. If there is not enough oxygen in cells, anaerobic respiration is instead performed, which produces a smaller amount of ATP. Thus, aerobic respiration is a more efficient process because it produces more energy from the food we eat.

Fig J-12: Steps in Aerobic Respiration

Glycolysis is a series of reactions that begins the process of metabolism in all cells. It takes place in the cytosol (sometimes also called “cytoplasm”), which is the fluid portion of the cell.
The important molecular product of glycolysis is called pyruvate, which can undergo either aerobic or anaerobic respiration. If sufficient oxygen is present, pyruvate gets transported to the mitochondria where it undergoes aerobic respiration. Each step of this process helps convert the food we eat from one molecule to another until ATP is produced as the end product.

HD and Cellular Metabolism

Exactly how mutant huntingtin interferes with energy production is unknown, but studies have revealed that it interacts with a variety of key proteins involved in energy metabolism. For example, the altered huntingtin protein interacts with a molecule known as GAPDH (which stands for glyceraldehyde-3-phosphate dehydrogenase), a key enzyme in glycolysis, the early part of metabolism described above. Huntingtin’s interaction with GAPDH partially prevents it from working properly. Research suggests that GAPDH interacts preferentially with small subunits of huntingtin protein rather than the full length protein. But this is precisely what the altered huntingtin becomes in people with HD: the altered huntingtin protein is readily cleaved into small pieces by proteins called caspases. (Click here to read more about caspases, or here for a figure depicting the effects of caspases in a nerve cell.) As HD progresses, cleavage by caspases is enhanced, generating more protein fragments. These fragments then interact with GAPDH and inhibit its activity, which leads to lower amounts of ATP available in cells and eventually causes cell death.

The mutant huntingtin protein is believed to have a greater impact on cellular metabolism when it has a longer glutamine tail, which happens when an individual’s copy of the HD allele has a longer segment of CAG repeats. Cells engineered to express huntingtin with particularly long polyglutamine tails were significantly worse at making ATP than cells expressing huntingtin with medium-length polyglutamine tails.

Damage to Mitochondria

Fig J-13: Electron Transport Chain

Aside from interfering with one of the enzymes involved in glycolysis, mutant huntingtin also interferes with oxidative phosphorylation, the final step in aerobic respiration. Specifically, mutant huntingtin makes the electron transport chain less efficient. The electron transport chain is a series of protein complexes that are found in the membrane of mitochondria, and is a vital component of oxidative phosphorylation. The protein complexes are named Complex I, II, III, and IV. As electrons are transported from one complex to another, protons (H+) are pumped out into the space between the inner and outer membrane of the mitochondria. As protons are pumped into the space between the two membranes, a proton gradient forms – more protons are present in the space between the two membranes. The proton gradient is essential in ATP production. The protons that accumulate between the two membranes are then transported through a molecule called ATP synthase. ATP synthase then produces ATP molecules that the cell uses as its source of energy.

Most studies report that HD cells exhibit reduced activity in complex II and III. A few studies have also reported decreased activity in complex I as well. Scientists are still not certain how the huntingtin protein interacts with these protein complexes. They currently speculate that that the altered huntingtin protein may indirectly interfere with these complexes by interacting with other molecules involved in the electron transport chain. As the altered huntingtin protein disrupts this step of metabolism, the cell experiences more energy deficits, with some experiments suggesting that neurons in the striatum, a region of the brain heavily affected in HD, make 30% less ATP than non-HD neurons. This makes those brain cells more susceptible to damage by toxic substances such as glutamate.

In summary, because of damage to mitochondria in neurons of people with HD, aerobic respiration is less efficient and therefore produces less energy. Compounds that target different parts of the pathways of aerobic respiration are currently being studied to determine if they increase the energy supply available to cells and may therefore be potential drugs for HD.

Anaerobic Respiration

As mentioned earlier, anaerobic respiration occurs when there is not enough oxygen available to cells. Anaerobic energy producing pathways are called fermentation. Organisms that do not need oxygen in order to grow and survive rely on fermentation as their main source of energy. Examples of such organisms include bacteria. During exercise, our skeletal muscles also rely on fermentation for energy during the few moments when insufficient amounts of oxygen are available. Fermentation produces lower amounts of energy and releases various by-products. In the muscle, the by- products of fermentation include molecules called lactate (also known as lactic acid). The accumulation of lactic acid is what makes our muscles hurt when we exercise. A summary of the steps involved in anaerobic respiration is shown below.

Fig J-14: Steps in Anaerobic Respiration

If you remember, the altered huntingtin protein has been found to partially inhibit the activity of the GAPDH enzyme, resulting in impairments in glycolysis. Given that fermentation requires the products of glycolysis in order to occur, how then can fermentation still occur in HD cells? It turns out that partial inhibition of GAPDH still allows some fermentation to occur, although complete inhibition would block glycolysis, and consequently, fermentation.

The altered huntingtin protein has been found to interfere with an enzyme involved in glycolysis and the electron transport chain. As a consequence, more fermentation occurs relative to aerobic respiration. Studies have reported that people with HD have increased brain lactate levels, indicating damage to mitochondria and impaired energy metabolism. Lactate levels are often used in studies to measure the efficiency of a drug or supplement. Lower lactate levels after treatment is seen as an indication of improved metabolism in cells.

The Big Picture

So what do defects in energy metabolism mean for people with HD? Brain scans reveal that people with HD metabolize glucose more slowly in certain parts of the brain. One of those regions, the basal ganglia, is responsible for controlling movements. Patients with particularly impaired metabolism in the basal ganglia have worse motor symptoms and lower functional capacity. Moreover, some scientists think that defective energy metabolism is partly responsible for the weight loss that many people with HD experience, as described in more detail here.

The drugs outlined in this “Abnormalities in Energy Metabolism” section are meant to boost energy, and hopefully reverse some of the effects described in this article.

-E. Tan, 9-21-01, updated M. Hedlin 12.22.11

https://www.stanford.edu/group/hopes/cgi-bin/wordpress/?p=3419
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TUDCA: Tauroursodeoxycholic Acid

What in the world do black bears have to do with treating Huntington’s disease? Believe it or not, a compound found in large quantities in the bile (a digestive fluid) of black bears may help prevent the death of brain cells in people with HD. (TUDCA) Tauroursodeoxycholic acid is also found in small quantities in human bile. It is already being used to treat a liver disease in humans.

One complication that leads to the progression of Huntingtohn’s disease is the death of nerve cells in certain areas of the brain. There are many theories as to what causes these cells to die. At least part of the story involves the cells undergoing apoptosis, or programmed cell death. (For more information on cell death and HD click here.) Scientists are working hard to find out both what causes nerve cells to initiate apoptosis as well as how to prevent it. This chapter discusses TUDCA, a drug that may help prevent nerve cell death.

What is the theory behind TUDCA?^

A part of the cell that is especially involved in apoptosis is the mitochondrion (plural: mitochondria). Mitochondria are responsible for providing energy to the cell. If they are prevented from carrying out their jobs, the cell and its parts will not be able to perform all of their necessary functions and the cell will die. (For more information on energy and HD click here.) Mitochondria release and activate certain molecules that play a role in initiating apoptosis. When something perturbs the mitochondrial membrane, the mitochondria release a molecule called cytochrome c.

Cytochrome c then recruits enzymes called caspases to help initiate a cascade of events leading to apoptosis. Caspases are a key element in this process and are especially relevant to people with HD. The altered huntingtin protein resulting from the HD allele has more glutamines than the normal huntingtin protein. In people with HD, caspases work by cutting the altered huntingtin protein into little fragments. These fragments, in turn, activate more caspases and a vicious cycle begins. The caspases go on to participate in the cascade leading to apoptosis, while the huntingtin fragments enter the nucleus and form harmful protein aggregations called neuronal inclusions (NI). Both of these elements – many activated caspases and huntingtin fragments – contribute to a greater likelihood of early cell death in people with HD.

Much of what is known about TUDCA comes from studies done on liver cells. These studies found that TUDCA is able to prevent apoptosis and protect mitochondria from cellular elements that would otherwise interfere with energy production. One of these elements is a molecule called Bax. When Bax is transferred from the cytosol to the mitochondria, it aggravates the mitochondria s membrane, causing the membrane to release cytochrome c and initiate the apoptosis pathway. TUDCA plays an important role in preventing Bax from being transported to the mitochondria. It therefore protects the mitochondrial membrane, as well as preventing the mitochondria from activating caspases. The exact mechanism of how TUDCA works is unknown, but it has to do with protecting the mitochondria. By intervening at an early point in the apoptosis pathway and preventing the transfer of Bax to the mitochondria, TUDCA has the potential to save certain kinds of cells from early death.

How can TUDCA help treat HD?^

A group of researchers tested TUDCA in animal models of HD to see if the above theory could translate into practice. In the mouse model of HD, the effects of TUDCA were observed in three ways. First, administering TUDCA helped nerve cells in the striatum both by preventing apoptosis and decreasing degeneration. (To learn more about parts of the brain affected in HD, click here.) In both people and mice with HD, the proteins formed from the HD allele tend to clump together and clog up the nucleus by forming aggregations called neuronal inclusions (NI). Second, the mice that were treated with TUDCA had fewer and smaller NIs compared to untreated mice. Finally, at the clinical level, treated mice showed decreased motor deterioration and other HD signs as compared to untreated mice.

What is the future of TUDCA in treating HD?^

Animal studies using TUDCA to treat HD are showing some initial promise. The next step is to obtain funding and begin clinical trials to test the drug on humans with HD. Once researchers overcome this hurdle, this traditionally lengthy process may be sped up by a few key factors. First, since TUDCA is produced (albeit in very small amounts) in the human body, there should be virtually no side effects in using it as a drug. Second, it can cross the blood-brain barrier, which is usually a major obstacle to drug delivery in the central nervous system.

Delivering a drug involves getting it into the body as well as to the exact place where it will take action. Finally, TUDCA is already being used to treat a type of liver disease, so the U.S. Food and Drug Administration deems it safe for at least one particular use. Because of its neuroprotective effects, TUDCA may also be used to treat other conditions such as Alzheimer’s, Parkinson’s, and ALS. Despite all of these positive aspects of the drug, TUDCA has yet to be tested for its effects on humans with HD.

For further reading^

  1. Bile acid inhibits cell death in Huntington’s disease. 2002. Huntington Society of Canada. Online.
    This article summarizes the research findings of TUDCA in the HD mouse model. It also provides a great low-tech explanation of apoptosis.
  2. Bile may treat Huntington’s. 2002. BBC News. Online.
    This short article concisely summarizes the research findings of TUDCA in the HD mouse model.
  3. Keene, C.D. et al. Tauroursodeoxycholic acid, a bile acid, is neuroprotective in a transgenic animal model of Huntington’s disease. 2002. Proceedings of the National Academy of Sciences of the U.S.A. 99(16): 10671-10676. Online.
    These are the published findings of the original study of TUDCA in the mouse model of HD. It is highly technical and only meant for a scientific audience.
  4. Knight, Tom M. TUDCA success. 2002. Ridder Newspapers. Online.
    This easy to understand article discusses TUDCA and its potential to treat many neurodegenerative disease. It also contains great quotes from one of the primary researchers.

-K. Taub, 11/14/2004

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Carnitine

Drug Summary: Carnitine acts to facilitate the entry of fatty acids into the mitochondria. Once these fatty acids are in the mitochondria, they can be used to produce energy. Because inefficient energy production is believed to contribute to the progression of HD, carnitine therapy could result in increased energy production, and could possibly delay HD progression.

essential

Carnitine as an energy buffer^

The food we eat is broken down into different sub-units. Carbohydrates are broken down into simple sugars, proteins into amino acids, and fats into fatty acids. Figure J-6 shows a diagram depicting an overview of the breakdown of the food we eat.

This section will focus on the processes by which fatty acids are used to supply our body’s energy.

Fig J-6: Food Breakdown
Fig J-7: Fatty Acid Metabolism

Fatty acids must first be activated in the outer mitochondrial membrane before they can be used in the mitochondria. An enzyme called acyl-CoA synthetase is responsible for the activation of fatty acids. Once activation occurs, the fatty acids are transformed into molecules called acyl-CoA. Figure J-7 shows the reaction that takes place when fatty acids are activated.

Fig J-8: The Entry of Acyl-CoA into the Mitochondria

Long chain acyl-CoA molecules do not readily move through the mitochondrial membrane, and so a special transport chain is needed. Activated fatty acids in the form of acyl-CoA are carried across the mitochondrial membrane by carnitine. Once the acyl-CoA is in the mitochondria, carnitine is recycled back to the outer mitochondrial membrane to be reused again as an acyl-CoA transporter. Figure J-8 shows how carnitine transports the acyl-CoA molecule into the mitochondria.

Once inside the mitochondria, the acyl-CoA molecules will undergo a series of breakdown reactions collectively known as beta-oxidation. The most important end product of beta-oxidation is acetyl-CoA, a key molecule in the cell’s energy production. Acetyl-CoA can then enter the Krebs Cycle (one of the steps in energy metabolism) and lead to the production of ATP. (For more on the Krebs Cycle, click here.)

Aside from being an essential component of fatty acid metabolism, carnitine may contribute to normal cellular functioning by “stabilizing” the membrane against damage from harmful free radicals. Free radicals are by-products of energy metabolism and are reactive molecules that cause various cell damages.

As described in other chapters, impaired energy metabolism and damage by free radicals are two disease mechanisms believed to play a role in the progression of HD. Since carnitine is an acyl-Co-A transporter, scientists hypothesize that carnitine supplementation may increase metabolism efficiency by increasing the amounts of fatty acid available for processing in the mitochondria, thereby slowing HD progression. In addition, carnitine’s potential ability to decrease free radical damage also makes it a possible treatment for people with HD.

Various studies have investigated carnitine’s potential for improving conditions caused by mitochondrial dysfunction and impaired energy metabolism. In a recent (2000) clinical trial studying the potential efficacy of acetyl-L-carnitine (ALC), the active form of carnitine in the body, on slowing the rate of neurological decline in early-onset AD, treatment failed to affect the rate of decline. Research on the efficacy of ALC in treating mouse models of HD, however, have shown positive results. Below is a summary of some of the recent research done on acetyl-L-carnitine.

Research on Carnitine^

Virmani, et al. (1995) studied the effects of acetyl-L-carnitine (ALC) in cells exposed to mitochondrial toxins (poisons). Exposure to mitochondrial toxins decreases metabolism efficiency. The researchers hypothesized that if ALC truly increases metabolism efficiency, then ALC treatment to cells exposed to mitochondrial toxins will show increased metabolism efficiency compared to cells exposed to toxins that are not treated with ALC.

Nerve cells of fetal rats were exposed to various mitochondrial toxins such as FCCP, Rotenone, NaCN, and 3-NP. All these toxins act to decrease metabolism efficiency by interfering with proteins in the mitochondria that are involved in energy metabolism.

Exposure to the toxins caused an increase in lactate levels and a decrease in mitochondrial activity. The increased lactate levels indicated that exposure to toxins decreased energy metabolism.

Part of the effect of ALC may also be related to the decrease in free-radical formation from the damaged mitochondria. Experiments by other scientists have shown that ALC protected rat nerve cells from damage caused by exposure to the free radical hydrogen peroxide.

Hagen, et al. (1998) investigated the effects of ALC in aging rats. Studies have reported that there is a decline in mitochondrial energy metabolism in normal aging. Researchers believe that mitochondrial DNA, proteins, and fats are continually damaged during our lifetime, resulting in a decline in mitochondrial function as we age. Furthermore, mutations accumulated in genes that encode the proteins needed by the mitochondria could alter the components of the electron transport chain, leading to inefficient electron transport. Inefficient electron transport is known to cause an increase in the production of free radicals, which causes further damage to the cell. Thus, mitochondrial dysfunction is speculated to be a contributing factor of the aging process.

Carnitine levels have also been found to decrease with age, depriving mitochondria of fatty acids for oxidation. The researchers found that treatment of aging rats with ALC increased cellular respiration and reversed the age-associated decline of certain molecules that contribute to the maintenance of the structure and function of the mitochondrial membrane.

Furthermore, ALC treatment improved the motor abilities of both young and old rats. ALC supplementation significantly restored overall activity levels in old animals, suggesting that decline in activity may be the result of mitochondrial damage. However, while ALC increased energy metabolism, it also led to an increase in the production of free radicals. This may indicate that while ALC can increase the supply of energy in cells, it cannot mask the age-associated loss of efficiency in the electron-transport chain. Long-term administration of ALC to animals must be done to determine whether it may improve mitochondrial dysfunction that occurs during the aging process and in pathological conditions such as HD.

Thal, et al. (2000) A 1-year, multicenter, double-blind, placebo-controlled, randomized trial was conducted. Two hundred twenty nine Alzheimer’s Disease patients ages 45 – 65 were enrolled in the study. They were treated with ALC (1 g tid) or placebo. Primary outcome measures were the Alzheimer’s Disease Assessment Scale-Cognitive Component and the Clinical Dementia Rating Scale.

Two-hundred twenty-nine patients were enrolled and randomized to drug treatment, with 117 taking placebo and 112 taking ALC. There were no significant differences between the two groups at baseline. For the primary outcome measures, there were no significant differences between the treatment groups on the change from baseline to endpoint in the intent-to-treat analysis. There were no significant differences in the incidence of adverse events resulting from treatment.

Overall, in a prospectively performed study in young-onset AD patients, ALC failed to slow decline. Less decline was seen on the MMSE in the completer sample only, with the difference being mediated by reducing decline in attention.

Vamos et al. (2010): A study of HD mice found that high doses of carnitine (45 mg/kg every day) caused improvements in HD mice. The treated HD mice lived 14.9% longer than untreated HD mice, and had improvements in motor activity: they moved more, and were faster. Furthermore, when the researchers performing the study looked at the brains of the treated HD mice, they found fewer neuronal inclusions, the clumps of mutant huntingtin. This suggests that carnitine is neuroprotective in HD mice, and might help treat HD.

For further reading^

  1. Virmani, et al. “Protective action of L-carnitine and acetyl-L-carnitine on the neurotoxicity evoked by mitochondrial uncoupling or inhibitors.” Pharmacological Research. 1995; 32: 383-89.
    This article reports that carnitine can improve energy production initially inhibited by various toxins.
  2. Hagen, et al. “Acetyl-L-carnitine fed to old rats partially restores mitochondrial function and ambulatory activity.” Proc. Natl. Acad Sci USA 1998; 95: 9562-66.
    This article reports that carnitine treatment can lead to beneficial effects in aging rats.
  3. Thal, et al. “A 1-year controlled trial of acetyl-l-carnitine in early-onset AD.” Neurology. 2000 Sep 26;55(6):805-10
  4. For information on uncouplers and inhibitors, visit http://www.bmb.leeds.ac.uk/illingworth/oxphos/poisons.htm
    This page contains information on various mitochondrial toxins.
  5. For information on fatty acid oxidation, visit http://web.indstate.edu/thcme/mwking/fatty-acid-oxidation.html
    This page contains detailed, comprehensive information on fatty acid metabolism. Includes figures, structures of various lipid molecules, etc. Link to this page to learn more about carnitine, beta-oxidation, and how fats are used in our body.
  6. http://www.degussa-health-nutrition.com/degussa/html/e/health/eng/kh/l3.1.htm
    This page contains a good overview of fatty acids and fatty acid oxidation.
  7. Vamos E, Voros K, Vecsei L, Klivenyi P. Neuroprotective effects of L-carnitine in a transgenic animal model of Huntington’s disease. Biomed Pharmacother. 2010 Apr;64(4):282-6. Epub 2009 Oct 27. This technical paper describes the study of carnitine supplementation in HD mice.

-E. Tan, 9-22-01; Updated by P. Chang, 5-6-03, Updated by M. Hedlin 8-5-11

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Riboflavin

essential

Drug Summary: Riboflavin acts as an integral component of two coenzymes: FAD (flavin adenine dinucleotide) and FMN (flavin mononucleotide). These flavin coenzymes are critical for the metabolism of carbohydrates, fats, and proteins into energy. Because riboflavin is an important component of these flavin coenzymes, riboflavin supplementation is believed to increase the efficiency of energy metabolism in cells.

Riboflavin, also known as vitamin B2, is a water-soluble vitamin that is found naturally in the food we eat. Sources of riboflavin include organ meats (liver, kidney, and heart) and certain plants such as almonds, mushrooms, whole grain, soybeans, and green leafy vegetables.

In the body, riboflavin acts as an integral component of two coenzymes: FAD (flavin adenine dinucleotide) and FMN (flavin mononucleotide). A coenzyme is a molecule required for the activity of another enzyme. FAD and FMN are known as flavins since they are derived from riboflavin. These flavin coenzymes are critical for the metabolism of carbohydrates, fats, and proteins into energy. Specifically, FAD and FMN are involved in the activity of the electron transport chain, an essential component of energy metabolism that is known to be impaired in people with HD. (For more on metabolism, link to HD and Energy Metabolism).

Fig J-1: Role of NAD/NADH

In the electron transport chain, FMN is one of the components of complex I while FAD is involved in the activity of complex II. FAD acts as an electron carrier and takes part in both the Kreb’s Cycle and oxidative phosphorylation. It accepts electrons and is transformed into FADH2. FADH2 then transfers its electrons to complex II of the electron transport chain. For each pair of electrons from FADH2 passed along the electron transport chain, a number of ATP molecules are formed. FAD also affects enzymes that are responsible for the synthesis of other vital coenzymes such as NAD. Severe deficiencies in riboflavin can lower levels of coenzymes, leading to inefficient energy metabolism and consequent energy depletion. Figure J-1 shows the roles of FAD and FMN in the electron transport chain.

Impaired energy metabolism has been found to be associated with the progression of HD. Because of the role of riboflavin derivatives in the electron transport chain, scientists are looking into the possibility of riboflavin supplementation as a way of improving energy metabolism. Researchers hope that improving energy metabolism will slow or even stop the progression of HD. However, as of this time (October 2001), most studies done on riboflavin supplementation have concentrated on people with energy deficits due to mitochondrial disorders, rather than people with HD. Some of the disease mechanisms of these mitochondrial disorders are similar to those of HD. Because of these similarities, studies on people with mitochondrial disorders may be of interest to people with HD as well.

Research on Riboflavin^

Bernsen, et al. (1993) evaluated the effects of riboflavin treatment in five (5) patients with mitochondrial myopathies. Mitochondrial myopathies are disorders often characterized by defects in the electron transport chain. Specifically, the participants in the study had a deficiency of Complex I, the largest of the electron transport chain enzymes.

Complex I removes electrons from NADH, an electron carrier, and passes them to ubiquinone. As mentioned above, complex I contains a flavin component, FMN, that is essential for the proper functioning of the complex. Riboflavin supplementation is hypothesized to improve the efficiency of the Complex I protein by increasing the concentrations of available FMN molecules in the cell.

Motor and muscle strength improvements, as well as lactate levels, were used by the researchers to measure the efficacy of riboflavin. Lactate levels are used by scientists as a measure of the efficiency of metabolism in the cell. In normal cells, a form of metabolism known as aerobic respiration is usually used for energy production. If aerobic respiration is impaired, such as in the case of people with HD and with mitochondrial disorders, cells switch to anaerobic respiration, a less efficient form of metabolism. Lactate is a by-product of anaerobic respiration and lactate levels indicate which form of metabolism is the primary form the cells use for its energy needs. High levels of lactate indicate low metabolism efficiency in that cells are “forced” to use anaerobic respiration. On the other hand, low levels of lactate indicate high metabolic efficiency in that aerobic respiration is the primary form of energy production.

Before treatment, the participants suffered from high lactate levels, exercise-induced weakness, muscle atrophy and other motor problems. Treatment with riboflavin resulted in varying degrees of improvement in three of the five patients. Two patients experienced no improvement, and the remaining three patients with improved conditions showed normalized lactate levels and improved muscle strength and motor abilities.

Ogle, et al. (1997) reported the effects of riboflavin in a case involving a female patient with a myopathy caused by Complex I deficiency. The patient had a mutation that caused instability in the assembly of the complex I protein and consequent deficiency in complex I activity. She suffered from frequent falls and could no longer climb the stairs due to muscle weakness. She also showed increased lactate levels.

Treatment with riboflavin during a 3-year period showed normalization in blood lactate levels. The participant was also able to walk longer distances and to rise from the floor without difficulty. An obvious worsening of symptoms occurred during one period when the participant failed to take riboflavin. Exercise tolerance deteriorated, muscle tone worsened, and lactate levels rose during the period when riboflavin was not used. The symptoms observed when riboflavin was not used suggest that the previous improvements were associated with riboflavin supplementation.

This case suggested that riboflavin may have beneficial effects on people with Complex I deficiencies.

For further reading^

  1. Bernsen, et al. “Treatment of complex I deficiency with riboflavin.” Journal of the Neurological Sciences. 1993; 118: 181-87.
    This article reports that riboflavin treatment may have beneficial effects in some people with mitochondrial myopathies.
  2. Matthews, et al. “Neuroprotective Effects of Creatine and Cyclocreatine in Animal Models of Huntington’s Disease.” The Journal of Neuroscience. 1998, 18: 156-163.
    This article reports the Creatine supplementation results in decreased nerve cell lesions often found in cells with energy depletion.
  3. Ogle, et al. “Mitochondrial myopathy with tRNA sup Leu(UUR) mutation and complex I deficiency responsive to riboflavin.” Journal of Pediatrics. Januargy 1997; 130(1): 138-145.
    This article reports that riboflavin supplementation may improve the conditions of people with Complex I deficiency.
  4. Riboflavin available online
    Information about riboflavin, including the recommended dietary allowance, food sources, and more.
  5. Riboflavin available online
    Contains information about the possible beneficial effects of riboflavin on a variety of diseases.

-E. Tan, 9-22-01

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Dichloroacetate

Drug Summary: Dichloroacetate stimulates an enzyme called PDC that is essential for the production of energy in cells. Because inefficient energy production is believed to contribute to the progression of HD, dichloroacetate therapy could result in increased energy production, and could possibly help delay HD progression.

The altered huntingtin protein seen in the nerve cells of people with HD has been known to cause a decrease in the amount of energy available in cells by disrupting energy metabolism. (For more on metabolism, click here.) The mitochondria of HD cells appear to be damaged by the altered huntingtin and are unable to perform aerobic respiration, a form of energy metabolism. The mitochondrial damage forces cells to resort to anaerobic respiration, a less efficient form of energy metabolism. The inability to perform efficient aerobic respiration leads to decreased energy production. This energy deficit in HD cells leads to various consequences: the cell is unable to perform its different functions as efficiently as it used to and is more vulnerable to toxicity by various molecules.

Researchers believe that increasing the efficiency of aerobic respiration, and in turn, increasing the energy available to the cell, is one way of slowing the progression of HD.

One way by which scientists measure the efficiency of metabolism is cells is by measuring the cells’ lactate levels. Lactate, a by-product of anaerobic respiration, is often found in higher concentrations in cells with decreased metabolism efficiency. High levels of lactate indicate that anaerobic respiration (the less efficient form of energy production) is the primary form of metabolism. On the other hand, low lactate levels indicate that aerobic respiration is the primary form of metabolism used by the cells.

Dichloroacetate in energy metabolism^

Dichloroacetate has been found to decrease lactate production in cells by stimulating the pyruvate dehydrogenase complex (PDC), a critical group of enzymes involved in energy metabolism. The PDC is a large complex that is composed of multiple copies of three enzymes – E1, E2, and E3. The PDC serves as the vital enzyme involved in pyruvate oxidation, the step in aerobic respiration in which pyruvate is converted to acetyl-CoA. Pyruvate is a product of glycolysis, the first step in energy metabolism where sugar molecules from the carbohydrates we eat are transformed into pyruvate to be used for further processing in metabolism.

Each of the three enzymes that make up the PDC performs specific reactions that collectively transform pyruvate to acetyl-CoA. Acetyl-CoA is then transported into the mitochondria and enters the Kreb’s Cycle, a step in aerobic respiration. Once acetyl-CoA enters the Kreb’s Cycle, it undergoes various reactions that ultimately end in the production of large quantities of ATP. The PDC acts as a gatekeeper that facilitates and regulates the entry of pyruvate in to the Kreb’s Cycle.

In essence, the PDC determines whether the pyruvate molecules will be transformed into acetyl-CoA. If pyruvate is converted to acetyl-CoA, the cells can use the acetyl-CoA to undergo aerobic respiration. If pyruvate is unable to be converted to acetyl-CoA, the pyruvate is used in anaerobic respiration. If the PDC is damaged, fewer pyruvate molecules are converted to acetyl-CoA, which results in a decrease in the rate of aerobic respiration and a decrease in the number of ATP molecules produced. Instead, the pyruvate molecules stay in the cytosol and undergo anaerobic respiration, producing increased amounts of lactate. An abnormal lactate buildup results in various symptoms such as severe lethargy (tiredness) and poor feeding, especially during times of illness, stress, or high carbohydrate intake.

How is PDC activity regulated?^

A family of enzymes called PDC Kinases acts to add phosphate groups to the E1 enzyme of the PDC. Adding a phosphate group to E1 inhibits the activity of the PDC complex. Acetyl-CoA usually activates these PDC kinases as a way to stop production of more acetyl-CoA when it is already present in large amounts and continued production is no longer needed.

Dichloroacetate therapy has been used to increase the efficiency of aerobic respiration. Researchers have reported that dichloroacetate stimulates the PDC by inhibiting the kinase that inactivates the PDC. Once the kinase is inhibited, the PDC continues to be activated and is able to perform its function of converting pyruvate to acetyl-CoA for use in aerobic respiration.

Given that impaired energy metabolism is implicated in the progression of HD, dichloroacetate treatment may improve metabolism and slow HD progression. In mouse models of HD, it is thought that the altered huntingtin protein interferes with the PDC kinases, causing a decrease in active PDC in nerve cells. This additional finding of decreased active PDC in HD nerve cells further supports the possibility of using dichloroacetate to stimulate the PDC and improve cell metabolism.

Dichloroacetate safety^

There is some concern about the toxicity of dichloroacetate. Accumulations of dichloroacetate in groundwater have been described by some reports as a potential health hazard. However, concern about dichloroacetate toxicity is mainly based on data obtained in rats who were administered dichloroacetate at doses thousands of times higher than those to which humans are usually exposed. In these animals, chronic administration of dichloroacetate was found to cause liver problems and tumors. (Stacpoole, 1998.) In contrast, the dosage given to most humans is much lower than that administered to the rats. In clinical trials where dichloroacetate is used as a medical drug, no major side effects have been reported. Dichloroacetate is currently the most effective treatment for a disease known as congenital lactic acidosis (CLA). People with CLA have defective PDC enzymes and are thus unable to efficiently produce energy. In one study, patients with CLA were treated with 25-50 mg of dichloroacetate per 1 kg of body weight. No major complications were observed in the participants. (Stacpoole, 1997.) However, more research is currently being done to study the possible toxicity of dichlororacetate.

Issues of dichloroacetate toxicity have also arisen in research not directly related to HD. Dichloroacetate has also been found to protect against neuronal damage in the striatum of rats whose nerve cells have been deprived of blood flow. (Peeling, et al., 1996.) However, a recent report on an ongoing trial of dicholoroacetate treatment in people with mitochondrial disorders has reported that some patients developed new pathological symptoms and some had worsening in the transmission of nerve impulses. (Haas, et al., 2000.) Long-term trials are necessary to clarify the side effects associated with dichloroacetate and its role in HD treatment.

Research on Dichlororacetate^

Gansted, et al. (1999) investigated whether dichloroacetate can improve the condition of people with mitochondrial myopathies (MM). The researchers hypothesized that dichloroacetate treatment in people with MM will result in improved energy metabolism.  Because a decrease in metabolism is hypothesized to also be associated with HD, results of studies on MM and dichloroacetate may lead clues to the efficacy of dichloroacetate in HD treatment.

The mitochondrial myopathies are a group of neuromuscular diseases caused by damage to the mitochondria. Some of the more common mitochondrial myopathies include Kearns-Sayre syndrome, myoclonus epilepsy with ragged-red fibers (MERRF), and mitochondrial encephalomyopathy lactic acidosis and stroke-like episodes (MELAS). Mitochondrial myopathies are often caused by mutations in the DNA encoding the electron transport protein complexes, resulting in decreased ATP production. Aerobic respiration is not as efficient, so the cells of people with MM have to resort to more anaerobic respiration for their energy needs. The increased anaerobic respiration results in accumulations of lactate during exercise and contributes to exercise intolerance.

Dichloroacetate treatment was administered for 15 days to 7 people with MM. The study showed that dichloroacetate administration lowered lactate levels in most of the patients, indicating that dichloroacetate may improve metabolism efficiency. However, three patients reported that dichloroacetate caused a considerable sedative effect.

Andreassen, et al. (2001) reported that dichloroacetate has therapeutic effects in two mouse models of HD. One model, called the R6/2 mice, had C-A-G repeat lengths of 141 to 152. These mice exhibited HD-like symptoms such as decreased weight, motor dysfunction, brain atrophy, neuronal inclusions, and an increased occurrence of diabetes. The second mouse model, called the N171-82Q mice, had 82 C-A-G repeats in their Huntington genes. These mice exhibited symptoms similar to those of the R6/2 mice except that their symptoms were less severe and more delayed in onset.

Dichloroacetate treatment began at 4 weeks of age and was terminated at 12 weeks of age. A dose of 100mg/kg of body weight was administered daily. The study showed that dicholoroacetate-treated mice of both models showed significantly improved survival and motor function, as well as delayed weight loss and nerve cell loss. The development of diabetes was also delayed. Dichloroacetate was also found to maintain normal amounts of the active form of PDC. However, formation of neuronal inclusions was not altered by dichloroacetate treatment. The results of this study raise the possibility that dichloroacetate might be a potential HD treatment with therapeutic benefits for people with HD.

For further reading^

  1. Peeling, et al. Protective effect of dichloroacetate in a rat model of forebrain ischemia. Neuroscience Letters. 1996; 208: 21-24.
    Peeling, et al. reported that dichloroacetate was able to protect against neuronal damage in the striatum of rats whose nerve cells have been deprived of blood flow.
  2. Haas, et al. Results of the UCSD open label dichloroacetate trial in congenital lactic acidosis. In: Zullo SJ, ed. Mitochondrial Interest Group Minisymposium (Mitochondria: Interaction of Two Genomes). Bethesda, MD: NIH, 2000 p.2.
    Haas, et al. reported that some patients treated with dichloroacetate had developed new pathological symptoms and some had worsening in the transmission of nerve impulses.
  3. Gansted, et al. Dichloroacetate treatment of mitochondrial myopathy patients. Neurology. 1999; 52 (Suppl 2): A544.
    This article reports that dichloroacetate treatment resulted in lowered lactate levels (and consequently, increased energy production) in people with mitochondrial myopathies.
  4. Andreassen, et al. Dichloroacetate exerts therapeutic benefits in transgenic mouse models of Huntington’s disease. Annals of Neurology. 2001; 50(1): 112-6.
    This article reports that dichloroacetate treatment resulted in various beneficial effects in mouse models of HD.
  5. Stacpoole, et al. Clinical Pharmacology and Toxicology of Dichloroacetate. Environmental Health Perspectives. 1998; 106: Supplement 4.
    This article reports that rats treated with dichlororacetate at dosages thousands of times higher than normally prescribed to humans exhibited various pathological side effects.
  6. Stacpoole, et al. Treatment of congenital lactic acidosis with dichloroacetate. Archives of Disease in Childhood. 1997; 77: 535-541.
    This article reports that dichloroacetate treatment resulted in lower lactate levels in people with congenital lactic acidosis.

-P. Chang, 7/5/04

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Nicotinamide

Drug Summary: Nicotinamide (also referred to as Vitamin B3) is believed to cause improvements in energy production due to its role as a precursor of NAD (nicotinamide adenosine dinucleotide), an important molecule involved in energy metabolism. Increasing nicotinamide concentrations increase the available NAD molecules that can take part in energy metabolism, thus increasing the amount of energy available in the cell. Nicotinamide has been shown to be effective at curing motor symptoms in a mouse model of HD.

Nicotinamide and Energy Metabolism^

Nicotinamide is a vitamin that plays an important role in the synthesis of components necessary for the production of ATP. A more familiar term for nicotinamide is Vitamin B3. Vitamin B3 can be found in various meats, peanuts, and sunflower seeds. Nicotinamide is the biologically active form of niacin (also known as nicotinic acid). Both nicotinamide and nicotinic acid, as well as a variation on nicotinic acid, called inosital hexaniacinate, are available as supplements.

The human body receives its necessary quantities of nicotinamide from two sources: diet, as described above, and by synthesizing nictonamide in the body itself. Our body is able to convert tryptophan, an amino acid regularly found in the body, into niacin. Niacin is then converted to nicotinamide, which the body uses for various purposes. Figure J-2 shows a diagram depicting how nicotinamide is produced in the body.

Nicotinamide is sometimes preferred as a supplement because it lacks some of the side effects of niacin. Niacin, but not nicotinamide, has been used as a drug to lower blood cholesterol levels. Nicotinamide, on the other hand, has been found to be effective in arthritis and early-onset Type I diabetes. Nicotinamide is also currently being studied for its effects in improving energy deficits caused by mitochondrial dysfunctions.

Fig J-3: Role of NAD/NADH

Various diseases such as Huntington’s disease, Parkinson’s disease, and mitochondrial disorders are associated with impaired energy metabolism due to various mitochondrial dysfunctions. Nicotinamide is believed to cause improvements in energy production due to its role as a precursor of NAD (nicotinamide adenosine dinucleotide) which is an important molecule involved in energy metabolism. NAD acts as an electron carrier, meaning that it can accept and donate electrons to various enzymes involved in energy metabolism. Specifically, NAD is transformed into NADH when it accepts electrons in a number of reactions involved in glycolysis and the Kreb’s cycle (steps in energy metabolism). NADH then donates its electron to complex I of the electron transport chain. For each pair of electrons passed along the electron transport chain from NADH, a number of ATP molecules are formed. Increasing nicotinamide concentrations increase the available NAD molecules that can take part in energy metabolism, thus increasing the amount of energy available in the cell. Figure J-3 shows an image tracing the role of NAD in the cell.

Nicotinamide can also increase cellular energy by inhibiting the enzyme poly-ADP-ribose polymerase. Under normal conditions, damage to DNA activates poly-ADP-ribose polymerase. When poly-ADP-ribose polymerase is activated, it depletes the supply of NAD by transferring poly-ADP-ribose subunits from NAD to various DNA repair enzymes. The depletion of NAD leads to the depletion of ATP due to the decrease in the activity of both glycolysis and the Kreb’s Cycle. When nicotinamide inhibits the poly-ADP ribose polymerase, it essentially prevents the NAD molecules from becoming depleted.

Relationship between Nicotinamide and Nicotine^

Fig J-4: Structures of Nicotine and NicotinamideNicotinamide was one of the first vitamins ever discovered. Around the same time that it was discovered, scientists also found that nicotine, the addictive substance in tobacco products, can be harmful to humans. One of the ways by which nicotine causes deterimental effects in humans is that it has a similar structure to nicotinamide and can interfere with the absorption and incorporation of the vitamin. Figure J-4 shows the structures of nicotinamide and nicotine.

Fig J-5: Competition between Nicotine and Nicotinamide

Nicotine competes with nicotinamide for the binding sites in the enzymes needed for the absorption of nicotinamide, thereby lowering the amounts of nicotinamide available to cells. Figure J-5 shows a diagram depicting the competition between nicotinamide and nicotine. This competition results in the depletion of NAD molecules that the cell needs to produce energy. This is one of the reasons why smoking can worsen the condition of people with mitochondrial dysfunction.

Research on Nicotinamide^

Beal, et al. (1994) examined whether Coenzyme Q10, nicotinamide, or riboflavin can block brain lesions produced by a compound that causes a dysfunction in the mitochondria. Coenzyme Q10, also known as ubiquinone, is an antioxidant and an essential component of the electron transport chain. (For more on Coenzyme Q10, click here.) Riboflavin is a precursor of another coenzyme needed by the electron transport chain. (For more on Riboflavin, click here.)

The researchers administered the mitochondrial toxin, malonate, to a group of male rats. Malonate acts as an inhibitor of complex II of the electron transport chain and has been known to disrupt oxidative phosphorylation, leading to lowered ATP concentrations. Administration of malonate has been known to cause lesions in brains due to the deficit in energy.

The measures used by the researchers to assess the efficacy of the various supplements were lesion size after malonate administration and ATP concentrations. The researchers discovered that rats treated with coenzyme Q10 alone or nicotinamide alone showed decreased lesion size, while treatment with riboflavin had no effect on lesion size. Mice treated with a combination of coenzyme Q10 and nicotinamide showed the greatest reduction in lesion size. Furthermore, the combination of coenzyme Q10 and nicotinamide increased ATP concentrations and prevented ATP depletion caused by malonate.

These results suggest that coenzyme Q10 and nicotinamide can block ATP depletions and may improve the efficiency of the electron transport chain. It is therefore possible that coenzyme Q10 and/or nicotinamide may be able to slow the progression of HD, given that inefficiency of the electron transport chain contributes to the progression of HD.

Schulz, et al. (1995) studied the potential neuroprotective effects of Coenzyme Q10 and nicotinamide on mouse models of Parkinson’s disease (PD). Impaired energy metabolism has been found to be associated with some of the symptoms of PD.

To mimic the symptoms seen in people with PD, the researchers administered MPTP, a poison that is toxic to nerve cells. Administration of MPTP disrupts the energy metabolism of cells that release the neurotransmitter dopamine. Specifically, MPTP administration results in an inhibition of complex I of the electron transport chain of dopamine-releasing nerve cells. The impairment in the electron transport chain results in decreased ATP and increased lactate levels in the brains of people with PD. The affected dopamine cells are also unable to release as much glutamate, resulting in decreased dopamine levels in people with PD.

Dopamine concentration in the brain of treated mice was used as a measure of the efficacy of coenzyme Q10 and/or nicotinamide.

The researchers divided the mice into two groups – one group was given water that contained MPTP while another group was given normal water. The mice were then treated with either coenzyme Q10 alone, nicotinamide alone, or a combination of coenzyme Q10 and nicotinamide. They found that in mild cases, the combination of coenzyme Q10 and nicotinamide significantly protected neurons, lowering the rate of dopamine depletion. However, treatment was ineffective in mice with more severe dopamine depletions. Nicotinamide alone produced significant neuroprotective effects and prevented dopamine depletion in mild cases, but coenzyme Q10 alone showed no significant effect.

Hathorn et al. (2011): Scientists studied nicotinamide in a mouse model of Huntington’s disease. They used R6/1 mice that had between 122 and 127 CAG repeats. Each mouse given a dose based on its weight; for every gram that a mouse weighed, it received 250 micrograms of nicotinamide a day. Mice began treatment when they were 8 weeks old, and treatment ended when they were 20 weeks old.

The mice were measured in two ways. First, the behavior of the mice was studied once every two weeks. Scientists found that HD mice treated with nicotinamide were much better at tasks that required motor skills than untreated HD mice. They also found that treated HD mice explored their cages just as much as mice that didn’t have the HD mutation – which is important because HD mice generally move around much less than healthy mice.

Scientists also studied the brains of the mice. They found that levels of BDNF, an important chemical in the brain that promotes neuron health, were restored to normal. There were also increased levels of PGC-1a, a chemical that is involved in energy metabolism in the cell. However, nicotinamide did not decrease protein aggregates, or prevent the late-stage weight loss that HD mice and patients with HD generally experience. The scientists suggested that nicotinamide could be a useful treatment when used in combination with other treatments that reduce protein aggregation and help fight weight loss.

For further reading^

  1. Beal, et al. “Coenzyme Q10, and Nicotinamide Block Striatal Lesions Produced by the Mitochondrial Toxin Malonate.” Annals of Neurology. 1994; 36(6): 882-88.
    This article reports that nicotinamide treatment was able to improve the conditions of cells exposed to a mitochondrial toxin.
  2. Hathorn T, Snyder-Keller A, Messer A. Nicotinamide improves motor deficits and upregulates PGC-1α and BDNF gene expression in a mouse model of Huntington’s disease. Neurobiol Dis. 2011 Jan;41(1):43-50. Epub 2010 Aug 22. This technical article describes the study in which HD mice are treated with nicotinamide.
  3. Schulz, et al. “Coenzyme Q10 and Nicotinamide and a Free Radical Spin Trap Protect against MPTP Neurotoxicity.” Experimental Neurology. 1995; 132: 279-283.
    This article reported that nicotinamide treatment improved the condition of mouse models of Parkinson’s Disease.
  4. Hathorn T, Snyder-Keller A, Messer A. Nicotinamide improves motor deficits and upregulates PGC-1α and BDNF gene expression in a mouse model of Huntington’s disease. Neurobiol Dis. 2011 Jan;41(1):43-50. Epub 2010 Aug 22. This study found that nicotinamide helped relieve symptoms in a mouse model of HD, and is fairly technical
  5. Vitamin B-3: Niacin. Online.
    This web page describes food sources, benefits, recommended daily allowances, as well as warnings and precautions with regards to supplementation.

-E. Tan, 9-22-01; Updated by P. Chang, 5-6-03, updated by M. Hedlin 7-20-11

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Creatine

Drug Summary: Creatine (Cr) is a molecule produced naturally in the human body at a rate of about one gram per day in the liver, pancreas, and kidneys. People also consume about one gram of creatine per day in their diets, mostly from meat. Creatine is distributed throughout the body, but about 95% is found in skeletal muscles. Once creatine reaches the muscles, it exerts several effects that are believed to be responsible for the improvement of muscle function and energy metabolism. Creatine supplements, as discussed below, have several potential therapeutic benefits in Huntington’s disease. Increasing the amount of creatine in the body can prevent energy depletion, stabilize biological membranes, and initiate other mechanisms that protect cells from damage.

Creatine as an energy buffer^

In muscles, creatine undergoes a chemical reaction that converts it to phosphocreatine (PCr), the molecule that results when a phosphate group is attached to a creatine molecule. When more creatine is ingested the amount of phosphocreatine inside our cells also increases. This can be helpful because phosphocreatine acts as a reservoir for the energy rich molecule ATP in the muscle. When there is not enough ATP in cells, phosphocreatine undergoes a reaction in which it loses the phosphate group and is transformed back to creatine. The phosphate group from phosphocreatine binds to a molecule called ADP and converts it to ATP, thus providing an additional energy supply to cells. The reaction is shown below:

During periods of low energy:

PCr + ADP -> Cr + ATP

The above reaction effectively increases the amount of ATP molecules available in the cell.

It is important to note that the reaction is reversible. During periods when the cell has sufficient ATP, creatine is converted back to phosphocreatine. At the same time, ATP is converted back to ADP. Phosphocreatine and ADP are then retained in the muscle and serve as forms of energy storage. If energy is depleted again, the reaction is reversed once more, and creatine and ATP are produced. Below is the reaction between creatine and ATP:

During periods of high energy:

Cr + ATP -> PCr + ADP

Creatine and phosphocreatine also act as shuttles that connect sites of energy production to sites of energy consumption. They transport ATP from the mitochondria, the cell’s energy generator, to the cytosol, the part of the cell where most energy consuming activities occur.

It is tempting to think that phosphocreatine supplements ought to offer the same beneficial effects as creatine supplements since phosphocreatine is the molecule needed to generate ATP. However, research to date has not confirmed this prediction.

Creatine’s role in stabilizing membranes^

Creatine could potentially prevent tissue damage by stabilizing biological membranes, particularly the membranes that form the outer boundary of nerve cells. Inside such cells, the protein mtCK (mitochondrial creatine kinase) exists in two different forms. When activated, it exists in a form that binds to certain molecules in the cell membrane, making the membrane more stable. But various toxic substances called free radicals can inactivate mtCK,making the membrane less stable. (For more information about free radicals, click here.) Once mtCK is inactivated, it transforms into a less stable form that does not bind to membrane molecules, making the membrane less stable. Decreased stability of the membrane allows essential molecules to pass through, leaving the cell susceptible to the loss of important substances. Furthermore, the unstable membrane can allow the entrance of foreign substances that are toxic to the cell. Creatine and phosphocreatine have been found to decrease the release of glutamate, thereby reducing the toxic effects of glutamate on nerve cells.

Other neuroprotective effects^

Researchers speculate that glutamate, an excitatory neurotransmitter, exerts toxic effects on nerve cells due to increased sensitivity of the nerve cells to glutamate. (Click here for background on the neurobiology of HD.) Experiments have shown that phosphocreatine has the ability to decrease the release of glutamate, thereby reducing the toxic effects of glutamate on nerve cells.

Research on Creatine^

Ferrante, et al. (2000)inserted expanded C-A-G repeats into the genes of a group of mice so that they exhibited symptoms similar to human HD. (For more on CAG repeats & HD, click here.) The researchers then supplemented the mice with 1, 2, or 3% creatine, or non-supplemented diets. Assuming that the average 70-kg man eats a mixed diet providing 2,700 kcal/day, a supplementation of 1% Cr would amount to about 6 grams of Cr per day. The researchers found that survival rates increased as supplementation increased from 1% to 2%. However, administration of 3% Cr only marginally improved survival and was not as effective as either 1 or 2% creatine supplementation. Mice supplemented with 1% and 2% Cr also showed improved motor performance, diminished loss of brain mass, reduced huntingtin aggregates, and delayed neuronal death. It is unclear why mice models with diets supplemented with 3% Cr did not exhibit significant improvements.  Researchers believe that creatine may be toxic at very high concentrations.

Matthews, et al. (1998) used a toxic compound known as 3 – NP (3- nitroproprionic acid) to mimic the changes in energy metabolism seen in people with HD. (Click here for more on abnormalities in energy metabolism.) 3-NP interacts with one of the protein complexes involved in the respiratory chain and produces lesions in cells due to energy depletion. The researchers discovered that administration of 1% Cr after 2 weeks showed a decrease in nerve cell lesions. The supplemented animals also showed improved energy production compared to non-supplemented mice. Scientists then wondered whether creatine analogs —that is, drugs that are structurally related to creatine but may have different chemical or biological properties—would exert similar neuroprotective effects. Additional experiments showed that animals treated with cyclocreatine, a creatine analog, showed no improvements. Results even indicated that cyclocreatine may be toxic to animals.

The Huntington Study Group (HSG), Massachusetts General Hospital, and the University of Rochester are currently conducting a phase III clinical trial to assess the effects of creatine supplements on slowing the progression of symptoms in HD patients. The study is called the Creatine, Safety, Tolerability, & Efficacy in Huntington’s Disease, or CREST-E. Participants are randomly selected to receive either 40g per day of powdered creatine monohydrate or 40g per day of a placebo. The study is a fairly large clinical trial. It will involve 44 research centers from around the world and enroll up to 650 participants. The study will last 37 months and is estimated to be completed in December of 2014. (For the most updated information on this study, click here.)

Side Effects^

Because creatine is naturally produced by the body and is often consumed in diet, few side effects have been reported thus far, with the exception of two case reports of renal dysfunction due to creatine supplementation. However, most studies show that short-term creatine supplementation produces no adverse side effects. Nevertheless, there has been concern about the effects of long-term supplementation. Some researchers are concerned that long-term supplementation could lead to reduction in the production of creatine by the body or decrease in its transporters. A reduction in creatine transporters was reported in rats fed 4% Cr for 3 to 6 months, equivalent to 24 g/day if given to a 70 kg male. (Conversion Factor: approximately 0.1 g/kg/day) However, a study in young male athletes supplemented with 10g/day of Cr for 2 months did not result in lower transporters. The difference in results has been attributed to the much larger dose of creatine given to the rats.

In conclusion, current studies indicate that short-term creatine supplementation may be safe, but the effects of long-term supplementation are still unknown. Please check back for updates on the phase III clinical trial.

For further reading^

  1. Ferrante, et al. “Neuroprotective Effects of Creatine in a Transgenic Mouse Model of Huntington’s Disease.” The Journal of Neuroscience. 2000, Jun 15; 20(12): 4389-4397.
    A technical article describing the role of creatine in improving symptoms in mouse models of HD
  2. Matthews, et al. “Neuroprotective Effects of Creatine and Cyclocreatine in Animal Models of Huntington’s Disease.” The Journal of Neuroscience. 1998, 18: 156-163.
    Very technical article describing the possible therapeutic effects of oral administration of creatine in animal models of HD.
  3. Persky, et al. “Clinical Pharmacology of the Dietary Supplement Creatine Monohydrate.” Pharmacological Reviews. 2001, Jun; 53(2): 161-176.
    Descriptive article on the function of and science behind creatine supplementation.
  4. Website for the Huntington Study Group phase III clinical trial

-A. Zhang, 1-12-11

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