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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.

How the Body uses Arginine^

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.

Arginine: Neurotoxic or Neuroprotective?^

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.

Role of NO and arginine in HD^

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:

  • In mice that did not receive arginine (0% group), there was no weight loss and no change in CBF. The degree of motor decline associated with HD was not reduced.
  • In mice given the highest amount of arginine (5% group), the severity and onset of weight loss and motor problems was accelerated and CBF at rest was increased.
  • Mice receiving 1.2% arginine had weight loss and CBF that was intermediate between the other groups, while, interestingly, motor function was better than the groups given higher or lower arginine concentrations.

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 as a Possible Diagnostic Tool for HD^

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.

Future of Arginine in HD Research and Treatment^

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.

For further reading^

  1. Deckel, et al. “Dietary arginine alters time of symptom onset in Huntington’s disease transgenic mice.” Brain Research Volume 875, Issues 1-2 , 1 September 2000, Pages 187-195. Online
    This is a study that tested the outcome of feeding HD transgenic mice varying levels of dietary arginine.
  2. Deckel, A. Wallace. “Nitric Oxide and Nitrous Synthase in Huntington’s disease.” Journal of Neuroscience Research. 2001 Apr 15;64(2):99-107. Online
    This paper gives some basic information about the role of nitric oxide in the body and in neurodegenerative diseases.
  3. Salvatore E, Rinaldi C, Tucci T et al. (2011) Growth hormone response to arginine test differentiates between two subgroups of Huntington’s disease patients. J Neurol Neurosurg Psychiatry 82:543–547. This paper investigated the role of growth hormone levels in the pathology of HD.

-A. Zhang, 10-11-11