Arginine and Huntington's Disease:Amino acids are the building blocks of proteins . In humans, they are either made in the body or they must be taken in from the proteins found in food. Recently, scientists have found that ingesting large amounts of the amino acid arginine has a marked effect on human brain chemistry. They hope that through investigating the way arginine interacts with the brain, they will find similarities in, and solutions to, the mental decline associated with age-related dementia, Parkinson's disease, and Huntington's disease.
How the Body uses Arginine
The role of dietary arginine in HD is only beginning to be understood. Arginine is a non-essential amino acid. This means that the human liver can synthesize its own arginine, and it need not be obtained directly from food. Arginine is the dietary precursor of nitric oxide, or NO. NO is a gas that is dissolved in both brain and body tissues. Although it is clear that NO plays an important part in all kinds of biological functions, such as blood vessel dilation and neurological function, scientists are still debating its role in HD.
Outside the body, NO is a compound commonly released when natural gases are burned. For a long time it was mainly only associated with air pollution. In 1986, scientists studying certain heart attack drugs found that these drugs, which were designed to widen blood vessels, also released NO. Scientists thought that NO might play a part in widening blood vessels, or vasodilation. One change in the brain associated with HD is increased blood flow to the brain, or cerebral blood flow (CBF). The correlations between arginine, NO, blood flow, and changes in CBF associated with HD led scientists to investigate the link between arginine and HD.
Arginine: Neurotoxic or Neuroprotective?
Cell death in HD causes gradual losses in the striatum of the brain. Because NO serves multiple functions in maintaining brain chemistry in non-HD brains, scientists are uncertain if and how much added NO would be beneficial or harmful to the brain. 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. So using dietary arginine as a treatment for HD 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, usually an oxygen gas molecule with an extra electron, or O2-. NO combines with superoxide to make peroxynitrite. Peroxynitrite is able to alter the nature of proteins, to fragment DNA, and to interfere with the energy metabolism of cells. All of these things are toxic to nerve cells and contribute to HD.
Besides these antioxidant effects, alpha-tocopherol affects several other cellular mechanisms and is also 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, but 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.
On the other hand, NO can be neuroprotective. Because the production of NO uses up free-radicals like the superoxide O2- it is considered an anti-oxidant and prevents the damage to nerve cells caused by free-radicals. However, it is also this characteristic that makes NO combine with peroxynitrite, the nerve cell toxin described above. Because arginine in the diet results in increased NO, it is like two sides of a coin: it could have two completely different outcomes.
Recent Research
Studies from the last few years are inconclusive as to whether or not a lack of NO contributes to HD. In one recent study, researchers at the University of Connecticut fed 71 one-year-old mice diets of 0%, 1.2% and 5% arginine. All the mice were HD transgenic, meaning that they had been genetically altered to have the CAG expansion that causes HD. The results were recorded for three symptoms of HD: weight loss, loss of motor control, and increase in cerebral blood flow (CBF).
In the 0% group, there was no weight loss and no change in CBF. The degree of motor decline associated with HD was not reduced.
In the 5% group, degree and onset of weight loss were accelerated, CBF at rest was increased, and the degree and onset of motor impairment were also accelerated.
In the 1.2% group, weight loss and CBF was much less than the 5% group but greater than in the 0%group. Interestingly, motor function was better than in either the 0% or 5% group. Both the 1.2% and 5% groups had elevated levels of peroxynitrite.
These results suggest that excess NO is toxic to nerve cells, though a slight increase in NO seems beneficial to motor function.
These findings are supported by a similar study of a compound called nitric oxide synthase (NOS), which promotes the production of NO. This study found that a substance that gets in the way of NOS, an "NOS inhibitor" called 7-nitroindazole, or 7-NI, reduced resting CBF 17-27% in rats and 30% in humans. So by slowing or stopping the production of NO, symptoms of HD were decreased.
The Future of Arginine
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 until more studies are done.
For further reading:
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.
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.
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Last Modified: 04/12/2007
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