Free radical damage
- About Free Radical Damage
- Vitamin E
- Vitamin D3 (cholecalciferol)
- Vitamin C
- Lipoic Acid
- Gingko Biloba
- Coenzyme Q10
Vitamin D has been called the “miracle vitamin” by many health experts due to mounting discoveries of its significance in promoting health and fighting numerous diseases, including cancer, heart disease, and diabetes. It may also be therapeutic for neurodegenerative diseases, which may be relevant to Huntington’s disease (HD). This particular vitamin is found in many food sources, including milk, eggs, and fish, and it can also be produced by the skin through sunlight exposure. While vitamin D is widely known for its role in maintaining strong and healthy bones by helping the body absorb calcium, it is much more than a bone-protecting vitamin. Research for the past few decades has shed light on the protective effects of vitamin D on immune and neural cells and has implicated a deficiency of vitamin D as a risk factor for various brain diseases. This article will focus primarily on a form of vitamin D called vitamin D3, also known as cholecalciferol, and how the vitamin may be protective against neurodegenerative diseases such as HD.
The term “vitamin D” actually refers to a group of fat-soluble vitamins. There are five different forms of vitamin D, but the two major forms are vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol). Vitamin D2 is produced by plants, while vitamin D3 is produced by the skin of animals in response to sunlight (UV light) exposure. UV light reacts with an enzyme called 7-dehydrocholesterol to create pre-vitamin D, which rearranges its structure to form vitamin D3. An enzyme then converts vitamin D3 into a compound called calcitriol, which is the active form of vitamin D that is responsible for the numerous health benefits.
After its conversion from Vitamin D3, calcitriol exerts its effects on the body by binding to and activating vitamin D receptors (VDRs), which are located in the nuclei of target cells. Once activated, VDRs can function as transcription factors that bind to cellular DNA and control gene expression, ultimately triggering a biological response.
The major physiological role of vitamin D is to facilitate the intestinal absorption of calcium, by stimulating the expression of proteins involved in calcium transport. Vitamin D also plays a crucial role in providing the proper balance of minerals necessary for bone growth and function. However, it turns out that VDRs are present in the cells of most organs in the body, suggesting that there is wide diversity in the types of responses that vitamin D3 can promote.
Initially it was believed that only the liver and kidneys contained the enzyme responsible for producing calcitriol from vitamin D3. It is now known that many tissues, including the brain, contain this enzyme. In addition, VDRs are widely present throughout the brain, implicating vitamin D3 as a contributor to a variety of neural processes. Several of these processes are thought to be neuroprotective.
Studies have indicated that calcitriol may possess antioxidant properties and also strengthens the role of existing antioxidants in the body. For instance, Garcion et al. (1997) demonstrated that calcitriol acts similarly to traditional antioxidant nutrients by inhibiting an enzyme called inducible nitric oxide synthase (iNOS), which is overactive in patients with Alzheimer’s and Parkinson’s disease. Baas et al. (2000) showed that calcitriol increases levels of glutathione, a natural antioxidant which protects oligodendrocytes, which are brain cells that provide support and insulation for neurons.
Calcitriol can also protect neurons by producing neurotrophins, including neurotrophin-3 (NT-3), glial cell derived neurotrophic factor (GDNF), and nerve growth factor (NGF) that promote the survival of neurons in aging and with neurological injury. As shown in studies by Naveilhan et al. (1993) and Neveu et al. (1994), calcitriol increases levels of GDNF and NT-3. NT-3 protects nerve transmission and synaptic plasticity, and GDNF influences the survival and differentiation of dopamine-producing cells. In animal models of Parkinson’s disease, treatment with calcitriol increased GDNF levels and reduced oxidative stress (Wang et al., 2001). On the other hand, in newborn rodents, depleting vitamin D3 while they were in their mother’s uterus reduced levels of GDNF and NGF and caused damaging structural brain changes (Becker et al., 2005). (To read more about neurotrophins, click here.)
While there has not been much research focused on its potential role in HD, vitamin D3 deficiency has been implicated as serving a role in a number of neurodegenerative disorders.
For instance, there is compelling evidence that low levels of vitamin D3 are a risk factor for multiple sclerosis (MS), a disease in which the immune system attacks the central nervous system and causes demyelination and axon degeneration. The prevalence of MS is linked with decreasing exposure to solar UV radiation, and a study by Munger et al. suggests that high circulating levels of vitamin D3 correspond to a lower risk of MS.
There is also evidence that vitamin D3 deficiency is relevant for Parkinson’s disease and Alzheimer’s disease. The greatest number of VDRs are found in the substantia nigra, the portion of the brain that primarily degenerates in Parkinson’s disease and can also be affected in HD. Treating substantia nigra neurons with vitamin D3 protects them from Parkinson-like insults (Shinpo et al., 2000). In Alzheimer’s disease, a condition characterized by dementia and neuron loss in the hippocampus, some evidence suggests that there may be a vitamin D3 deficiency early in the disease (Landfield et al., 1991), and, in aging rats, treating with calcitriol reduced hippocampus shrinkage and prevented decreases in neuron density (Landfield and Cadwallader-Neal, 1998). Although more extensive research into this area is needed, these results suggest that vitamin D3 could have a potential role in the prevention of neurodegenerative disorders.
Despite the many exciting findings about this “miracle vitamin” over the years, determining the many health benefits of vitamin D3 is still an active area of research. While the extent to which vitamin D3 contributes to neural processes is not clearly understood, there is currently much evidence to support a neuroprotective role for vitamin D3 in the brain, as well as promising evidence that it may have preventative effects against neurodegenerative disorders.
Becker, Axel et al. “Transient prenatal vitamin D deficiency is associated with subtle alterations in learning and memory functions in adult rats.” Behavioural brain research 161.2 (2005): 306–312.
Garcion, E et al. “1,25-Dihydroxyvitamin D3 inhibits the expression of inducible nitric oxide synthase in rat central nervous system during experimental allergic encephalomyelitis.” Brain research. Molecular brain research 45.2 (1997): 255–267. Print.
Landfield, P W et al. “Phosphate/calcium alterations in the first stages of Alzheimer’s disease: implications for etiology and pathogenesis.” Journal of the neurological sciences 106.2 (1991): 221–229. Print.
Landfield, P W, and L Cadwallader-Neal. “Long-term treatment with calcitriol (1,25(OH)2 vit D3) retards a biomarker of hippocampal aging in rats.” Neurobiology of aging 19.5 (1998): 469–477. Print.
Shinpo, Kazuyoshi et al. “Effect of 1,25-dihydroxyvitamin D3 on Cultured Mesencephalic Dopaminergic Neurons to the Combined Toxicity Caused by L-buthionine Sulfoximine and 1-methyl-4-phenylpyridine.” Journal of Neuroscience Research 62.3 (2000): 374–382. Web. 7 Apr. 2013.
Wang, J Y et al. “Vitamin D(3) attenuates 6-hydroxydopamine-induced neurotoxicity in rats.” Brain research 904.1 (2001): 67–75. Print.
J. Nguyen 2013More
It has long been known that melatonin, a hormone produced in the brain, plays an important role in regulating the body’s natural sleep-wake cycle by causing drowsiness and inducing sleep. The pineal gland, a small structure located beneath the center of the brain produces and releases melatonin in response to the intensity and type of light detected by the eyes. Darkness causes increased melatonin release, while light inhibits melatonin release. What results is a daytime decline and nighttime rise in melatonin levels that mirrors waking and sleeping. Thus, melatonin plays an important role as a regulator of the biological clock. Because of this, melatonin is sometimes prescribed as a treatment for sleep disorders. Disruption of normal sleep is a common symptom in HD, and more information about sleep and HD can be found here.
Outside of sleep regulation, melatonin is also involved in many human bodily processes including learning, memory, and aging. Some of these functions are brought about by the antioxidant properties of the hormone itself, while others are attributed to melatonin binding with its receptor proteins, MT1 and MT2. There has been a great deal of interest in studying these additional benefits of melatonin, since it is already an FDA-approved drug. In terms of HD specifically, researchers have recently identified melatonin as a neuroprotective agent due to its role in inhibiting the neuronal death characteristic of HD. Since melatonin acts through so many different possible mechanisms, how exactly can melatonin produce its therapeutic effects against HD and affect disease progression?
In order to understand the role of antioxidants like melatonin in HD, we must first briefly review free radical damage, a phenomenon implicated in HD-associated neuron death. Free radicals are highly reactive molecules that are natural byproducts of biochemical processes in the body, but high levels of free radicals can be toxic to cells in the body because they cause oxidative damage. Neuron cells in the brain, seem to be particularly susceptible to oxidative damage. For more information about free radicals and how they damage cells, click here.
One cause of free radical excess is glutamate excitotoxicity. Glutamate is an important neurotransmitter, a chemical signal used by neurons to communicate with each other. Normally, binding of glutamate to NMDA receptors on neurons is responsible for processes such as learning and memory in the brain. Scientists believe that in HD, the mutant huntingtin protein causes problems that lead to excess binding of glutamate (for more information about NMDA receptors and glutamate toxicity, click here). One of the eventual results of this defect is the overproduction of free radicals.
Another mechanism that can lead to free radical damage in HD is dysfunction of the mitochondria, the parts of the cell that act as energy power plants. A normal byproduct of the mitochondria producing energy for the cell is the generation of free radicals. However, if mitochondria are defective they may overproduce free radicals, leading to increased damage in the cell. This is one possible explanation for the mitochondrial defects observed in some patients with HD.
As a defense mechanism against harmful free radicals that are normally produced, the body employs molecules known as free radical scavengers, which we more commonly refer to as antioxidants. As their name implies, free radical scavengers encounter free radicals and detoxify them before they can damage cells or tissues. Melatonin, in addition to being a hormone that regulates sleep-wake cycles, is also a potent antioxidant. Its antioxidant properties go beyond free radical scavenging. There is evidence suggesting that melatonin can stabilize cell membranes and thereby increase the cell’s resistance against free radicals, that it can stimulate cellular production of other antioxidants, and that it may even play a role in directly inhibiting production of certain types of free radicals. Melatonin is also among the few antioxidants that can cross the blood-brain barrier, thus extending its protective properties to neurons in the brain.
Much research has been done to determine whether melatonin is truly effective for reducing oxidative damage. In order to mimic neuronal damage as a result of uncontrolled free radical levels in HD, scientists use chemicals such as quinolinic acid and 3-nitropropionic acid. The former is a molecule that binds to NMDA receptors which mimics glutamate, while the latter interrupts mitochondrial activity, and injection of either chemical into animal models result in oxidative damage similar to the neuropathology seen in brains of HD patients. In a 1999 study performed by Southgate et al., rat brains were treated with quinolinic acid, which caused oxidative damage to cell membranes. However, after the addition of melatonin, the amount of damage decreased significantly, suggesting that melatonin has protective antioxidative effects. In a more recent 2005 study by Nam et al., 3-nitropropionic acid was injected directly into the striatum of rats, creating neuronal lesions similar to those seen in HD. Treatment with melatonin reduced the amount of free radical damage to levels comparable to control mice that did not have a 3-nitropropionic acid injection, and significantly decreased the size of neuronal lesions in 3-nitropropionic acid injected mice. All of these studies provide evidence that melatonin has protective effects against these chemically-induced HD models through antioxidant action. However, it is important to remember that these chemical treatments do not precisely replicate HD and further research must be done to demonstrate the effects of melatonin on oxidative damage in HD.
The reasons why melatonin demonstrates neuroprotective effects are still unknown, but aside from its antioxidant properties, researchers have also shown that the interaction of the hormone with its receptors could be another way it protects the brain from damage by HD. Like all hormones, melatonin is a chemical signal, and in order to bring about responses, melatonin must bind to one of its two receptors in the body – MT1 and MT2. Since altered levels of MT1 and MT2 receptors have been observed in other neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease, it is possible that the melatonin receptors can play a role in HD as well.
In 2011, Friedlander’s research group conducted a study on the interaction between melatonin and its receptors in HD models and the therapeutic potential of melatonin treatment. Their results shed light on the means by which melatonin might protect neurons. Firstly, they found that in addition to its free radical scavenging abilities, melatonin treatment in vitro also blocked cellular pathways that lead to neuron death, or apoptosis, which some research suggests is increased by the mutant huntingtin protein in HD. More importantly, they found that this effect is achieved by melatonin binding specifically to MT1 receptor. However, in brain tissue samples of both mice carrying the mutant huntingtin gene and patients with HD, levels of MT1 receptor seemed to decline along with HD progression – samples that had more severe, late-stage HD pathology also had significantly lower levels of MT1. This fact, coupled with the earlier findings that melatonin provides cell survival signals via the MT1 receptor, suggests that this interaction is disrupted in HD and is a potential target for HD therapeutics.
The Friedlander research group subsequently tested the effect of melatonin treatment in HD mouse models. In contrast to the earlier animal models mentioned which were induced by chemicals to exhibit HD-like symptoms, they chose to employ transgenic mice that carry a version of the mutant huntingtin gene. Daily melatonin treatment showed a beneficial effect on HD mice. Not only did melatonin-treated mice retain normal movement control longer before onset of disease, but they also survived 21% longer than HD mice with no treatment. Brain tissues were also less damaged in melatonin-treated mice than in untreated mice. However, some key characteristics of HD – such as weight loss and levels of mutant huntingtin protein aggregates – remained unaffected by melatonin. Nevertheless, the results of this in vivo study was a physiological reflection of the in vitro findings that melatonin binding with MT1 may help protect neurons by inhibiting certain pathways that cause cell death.
Melatonin’s antioxidative properties and its interaction with MT1 receptors both seem to contribute to its protection of neurons in HD and make it a promising therapeutic candidate for the disease. However, research on melatonin’s effect on HD progression is still in its early stages and further work must be done to validate these results before melatonin can potentially be studied in clinical trials. On the bright side, the fact that melatonin is already an approved drug for treating certain sleep-related conditions could expedite the approval process required for future clinical studies in human patients.
-J. Choi, 1-27-13
Aside from impaired energy production, damage to the mitochondria leads also to increased production of toxic molecules called free radicals. Compounds called antioxidants act as free radical scavengers by initiating reactions that make free radicals non-toxic to cells. Evidence indicates that damage by free radicals is a contributing factor to the pathology of HD. Consequently, compounds with antioxidant properties are being studied to see if they can serve as possible treatments for HD.
Free radicals are atoms or molecules that are highly reactive with other cellular structures because they contain unpaired electrons. Free radicals are natural by-products of ongoing biochemical reactions in the body, including ordinary metabolic processes and immune system responses. Free radical-generating substances can be found in the food we eat, the drugs and medicines we take, the air we breathe, and the water we drink. These substances include fried foods, alcohol, tobacco smoke, pesticides, air pollutants, and many more. Free radicals can cause damage to parts of cells such as proteins, DNA, and cell membranes by stealing their electrons through a process called oxidation. (This is why free radical damage is also called “oxidative damage.”) When free radicals oxidize important components of the cell, those components lose their ability to function normally, and the accumulation of such damage may cause the cell to die. Numerous studies indicate that increased production of free radicals causes or accelerates nerve cell injury and leads to disease.
Antioxidants , also known as “free radical scavengers,” are compounds that either reduce the formation of free radicals or react with and neutralize them. Antioxidants often work by donating an electron to the free radical before it can oxidize other cell components. Once the electrons of the free radical are paired, the free radical is stabilized and becomes non-toxic to cells. Therapy aimed at increasing the availability of antioxidants in cells may be effective in preventing or slowing the course of neurological diseases like HD.
-E. Tan, 9-21-01More
Drug Summary: Mithramycin (also known as MIT and plicamycin) is an antibiotic that binds to DNA to regulate transcription. It attaches to specific regions of DNA that are rich in guanine and cytosine. While it is currently prescribed for the treatment of certain types of cancer and a few other conditions, recent research shows that it is helpful in treating motor symptoms and prolonging life in a mouse model of HD.
Normally in the course of Huntington’s disease certain genes are prevented from being expressed in their normal protein products. This abnormal repression of genes is referred to as transcriptional dysregulation. Remember that “transcription” is the process by which the information of DNA is copied into messengers that are then used as templates for protein synthesis. Many of the genes that are prevented from being expressed are important for nerve cell health and survival. So, when these genes are blocked from producing their respective proteins, they cannot help to prevent the neurodegeneration that is typical of HD. This repression is caused by the mutant huntingtin protein, which interacts with molecules that would normally aid in the transcription of these helpful genes. The proteins that are encoded by the repressed genes have a wide variety of functions, which may explain why there are so many different symptoms associated with HD. One possible way to prevent many of these symptoms is to restore normal transcription, which is the proposed function of the drug mithramycin.
A number of hypotheses exist for how mithramycin acts in the body, but a group of researchers recently discovered what may be the key mechanism by which it prevents gene repression. One way that genes are repressed, or “silenced,” is through a process called methylation. Before explaining exactly what methylation is, we will first review how DNA is organized.
The entire DNA code is extremely long, and in order to be able to fit it into each cell, it needs to be very tightly compacted into chromosomes. (For more information on chromosomes, click here.) To accomplish this compression, the DNA is wound around structures called nucleosomes. You can think of a nucleosome as a spool and the DNA as the thread. Nucleosomes are made up of smaller proteins called histones. There are four different core histones (H2A, H2B, H3, and H4), and two of each are present in every nucleosome, along with one helper histone (H1). Histones play a very important role in the regulation of transcription.
By controlling access to DNA, histones determine if and when transcription occurs. When the histones keep the DNA tightly wound up, transcription factors cannot access the DNA, and it therefore cannot be transcribed. Different chemical groups (a chemical group can be a single atom or a small molecule) can be added to the histones in specific spots, causing the DNA to coil up to prevent transcription or causing the DNA to uncoil to allow transcription.
One way to control transcription is by methylation. In methylation, a chemical group called a methyl group is added to histone H3 or H4 at specific spots. When a histone is methylated at one of these spots, a protein called HP1 recognizes this signal and binds to the methyl group. These HP1 proteins also recognize each other and bind together, winding the DNA up into the coiled form of chromosomes in the process. Remember that in this coiled form, transcription factors cannot bind to the DNA so transcription cannot occur: the genes have been silenced. Methylation is a fairly permanent way of controlling transcription, so it can be devastating for an important section of the DNA to be wrongly methylated.
According to an important hypothesis, mithramycin helps restore normal transcription by regulating methylation. Researchers have discovered in a mouse model of HD that histone H3 was hypermethylated (methylated more that usual) at its ninth amino acid (recall that histones are proteins made up of amino acids in a long string or “chain”). It is already well known that increased methylation at this particular spot affects transcription. After conducting several experiments, the researchers concluded that mithramycin exerts its neuroprotective effects by preventing this hypermethylation and restoring normal transcription. Exactly how mithramycin prevents the hypermethylation has yet to be decisively determined, but the researchers have proposed a likely explanation.
Mithramycin is known to bind to areas of DNA that are rich in guanine (G) and cytosine (C), two DNA bases. (For more information on DNA bases, click here.) By binding to a GC-rich section of DNA, mithramycin likely prevents another molecule, which plays a role in methylation, from binding. Such molecules that aid in methylation could be either transcription factors or a type of enzyme called histone methyltransferase (HMT). HMT adds methyl groups to histones, causing the DNA to coil up as noted earlier and make it inaccessible for transcription. Transcription factors can also play a role in gene silencing by recruiting HMT. One type of transcription factor (TF) is already known to recruit an HMT that specifically binds to histone H3 at the ninth amino acid. These transcription factors bind to the DNA and recruit a specific HMT. The HMT then methylates the histone, preventing transcription. While a transcription factor that binds to GC-rich areas of DNA has yet to be found, researchers hypothesize that if there is such a molecule, mithramycin displaces it, preventing methylation. By preventing hypermethylation, mithramycin restores normal transcription, preventing much of the neurodegeneration typical of HD in the mouse model.
Ferrante, et al. (2004) tested the effects of mithramycin on a transgenic mouse model of HD. The researchers daily injected one group of mice with one of five different doses of mithramycin and another group of mice with a placebo to serve as a comparison group. The mice were tested for body weight twice a week, motor performance once a week at first and later twice a week, and observed twice a day for survival. The researchers found that the dose of mithramycin influenced how long the mice lived. The benefits of mithramycin peaked at a dose of 150 micrograms per kilogram per day, since lower doses were less effective and higher doses were not well tolerated (and even resulted in death). The optimal dose of mithramycin led to the longest extension of survival ever seen in the HD transgenic mouse, extending survival by 29.1%. While this finding is very encouraging, we must remember that the experiment was done on mice and issues with drug safety and tolerability may prevent mithramycin from being so effective in humans.
In addition to their longer lives, the mithramycin-treated transgenic mice also performed better than the placebo-treated mice on the motor performance test each time they were tested. Motor performance was tested using the “rotarod” apparatus, which is a rotating rod on which the mice are placed and timed for how long they can stay on. The total motor improvement over placebo-treated mice was 42.6%. Mithramycin did not appear to affect the body weight of the transgenic mice.
When HD in the transgenic mice had become so advanced that they were no longer able to feed or move when prodded, they were euthanized and their brains examined. Amazingly, the researchers found that the mice that were treated with mithramycin had almost none of the typical brain deterioration seen in HD. The mithramycin-treated mice did not exhibit brain atrophy, enlarged ventricles, or loss of nerve cells in the striatum, which are typical symptoms of HD in both mice and humans. (For more information on HD and the brain, click here.) While the placebo-treated mice had a 21.3% reduction in brain weight, those treated with mithramycin experienced only a 2.8% reduction in brain weight. Also, the size of the nerve cells in placebo-treated mice decreased by 41.9%, while the mithramycin-treated mice did not have any significant decrease in nerve cell size compared to non-HD mice. These results show that mithramycin improves survival and is neuroprotective, since fewer nerve cells in the brain die and they remain at the normal size.
Once the researchers determined the effectiveness of mithramycin in treating HD mice, they tested several different hypotheses to find out how exactly the drug works. These experiments ruled out several mechanisms. They found out that mithramycin does not reduce the amount that the HD allele is transcribed (which would result in less of the harmful huntingtin protein); it does not change the amount of glutamate receptors or their activity (which would reduce the amount of excitotoxicity); and it does not change the permeability of mitochondria (which would reduce programmed cell death). The final hypothesis left was that mithramycin prevents the mutant huntingtin protein from interfering with transcription of specific genes that are important for nerve cell survival. There are several ways that mithramycin could restore normal transcription, and the researchers determined that it was by preventing methylation at a specific spot of histone H3 (as explained earlier). By preventing too much methylation, mithramycin allows genes to be expressed that promote survival in the presence of mutant huntingtin.
This initial study of mithramycin on the HD transgenic mouse shows very promising results. While the drug is already approved by the Food and Drug Administration (FDA) for the treatment of cancer and other diseases, it is too early to tell if mithramycin will be useful in treating people with HD. Since HD is a chronic condition, it important to determine whether a potential treatment can safely be used for long periods of time. Unfortunately, mithramycin is not well-tolerated in people at the typical dose for long-term use. In fact, the typical human dose is 25-30 micrograms per kilogram per day (recall that the optimal dose given to mice was much larger at 150 micrograms per kilogram per day) and is only given up to ten days. Mithramycin has been shown to cause unpleasant side effects, including nausea and vomiting, and long-term use has been shown to lead to excessive bleeding. Research on humans with HD will have to be conducted to test the efficacy of mithramycin given at non-continuous doses and/or smaller doses.
-K. Taub, 8-10-05
Arginine and Huntington’s Disease:
Arginine is an amino acid produced naturally in the body and has a significant effect on human brain chemistry. Amino acids are the building blocks of proteins and, in humans, are either produced in the body or consumed in the diet. Scientists hope that through investigating the way arginine interacts with the brain, they can learn more about the mental decline associated with age-related dementia, Parkinson’s disease, and Huntington’s disease (HD) to search for potential solutions.
Arginine is a non-essential amino acid meaning that the human liver can make its own arginine, so, in most cases, it does not need to be obtained from food. It can stimulate the secretion of growth hormone, which as the name suggests causes growth and cell regeneration. Thus, it can aid in the healing time of damaged tissues.
Arginine is also the dietary precursor of nitric oxide (NO), which is a gas that can serve as a cellular messenger in both the brain and body. NO plays an important role in a variety of biological functions, including blood vessel dilation, immune responses and neurotransmission.
NO serves multiple functions in maintaining brain chemistry in non-HD brains. Depending on its concentrations in local tissues, NO can be both neuroprotective – protecting nerve cells from damage – and neurotoxic – toxic to nerve cells, possibly causing apoptosis or cell death. Since NO serves many different purposes, scientists are uncertain whether increases in NO levels would be helpful or harmful to the brain, and how much of an effect it would have. Therefore, using dietary arginine as a treatment for HD – which would increase levels of NO – could be either beneficial or harmful.
Overproduction of NO can be toxic to nerve cells. NO combines with superoxide, a very unstable and reactive molecule, to make peroxynitrite. Peroxynitrite is able to alter proteins, fragment DNA, and interfere with the energy metabolism of cells- all of which are toxic to nerve cells and contribute to HD.
On the other hand, NO can be neuroprotective. Because NO production depletes free radicals like superoxide O2-, NO is considered to be an anti-oxidant and prevents the damage to nerve cells caused by free radicals. However, it is this very characteristic that allows NO to combine with peroxynitrite, the nerve cell toxin described above. Since arginine in the diet increases NO, arginine supplements could have two completely opposite outcomes, like two sides of a coin – and researchers are working to understand how this coin toss plays out in the body.
NO may also be involved in HD, although scientists are still debating its role in the disease. One HD-related change in the brain is increased blood flow to the brain, or cerebral blood flow (CBF). In 1986, scientists found that heart attack drugs, which were designed to widen blood vessels, also released NO. They suspected that NO might play a part in widening blood vessels. The correlations between arginine, NO, blood flow, and changes in CBF associated with HD led to studies investigating the link between arginine and HD.
Studies from the past decade are inconclusive as to whether or not a lack of NO contributes to HD. In one study, researchers at the University of Connecticut fed aged HD transgenic mice (For more information on animal models, click here.) diets of differing concentrations (0, 1.2 or 5%) of arginine. They looked at the effect of dietary arginine on three symptoms of HD: weight loss, loss of motor control, and increase in CBF:
Both the 1.2 and 5% groups had elevated levels of peroxynitrite, which suggests that excess NO is can be toxic to nerve cells, though a slight increase in NO, as seen in the 1.2% group, seems to be beneficial to motor function.
These findings are supported by earlier studies which showed that decreasing NO levels in the body with a compound, 7-nitroindazole, which blocks the enzyme that synthesizes NO, called nitric oxide synthase (NOS), reduced resting CBF by 17-27% in rats and 30% in humans.
Arginine could also potentially be used to measure degeneration in HD patients. In a recent study of HD pathology, patients were injected with arginine and tested for levels of growth hormone in the blood. Growth hormone levels can indicate whether there is any impairment in the hypothalamus, a part of the brain responsible for many metabolic processes, so researchers were hoping this could be another method to measure the progression of HD. Results showed that there were two subgroups of HD patients: those with the normal response of increased growth hormone levels, and those that did not show an increase in growth hormone levels. It remains unclear whether the two subgroups exist due to different stages of the disease or to different patterns of neurodegeneration. Further research needs to be conducted in this area.
Scientists are still unsure whether NO plays a part in primary or secondary disease mechanisms of HD. In other words, it is unknown if NO itself causes HD symptoms or is only a part of a chain of events in the brain leading to nerve cell death. Both arginine and NOS inhibitors will remain in the experimental phase for HD treatments until more studies are done.
-A. Zhang, 10-11-11More
Drug Summary: Vitamin E is commonly found in the diet, in oils, margarine, and dressings. It is a lipid-soluble vitamin that protects cell membranes and other lipid-containing substances in the body, by interacting directly with free radicals and neutralizing them to prevent oxidative damage. Vitamin E could potentially help treat neurodegenerative diseases such as HD by protecting nerve cell membranes (which are made of lipids) from oxidation by free radicals, which can lead to cell death. (For more information on free radical damage, click here.) Studies in people with Parkinson’s disease or Alzheimer’s disease have shown some correlation between higher vitamin E intake and decreased risk of developing these diseases. (For more information on Alzheimer’s and Parkinson’s, click here.) However, there have been contradictory results in studies that tested whether vitamin E treatment could slow the progression or improve the symptoms of these diseases. Not many studies have been conducted to test the effects of vitamin E in people with HD. Unfortunately, the few results that exist have been inconclusive, with some indicating only slight benefits among some patients with mild symptoms, while others suggesting that vitamin E could potentially even have negative effects on health.
Vitamin E is lipid-soluble, meaning that it dissolves in fats. It has to be ingested with minimal amounts of dietary fat to be properly absorbed in the gastrointestinal (GI) tract. Vitamin E exists in eight different chemical forms, but the most common form in the human body is called alpha-tocopherol (α-tocopherol). Alpha-tocopherol’s main role inside the body is to act as an antioxidant. Alpha-tocopherol is lipid-soluble, so it mostly exerts its antioxidant effects on parts of the cell that are also lipid-soluble, such as the cell membrane, an important part of the cell that is made of lipids. Because cell membranes are made of lipid molecules, they are vulnerable to oxidation by free radicals, which can lead to cell death. Alpha-tocopherol plays a very big role in protecting cell membranes by donating its own electrons to free radicals in order to neutralize them.(For more information on free radical damage, click here.) Although alpha-tocopherol loses its antioxidant activity once it donates an electron, other antioxidants like vitamin C can restore alpha-tocopherol’s antioxidant properties. (For more information on vitamin C, click here.)
Besides protecting cell membranes, alpha-tocopherol has also been shown to protect low density lipoproteins (LDL) from oxidation by free radicals. LDL’s are particles made of both lipids and proteins that carry fats and cholesterol through our bloodstream. Research shows that oxidized LDL may increase a person’s risk of developing heart disease. Alpha-tocopherol may therefore exert positive effects in people with HD not only by protecting nerve cell membranes, but also by helping to prevent other complications such as heart disease. (For more information on heart disease and other complications of HD, click here.)
In addition to having these antioxidant effects, alpha-tocopherol affects several other cellular mechanisms and is known to act as a blood-thinner. Blood thinners can help reduce one’s risk of heart attack and stroke by preventing the formation of blood clots in blood vessels. It is important to remember that taking high doses of a blood-thinning compound like vitamin E along with other blood thinners is not advised, and anyone who wishes to take vitamin E as a blood thinner should first consult their doctors.
Several laboratory studies have shown that vitamin E has great potential as an antioxidant. One such study showed that another form of vitamin E, alpha-tocotrienol, protected nerve cells from increased free radical damage and toxicity caused by the neurotransmitter glutamate (Khanna, et al. 2003). Because the nerve cells of people with HD are especially sensitive to glutamate, the prevention of glutamate-induced oxidative damage is very important. (For more information on glutamate toxicity, click here.) In this laboratory study, treatment of nerve cells with alpha-tocotrienol not only decreased cell death but also helped them grow at a normal rate even when treatment with glutamate was continued.
The same researchers found that alpha-tocotrienol not only protects nerve cells by reacting with free radicals directly, but can also prevent free radicals from forming. Alpha-tocotrienol can prevent excessive oxidative damage by inhibiting an enzyme called 12-lipoxygenase (12-LOX), an effect independent of its antioxidant properties. Increased levels of glutamate around the nerve cells cause activation of 12-LOX within the cells, which when activated leads to a cascade of events that lead to production of free radicals and an influx of calcium ions into the nerve cells. These events eventually lead to nerve cell death. Alpha-tocotrienol inhibits 12-LOX from setting off this cascade by binding to it close to its active site. The active site is the spot where an enzyme would normally bind to other molecules, or substrates, in order to set off a reaction in the cell. 12-LOX normally binds to a molecule called arachidonic acid to set off the above-mentioned cascade of events. By binding close to the active site, alpha-tocotrienol prevents 12-LOX from binding arachidonic acid and setting off the reactions that would eventually lead to nerve cell death.
Besides laboratory findings, there is also some clinical evidence that increased intake of vitamin E may help reduce the risk of developing Parkinson’s and Alzheimer’s disease, both of which also involve increased oxidative stress. However, studies that tested whether vitamin E supplementation could help reduce symptoms or slow the progression of these diseases have had varied results. One study of a total of 341 people with Alzheimer’s disease showed that treatment with alpha-tocopherol was associated with a delay in the progression of cognitive symptoms when compared to the placebo group. The group treated with alpha-tocopherol also demonstrated a slower decline in their abilities to perform everyday functions. Research on the protective properties of vitamin E in Parkinson’s disease has been inconclusive in both animals and humans; some studies have shown vitamin E to be protective and others have not.
Peyser, et al. (1995) conducted a 1-year clinical trial with 73 HD patients who were randomly assigned to receive either alpha-tocopherol treatment or a placebo. Since vitamin E interferes with the absorption of vitamin A in the intestines, these researchers decided that subjects in the treatment group should also take a vitamin A supplement in order to prevent the potential development of Vitamin A deficiency. Because vitamin C can restore vitamin E’s antioxidant abilities after it has neutralized a free radical, the treatment group also received daily vitamin C supplements.
These researchers reported that they unfortunately were not able to obtain placebo vitamin A and C pills for the control group, so both the vitamin E treatment group and the control group ended up taking vitamin A and C supplements, which are also antioxidants. Giving both groups these additional vitamins could not produce the same strong evidence as would the use of completely neutral placebo pills. The control group may have also showed some sort of improvement simply because they were given these two vitamins. Furthermore, the vitamin E treatment group may have benefited from the additional vitamins. However, the researchers were still able to establish some specific effects of adding vitamin E to the vitamin A and C combination.
These researchers realized that participants responded differently to the vitamin E supplementation depending on which stage of HD they were in when they started treatment. In order to analyze the results, they split both the treatment and placebo group in two based on the participants’ initial scores on a neurological test. Participants who entered the study with a score of 45 or less were considered to be in the early stages of HD, and participants who had initial scores of more than 45 were considered to be in the late stages. Based on this grouping, the researchers showed that on average, early-stage participants who were treated with vitamin E improved on the neurological examination by the end of the study. Meanwhile, late-stage participants did not show this improvement. This study is important because it shows that vitamin E may have potential to slow HD progression caused by free radical damage, but only if treatment is started before severe nerve cell damage takes place.
A newer study by Kasparova et al. (2006) done on rat models of HD showed that administration of a combination of vitamin E and coenzyme-Q10 (For more information on coenzyme-Q10, click here.) could have potential benefits for HD patients. The rats received coenzyme-Q10 and vitamin E for 10 days before they were injected with 3-NP, a chemical that would create lesions in the striatum, resulting in symptoms similar to HD. Results showed that the increase of creatine kinase, an indicator of brain energy metabolism dysfunction, as well as the decrease of coenzyme-Q10, were prevented in the brain tissue of these rats as compared those in the control group. However, coenzyme-Q10 and vitamin E were not effective in preventing the decline of electron transport chain function (For more information on electron transport chain function and abnormalities in energy metabolism, click here.).
In recent years, researchers at John Hopkins University have reported that patients who take high doses of vitamin E (more than 400IU) had higher risks of death, although it remains unclear why. Vitamin E supplements typically contain 400-800IU (1IU = 2/3 mg), which meets the criterion for high dosage. The data is still inconclusive as to whether lower doses of vitamin E are also associated with this risk. Furthermore, the studies were conducted on older adults, and many of them had heart diseases and other diseases. Nevertheless, HD patients taking high doses of vitamin E should consult with their doctors and might want to consider taking other types of antioxidants.
In conclusion, while vitamin E has beneficial antioxidant effects, it may be toxic at higher doses. Further research needs to be completed to determine whether vitamin E can be a safe and effective therapeutic treatment for Huntington’s disease. As of Spring 2012, not many studies have been conducted investigating the relationship between vitamin E and Huntington’s disease specifically.
– A. Milczarek, 05/03/05, updated A. Zhang, 4/18/12
Drug summary: Vitamin C, also known as ascorbic acid, has been shown to have antioxidant properties. Research shows that in nerve cells, vitamin C has the ability to directly react with free radicals to prevent oxidative stress, which contributes to the progression of the HD disease process. (For more information on free radicals and antioxidants, click here.) Vitamin C may also have the potential to prevent toxicity caused by a neurotransmitter called glutamate. (For more information on glutamate toxicity, click here.)
In the 1970’s, famous Nobel Prize-winning scientist Linus Pauling advocated Vitamin C use to prevent and cure anything from the common cold to heart disease and cancer. While the recommended daily intake of vitamin C is around 60-75 mg, Pauling himself supposedly took 12,000 mg daily and increased that value to 40,000 mg if he felt a cold coming on! While most doctors and researchers have never agreed with Pauling about the wonders vitamin C could work, there is now evidence that vitamin C actually plays an important role in protecting nerve cells from oxidative damage, which may prove vitamin C supplementation to be a promising treatment for people with HD.
Vitamin C, or ascorbic acid, is a water-soluble vitamin. While most animals can make their own vitamin C, humans and a few closely related animals have lost this ability because of a mutation in their DNA that occurred earlier in their evolution. This means that we have to supply the body with small daily amounts of vitamin C through our diet. In the body, vitamins work as coenzymes, meaning that they help enzymes facilitate necessary reactions. Vitamin C’s job is to help in the reactions by which the body makes necessary molecules. One of these is collagen, which makes up connective tissue throughout the body. Another is the molecule carnitine, which shuttles fats into the mitochondria, where they are converted into energy. (For more information on how carnitine can help treat HD, click here.) Vitamin C is also necessary in the synthesis of the excitatory neurotransmitter noradrenaline (also called norepinephrine).
Vitamin C also has antioxidant properties that may prove to be helpful in treating HD. Inside the body, ascorbic acid (vitamin C) changes form to become the negatively charged ascorbate. Ascorbate can then directly neutralize very reactive free radicals by donating its own electrons to them. In this way ascorbate can protect other cell components from oxidation by free radicals. Oxidation can cause cell components to lose their ability to function normally, and excessive oxidative damage may eventually lead to nerve cell death. It has even been found that ascorbate prevents free radicals from oxidizing its fellow vitamin, vitamin E! (For more information on vitamin E, click here .)
In humans, there is normally a very high concentration of ascorbate in the part of the brain called the striatum. Interestingly, the striatum is the same part of the brain that is most affected by HD. (For more information about the brain and HD, click here.) Most of the ascorbate in this part of the brain exists in the extracellular fluid, or in the spaces between the nerve cells. Scientists now know that ascorbate is actually released from the nerve cells into the extracellular space during times of motor activity. Researchers recently found that in HD mice, this releasing mechanism does not work as well as it does in normal mice. This finding suggests that a decline in motor functions in HD could be tied to lowered levels of ascorbate in specific areas of the brain.
The release of ascorbate from nerve cells is actually linked to the uptake of another molecule into the nerve cells. This molecule is glutamate, an excitatory neurotransmitter that can be toxic to nerve cells. It can exert toxic effects either when it is present in large amounts or when the nerve cells are overly sensitive to it, as are nerve cells in many people with HD. Because glutamate is excitatory, it is often released by nerve cells during times of motor activity. When it is released by one nerve cell, it travels to the next nerve cell to stimulate it. (For more information on nerve cells, click here.) When glutamate has done its job as messenger, it can either be broken down or taken back up by the nerve cells that released it.
Researchers found that when glutamate is taken back up by the nerve cells, these cells simultaneously release ascorbate. Because glutamate release is tied to increased production of free radicals, this ascorbate release mechanism might have evolved in order to protect nerve cells. The more glutamate that is released by the nerve cell, the more is taken back up later. Because glutamate is “exchanged” with ascorbate when it goes back into the nerve cell, the cell can regulate how much ascorbate it releases based on how much glutamate was originally released. This mechanism allows the cell to release appropriate amounts of ascorbate because it can measure how much free radical production may have been stimulated by the glutamate release. But glutamate is not the only factor responsible for increasing free-radical formation during this time. When a cell is more active, it has to carry out more metabolic processes, and at a faster rate, which also increases the natural production of free radicals. Therefore, the levels of extracellular ascorbate should be highest during times of motor activity: this is a time when the cells are most likely producing increased levels of free radicals themselves and may need extra protection from glutamate toxicity.
Researchers recently found that nerve cells in the striatum of HD mice release much less ascorbate during motor activity than do the nerve cells of normal mice. Because it is also known that loss of ascorbate in the striatum can impair motor behavior, they decided to test whether injections of ascorbate could improve the motor symptoms of HD mice. They found that injections of ascorbate allowed the nerve cells of HD mice to release normal amounts of ascorbate when they were active. The researchers also found that HD mice treated with ascorbate performed better on two out of three motor tests than did untreated HD mice. These studies show that an inadequate amount of ascorbate in the striatum of HD mice may play a role in worsening their symptoms. While some studies have also shown a connection between increased vitamin C intake and decreased risk of developing Alzheimer’s disease, there are still no studies on the effect of the vitamin on people with HD. Researchers first need to find out if these animal model findings translate to humans with HD before considering ascorbate as a possible treatment.
Rebec, et al. (2002) discovered that the nerve cells in the striatum of HD mice release much lower quantities of ascorbate than do nerve cells of normal mice. The researchers used two groups of mice: one group was composed of HD mice, and the other was the control group (composed of normal mice). They first put both groups of mice under anesthesia so that they could place electrodes into the striatum of the brain that would measure ascorbate levels. When the mice were under anesthesia, the levels of ascorbate in the striatum were the same in both groups. As the normal mice woke up, their ascorbate levels increased and continued increasing as they became more active. As the HD mice woke up, their ascorbate levels actually decreased by up to 50% below the anesthesia level. The HD mice also went on to engage in less motor behavior and spent more time resting than the control mice. These findings suggest that the brains of HD mice are unable to release the normal amounts of ascorbate when necessary.
Rebec, et al. (2003) went on to test whether treatment with ascorbate would help alleviate motor symptoms in HD mice. This time there were four groups of mice: two groups of HD mice and two groups of normal mice; only one group of HD mice and one group of normal mice was treated with ascorbate. These groups received injections of ascorbate 4 days of the week and then were allowed 3 days of recovery. The two groups that were not treated (one of the HD mice, the other, normal mice) got injections of a placebo to control for any effects that the actual injections and handling may have had on the mice. Treatment and observation went on for three weeks and ascorbate levels in the striatum of the mice were measured twice during the study.
In order to measure the ascorbate levels, the mice were once again put under anesthesia. When they were in this state, mice in all four groups had similar levels of extracellular ascorbate. As they woke up, both groups of normal mice, whether they had been treated with ascorbate or not, showed the expected increase in ascorbate. HD mice that had not been treated with ascorbate showed the same decrease in extracellular ascorbate that had been seen in Rebec, et al.’s previous study (2002, see above). However, HD mice that had been treated showed an increase in ascorbate levels that was similar to the increase seen in both groups of normal mice. These findings are important because they show that treatment with ascorbate can help restore the ascorbate-releasing ability to active nerve cells in HD mice. They also show that treatment with ascorbate only affected the HD mice, since normal mice that were treated did not show a greater increase in ascorbate release than was expected.
Next, the behavior of the mice was observed to determine whether ascorbate treatment actually helped improve motor symptoms. The researchers used three motor tests and behaviors as their criteria. The first was the performance of a repetitive grooming movement that is a sign of nerve cell damage in the HD mice. The next was a test of motor flexibility that recorded how often the mice would choose to turn left or right instead of going straight through a maze, with more turns indicating more flexibility. The final test measured general movement in an open area. The researchers found that HD mice treated with ascorbate performed the repetitive grooming movement less often and had increased flexibility in the maze than did untreated HD mice, suggesting that ascorbate treatment is beneficial to these mice (specifically, by acting as an antioxidant in the striatum). Despite the fact that there was no significant difference between the two groups in the third overall movement test, the researchers still believe that continued study of ascorbate (and vitamin C) may be helpful in understanding more about nerve cell damage in HD.
A. Milczarek, 12/24/04
Treatment summary: Lipoic acid is a coenzyme present in the mitochondria of cells. It helps to produce energy by aiding enzymes in breaking down sugar during the Krebs cycle. The body makes enough lipoic acid to fulfill its basic metabolic functions, but the compound can also act as an antioxidant when it is in excess. Lipoic acid is special because it is the only antioxidant that is able to deactivate free radicals that are both fat-soluble and water-soluble. (For more information on free radicals and antioxidants, click here.) Because of its antioxidant properties, lipoic acid is being investigated as a possible treatment for HD.
Lipoic acid can be found in many common foods such as potatoes, carrots, broccoli, yeasts, beets, yams, and red meat. This antioxidant is slowly becoming recognized as having unique properties in the prevention of and therapy for a broad range of diseases. For example, lipoic acid protects the liver from damage caused by alcohol, shields the lungs from damage caused by smoke, and enhances glucose disposal in type II diabetes (and reduces associated neuropathy and cataracts). Since humans are not usually deficient in lipoic acid, no recommended dietary allowance (RDA) has been established, but supplementation may help in some conditions. Few studies have investigated the effects and safety of lipoic acid supplementation in humans.
Andreassen, et al. (2001) investigated the effects of lipoic acid supplementation in two mouse models of HD (we’ll call them strain 1 and strain 2). The researchers mixed lipoic acid into the food of 17 strain 1 mice and 11 strain 2 mice. Other mice were not given lipoic acid and were used as a comparison (there were 55 strain 1 mice and 22 strain 2 mice that did not receive lipoic acid). The mice were weighed each week and successful treatment was evaluated based on weight changes and survival.
The strain 1 mice that were given lipoic acid did not lose weight as fast those not given lipoic acid and continually weighed more than the untreated group. However, the weight of the strain 2 mice was not significantly affected by lipoic acid treatment.
Regardless of its effect on weight, both types of mice receiving lipoic acid survived longer than the untreated mice. The strain 2 mice receiving lipoic acid survived an average of a week longer than untreated strain 2 mice, while the strain 1 mice receiving lipoic acid survived an average of about 11 days longer than untreated strain 1 mice.
These results, while positive, are not as significant and extensive as those found for some other supplements such as creatine (For more information on creatine, click here.) Furthermore, these are only the results of one experiment and much more research needs to be done to find out the safety and efficacy of lipoic acid in humans with HD. However, this study does confirm the role of oxidative damage in HD and suggests that lipoic acid may act to slow its progression.
-K. Taub, 11/21/04
Drug Summary: Selenium is a mineral found in small quantities that is essential to the diet. Selenium contributes to the normal functioning of the immune system and the thyroid gland. It is the central element in glutathione peroxidase (GPx), an antioxidant enzyme that protects cells against the oxidative damage caused by peroxides and free radicals. (For more information on free radicals and antioxidants, click here.)
Because of its antioxidant role, selenium has been studied for its potential to protect the body from many degenerative diseases, including Parkinson’s disease and cancer. (For a comparison between Parkinson’s and HD, click here.) Selenium is thought to protect against cancer because a form of selenium from yeast was found to have caused cancer cells in test tubes and in animals to undergo apoptosis, or programmed cell death.
Selenium can be found in a variety of foods including brazil nuts, yeast, whole grains, and seafood. Plant foods in most countries are also major dietary sources of selenium. The Recommended Dietary Allowance (RDA) is the average daily dietary intake level that is sufficient to meet the nutritional requirements of nearly all healthy individuals in each life-stage and gender group. The RDAs for selenium in adults is 55 micrograms (mcg), for pregnant women it is 60 mcg, and for lactating (breast feeding) women it is 70 mcg. While selenium can be taken as a supplement, most healthy adults get enough from the diet alone. One brazil nut alone has 100 mcg, an egg has 12 mcg, and a slice of whole wheat bread has 11 mcg of selenium.
People who eat foods grown primarily on selenium-poor soils are at risk for deficiency, but selenium deficiencies are rare in Western countries. However, studies have shown that the amount of selenium found in the blood decreases significantly with age and that decreased amounts of selenium might be a risk factor for dementia.
Santamaría, et al. (2003) recognized that in neurodegenerative diseases such as HD, oxidative stress and free radicals contribute to the degeneration of nerve cells. In order to study these effects and a possible treatment, these researchers gave rats a substance called quinolinic acid (QUIN). QUIN has traditionally been used to produce a model of HD in rats and primates because it mimics what the nerve cells of someone with HD would look like. QUIN causes damage to nerve cells by producing free radicals and causing oxidative stress. This is similar to what occurs in HD: damaged mitochondria produce free radicals, which contribute to the progression of the disease. Researchers can then study the effects of different substances on these cells.
In this study, researchers at the National Institute of Neurology in Mexico City, Mexico tested how selenium affected the QUIN rats. They did this by studying the effects of selenium both in vitro and in vivo. The in vitro studies looked at the brain cells directly (outside of the body, after death), while the in vivo studies look at the effects on the bodies of the living rats as a whole. The researchers measured the activity of the enzyme GPx in the cells because it depends on selenium for its antioxidant properties. They also looked at the physical behavior of the rats. To determine the degree of damage, the researchers examined the rat brains and counted samples for how many nerve cells were preserved and how many were damaged.
Because of its antioxidant effects, selenium was able to reduce toxicity caused by QUIN in rats. Different concentrations were found to be effective in different parts of the brain, but selenium specifically reduced the damage caused by QUIN in the and striatum and and hippocampus. The animals that were given QUIN alone had nerve cells that were very damaged; many of these nerve cells died. The animals that were given QUIN and then treated with selenium had only a few sick nerve cells and most were healthy. Selenium decreased nerve cell degeneration by 70%. As expected, the presence of selenium increased GPx activity, most likely helping to reduce the toxic effects on the nerve cells.
Rats treated with selenium did not differ in bodyweight significantly compared to rats not receiving treatment. Moreover, an equal number of rats died in the treated and non-treated groups (two in each). Because of these results, the researchers concluded that this level of selenium does not cause any harmful side effects in rats.
Since selenium was found to protect against QUIN-related damage, and QUIN causes damage similar to that present in HD, treatment with selenium could possibly slow the progression of Huntington’s disease.
Zafar, et al. (2003) studied the effects of selenium on protecting nerve cells in the brains of rat models of Parkinson’s disease. Damage to nerve cells caused by free radicals and oxidative stress contributes to the progression of both Parkinson’s and Huntington’s diseases.
The researchers gave rats selenium in the chemical form of sodium selenite for seven days before inducing Parkinson’s-like symptoms. They were then tested for a variety of things including antioxidant activity and behavioral effects.
Rats treated with selenium were found to have greater antioxidant activity compared to those not treated. In the physical tests, selenium treatment was found to significantly lessen the harmful effects of Parkinson’s on the rats. They were less prone to circling around, had better muscle coordination, and wasted less time in traveling a specific distance.
These results confirm the fact that selenium plays an important role in decreasing oxidative stress. This study and others suggest that selenium may be helpful in treating neurodegenerative diseases such as Parkinson’s and HD.
-K. Taub, 11/21/04
Huntington’s Disease (HD) is associated with a genetic mutation that results in an expanded polyglutamine chain in the huntingtin protein. In HD, huntingtin becomes a misfolded protein, which can cause many problems for the nerve cell. Scientists have not yet found a straightforward way to explain how a single genetic mutation can lead to the complex symptoms of HD. It is thought that misfolded huntingtin damages the nerve cell in many different ways.
One proposed mechanism suggests that misfolded huntingtin damages an organelle in the nerve cell called the mitochondrion. Mitochondria are important because they help the cell produce energy and regulate the number of free radicals in the cell. When the mitochondria are not working correctly, oxidative damage occurs in the cell because there are too many free radicals. This is thought to contribute to nerve cell death in HD. Therapies that reduce the amount of free radicals in the nerve cell might prevent some HD symptoms.
One potential treatment to reduce free radicals involves a molecule called coenzyme-Q10, which is naturally produced throughout the body. It plays a role in the electron transport chain and helps produce ATP, the cell’s major source of energy. (For more information on coenzyme-Q10 and the electron transport chain, click here.) Coenzyme-Q10 also reduces oxidative damage by interacting directly with free radicals, inactivating them so they cannot damage the cell. The level of coenzyme-Q10 in the brains of HD patients is lower than normal, potentially reducing the ability of affected nerve cells to manage free radicals that accumulate. Because the nerve cells can no longer deactivate all of the free radicals, they become damaged. Drug supplements may be useful to raise the level of coenzyme-Q10 in the brain and prevent the damage caused by free radicals.
This section describes several that tested the effects of coenzyme-Q10 treatment in both humans and mice. The studies show that coenzyme-Q10 is at least somewhat effective in delaying the symptoms of HD and increasing survival, and could serve as a potential treatment for HD and other neurodegenerative disorders.
Ferrante, et al. (2002) tested coenzyme-Q10 as a treatment in a mouse model of late stage HD. In this study, they found that coenzyme-Q10 given to transgenic mice increased survival by 14.5%. Human trials did not show that coenzyme-Q10 significantly affects survival, so it was thought that coenzyme-Q10 would not make an effective treatment for HD patients. Later research that studied the effects of coenzyme-Q10 in human patients with neurodegenerative disorders similar to HD, such as Parkinson’s disease and ALS, showed that higher doses of coenzyme-Q10 than those previously used produced more promising results. The patients had a significantly declined rate of nerve cell death and symptom progression. (For more information on other neurodegenerative and related diseases, click here.)
The Huntington Study Group (2001) conducted a clinical trial involving 347 early-stage HD patients at various sites in the United States and Canada. The trial was done to test the efficacy of coenzyme-Q10 and remacemide, an anti-glutamate drug. The participants were monitored between July 1997 and June 1998 and 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. 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 average TFC score of the participants before the study was 10.2. None of the treatments significantly altered the decline in TFC. However, subjects treated with coenzyme-Q10 showed a delayed decline in the TFC compared to subjects who were not treated translating into approximately one more year of independence for people with HD. The supplement was well-tolerated by the study participants and showed no adverse effects on the participant’s other capacities. No changes in the decline in TFC relative to the placebo group were seen in the participants treated with remacemide. However, improvements in chorea were observed. (For more information on remacemide, an anti-glutamate drug, click here.)
The researchers concluded that although there was a trend toward slowing of the progression of HD with coenzyme-Q10 treatment, the effects were not large enough to recommend coenzyme-Q10 as a treatment for early HD. In part, this is because the financial costs of coenzyme-Q10 are considerable. Since coenzyme-Q10 is a nutritional supplement, it is worth remembering that it is not subjected to the same quality and content regulations as pharmaceutical drugs are. Different brands and formulations of coenzyme-Q10 may differ chemically or may contain additives, and there is little information about how these different contents might affect a person with HD. Finally, it should be emphasized that the findings of this study are not applicable to people at risk for HD, or for people at the intermediate or advanced stages of HD.
Nevertheless, the results of the study suggest that therapies that affect the energy supply in cells can affect the course of HD. Additional studies are called for to identify dosage effects and to study effectiveness for people in different stages of HD.
Koroshetz, et al. (1997) treated 18 early-stage HD patients with oral coenzyme-Q10 for 2 to 8 weeks. The patients were recruited from the Massachusetts General Hospital HD Unit and were all able to walk, with half of them still working. Brain lactate level was used as the criteria to measure the effectiveness of the supplement. They hypothesized that treatment with coenzyme-Q10 could increase the efficiency of the respiratory chain, and consequently, lower lactate levels. (For more on lactate, click here.)
The researchers discovered that upon treatment with coenzyme-Q10, the participants experienced significant decreases in brain lactate levels. Lactate levels reversed back to their original levels following withdrawal of therapy, indicating that the findings were indeed due to coenzyme-Q10 treatment. This study supports the theory that coenzyme-Q10 could increase the amount of energy available in cells, perhaps by increasing the efficiency of the respiratory chain.
Smith, et al. (2006) tested higher doses of coenzyme-Q10 with a late stage HD mouse model. This model demonstrated some features of human HD, including progressive loss of motor function. They also compared two commercially-available preparations of coenzyme-Q10, one from a company called Tishcon and one from a company called Chemco. The researchers administered different doses of each substance, seeking an optimal dosage to treat HD.
Results showed that higher doses of coenzyme-Q10 significantly slowed the progression of HD symptoms, such as declining motor performance and grip strength. Smith tested several different doses and found that for the Chemco formulation of coenzyme-Q10, 5000 mg/kg/day was the most effective dosage in extending the lifespan of HD mice. Tishcon coenzyme-Q10 extended survival by a greater amount and at a lower dosage of 1000 mg/kg/day. Moreover, HD mice treated with higher doses of coenzyme-Q10 did not lose as much weight, have as much nerve cell death, or form as many huntingtin aggregates as untreated HD mice. Administering high doses of coenzyme-Q10 to mice in the form of a pellet significantly raised the level of coenzyme-Q10 in their bloodstream and nerve cells. These findings suggest that oral administration of the drug would be effective. Finally, high doses of coenzyme-Q10 also significantly reduced the amount of OH8dG (8-hydroxydeoxyguanosine) in the brain. OH8dG is a molecule that appears in unusually high concentrations in the brains of HD patients, and is associated with oxidative stress in the nerve cell. In summary, this study shows that high doses of coenzyme-Q10 can prevent some motor symptoms, prolong lifespan, and reduce oxidative stress and nerve cell death in HD mice. However, doses that are too high are less effective, possibly because of side effects.
In comparing the effectiveness of two commercially available coenzyme-Q10 preparations, the study found that the supplement produced by Tishcon was 5 times more effective in extending lifespan than that produced by Chemco. More of the coenzyme-Q10 in the Tishcon pellet was absorbed into the bloodstream in comparison to the Chemco pellet. It is important to remember that coenzyme-Q10 is a nutritional supplement and can be bought in many different prepared forms. Nutritional supplements are not regulated by Food & Drug Administration (FDA) guidelines Often there is little standardization and poor quality control for these supplements. Little is known about how each of these prepared forms may affect HD patients differently, and so more comparative studies are needed.
The Cure HD Initiative (CHDI), a nonprofit drug development research organization for HD, has recently begun to work on creating treatments for HD using coenzyme-Q10. On August 2, 2006 CHDI announced a partnership with Edison Pharmaceuticals, Inc. Edison is a small company that specializes in drug development for diseases related to problems with mitochondria, oxidative damage, and energy levels in the cell. This partnership will be an opportunity for Edison to specifically focus on oxidative damage in HD. The partnership hopes to develop a second generation coenzyme-Q10 molecule to be used to treat HD. Scientists at Edison Pharmaceuticals will contribute their expertise in the biology and pharmacology of free radicals and oxidative damage, while members of CHDI Foundation will contribute their expertise in HD and drug development.
Earlier in 2009, the Huntington Study Group received funding from the NIH to test safety and tolerability of coenzyme-Q10 in individuals who have tested positive for HD but do not show any motor signs of HD. The study is called PREQUEL (Study in PRE-manifest Huntington’s disease of coenzyme Q10 (UbiquinonE) Leading to preventive trials). The study will be conducted at 10 clinical sites throughout the nation and is the first therapeutic research study in pre-manifest HD. The principal investigators hope that this initial trial will lead to later trials that study the delay of onset of HD. The study is estimated to be completed by summer 2010. (For updates on the study, click here.)
Numerous studies conducted in the past decade show that coenzyme-Q10 may prove to be an effective drug in treating HD since it can enhance ATP production. Studies in the past have shown it to significantly delay HD symptoms and increase survival, especially in mice. However, side effects are still common, with gastrointestinal upset being the most common side effect in both human and animal trials. The PREQUEL clinical trial will study the effectiveness of coenzyme-Q10 in delaying the onset of HD in individuals who do not yet exhibit the symptoms of the disease. Overall, coenzyme-Q10 holds promise as a supplement to treat HD.
-A. Zhang, 6-8-10
Drug Summary: Ginkgo biloba has been shown to have antioxidant and anti-inflammatory properties. Because free radicals and inflammation are believed to be factors involved in the progression of HD, Ginkgo biloba may help in alleviating the symptoms of HD. However, no studies have been done yet on the effects of Ginkgo biloba on people with HD. Instead, preliminary research is being conducted to test the effects of Ginkgo biloba on diseases that also involve inflammation such as Alzheimer’s Disease.
Ginkgo biloba (G. biloba) is a type of tree that has existed for over 200 million years. Medicinal extracts are made from the dried leaves of the tree and have been used for 5000 years in traditional Chinese medicine for various purposes. The extract has been shown to have protective effects against mitochondrial damage and oxidative stress. Figure K-1 shows an image of Ginkgo leaves.
There are different variants of Ginkgo biloba extracts available on the market today. Among them are EGb 761, LI 1379, and Chinese Ginkgo extract ZGE. These extracts differ in their extraction process as well as composition. The principal constituents of Ginkgo biloba extract include flavonoids, terpenoids (ginkgolides and bilobalide) and different organic acids. The standardized extract usually contains 24% flavonoids and 6% terpenoids. Let us review the different biological activities of these components.
The flavonoids contribute to Ginkgo’s antioxidant properties. They have been found to reduce the levels of free radicals, which are highly reactive molecules with unpaired electrons. One way by which flavonoids protect the cell is by reducing cell membrane lipid peroxidation. Lipid peroxidation is defined as the process whereby free radicals “steal” electrons from the lipids in our cell membranes, resulting in cell damage and increased production of free radicals. Lipids include molecules such as fatty acids, cholesterol, and other related compounds. As antioxidants, the flavonoids neutralize the free radicals in our cell, lowering the levels of free radicals available for lipid peroxidation. (For more on free radicals, click here.)
Bilobalides are closely related in structure to the ginkgolides. Bilobalides have been proposed to have protective effects on nerve cells and on the nervous tissue through their role in motor nerve cell regeneration.
The ginkgolides inhibit the activity of the compound known as platelet-activating factor (PAF). PAF reduces inflammation by increasing permeability of blood vessels and contracting various involuntary muscles such as those in airways. (For more on inflammation, click here). PAF activation is also associated with the aggregation of platelets, which aid in blood clotting. Ginkgo supplementation has therefore been associated with anti-inflammatory effects as well as reduced blood clotting.
Based on these biological properties of its constituent compounds, Ginkgo biloba supplementation may result in antioxidant, anti-inflammatory, and neuroprotective effects. Although the primary cause of HD is still unknown, prominent hypotheses center around injury caused by free radical oxidation damage and chronic inflammation. Given its antioxidant and anti-inflammatory properties, Ginkgo biloba may therefore be beneficial to people with HD. To date, no studies have been done regarding Ginkgo biloba’s effects on people with HD; however, some studies have investigated the effects of Ginkgo biloba on individuals with Alzheimer’s Disease (AD). AD is associated with disease mechanisms that are similar to HD, and so it is possible that some of these findings may be useful for future HD research.
In most of the clinical studies of Ginkgo biloba and Alzheimer’s patients, no serious side effects were noted. However, some case studies reported that people taking Ginkgo experience prolonged bleeding times due to its inhibition of PAF. Two case reports of hemorrhage were reported by people who were taking Ginkgo. Compounds such as aspirin and warfarin that are known to inhibit blood clotting have been found to result in bleeding complications when taken with Ginkgo. However, as of this writing (November 2001), the frequency and magnitude of bleeding complications with Ginkgo supplementation is still unclear.
Oyama, et al. (1996) hypothesized that Ginkgo biloba treatment would have beneficial effects on cells exposed to the free radical hydrogen peroxide. The researchers first exposed nerve cells to hydrogen peroxide to see what happens to the cells after administration of hydrogen peroxide. They discovered that prolonged exposure to hydrogen peroxide resulted in the death of many nerve cells. To test the protective effects of Ginkgo biloba, nerve cells were treated with Ginkgo biloba extract for 1 hour before adding hydrogen peroxide. Ginkgo biloba treatment was found to increase the number of surviving nerve cells after hydrogen peroxide exposure. The researchers then compared the effects of Ginkgo biloba treatment 1 hour before, immediately after, and 1 hour after cells were exposed to hydrogen peroxide. They discovered that although Ginkgo biloba had protective effects when applied either immediately after or 1 hour after hydrogen peroxide exposure, the beneficial effects were weaker than that of treatment before hydrogen peroxide exposure. Figure K-3 shows a graph depicting the effects of Ginkgo biloba treatment.
Studies by other researchers showed that Ginkgo biloba extract exerted neuroprotective effects on nerve cells exposed to the hydroxyl radical, another type of free radical. The extract also had a scavenging effect on superoxide anions, which are also free radicals. Together with the results of the current study, it is believed that Ginkgo biloba may have neuroprotective effects on nerve cells suffering from cell damage induced by free radicals. Because free radical damage is hypothesized to play a role in the progression of HD, Ginkgo biloba treatment on HD cells may have beneficial effects.
Le Bars, et al. (1997) examined the effects of a particular extract of Ginkgo biloba on people with Alzheimer’s Disease (AD). Damage by free radicals and inflammation has been implicated as one of the mechanisms by which AD cells die. The researchers hypothesized that treatment with an antioxidant and anti-inflammatory molecule such as Ginkgo biloba may have beneficial effects on people with AD.
The extract the researchers used in this study was EGb 761, which is a particular extract of Ginkgo biloba used in Europe to alleviate symptoms associated with several cognitive disorders. Participants included 309 demented patients with mild to moderately severe cognitive impairment caused by Alzheimer’s Disease.
The participants were randomly assigned to treatment with Egb (120 mg/day) or a placebo. The trial was conducted for 52 weeks (13 months) in 6 research centers in the United States. The researchers assessed changes in 3 areas: cognitive impairment, daily living and social behavior, and overall psychopathology.
The results of the study indicated that Ginkgo biloba treatment was able to produce beneficial effects in 2 of the 3 outcomes: cognitive impairment and daily living and social behavior. No differences in overall psychopathology between the treated and placebo group were observed.
The results of this study indicated that Ginkgo biloba treatment may slow the deterioration of some people with AD. However, the researchers stated that more trials should be conducted to examine the effects of various dosages on slowing deterioration caused by AD to ensure that the proper dosage is administered. Furthermore, the exact mechanism of action by which Ginkgo biloba exerts its effects remains unknown. More research is also needed to reveal these mechanisms, in order to better explore the full therapeutic potential of Ginkgo biloba.
Mahdy et al. (2011) found that ginkgo biloba might repair some of the neurological problems caused by a toxin, 3-Nitropropionic acid (3-NP). When injected into the brains of mice, 3-NP mimics the effects of HD: it causes many of the biological and behavioral changes that are seen in people with HD. But mice that were treated with both 3-NP and ginkgo biloba showed milder neurodegenerative problems than those treated with 3-NP alone. Several biochemical changes that occur upon exposure to 3-NP were mitigated in animals that were treated with ginkgo biloba. Authors suggest that ginkgo biloba’s antioxidant properties, antiapoptotic effects, and improvement of energy metabolism were responsible for the neuroprotective effects.
-E. Tan, 11-22-01; Updated by P. Chang, 5/6/03; updated by M. Hedlin, 8/11/11