What is Glutamate?

Prolonged excitation is toxic to nerve cells. Neurobiologists recognize that the nerve cell messenger, glutamate, can cause harm when its messages are overwhelming. Normally glutamate is swiftly cleared from the nerve cell junctions to keep the messages brief. Molecules called transporters aid in keeping glutamate in proper concentrations around nerve cells. Abundant evidence points to glutamate as a destructive factor in ALS and investigators are working to find out how this can be changed. Gene therapy approaches are under investigation to deliver glutamate transporters to cells affected by ALS. Other avenues towards control of glutamate in ALS are also under active investigation.

 

What is Glutamate?

Nerve cells pass signals to each other and to their target organs by releasing messenger molecules, called transmitters. Many are simple amino acids such as the one called glutamate.

The message is intended to tell the recipient neuron whether to fire off its own neurotransmitters. As with all neurotransmitters, glutamate docks at specific recognition molecules on the receiving neuron. Glutamate is then swiftly cleared from the nerve cell junctions to keep the message brief. Prolonged excitation is toxic to nerve cells, and neurobiologists recognize that glutamate can cause harm when the messages are overwhelming, as in stroke or epilepsy.

Glutamate’s toxicity is apparently due to calcium flooding the cell. Calcium is supposed to briefly enter the neuron with each signal and triggers the cell to fire off its own signals and adjust its own activities accordingly. But prolonged calcium inside the cell evidently can do damage, and will even activate programmed cell death (see section on apoptosis).

 

Research in the early 1990s determined that ALS patients have raised levels of glutamate in the fluid bathing the brain and spinal cord. In fact, 40 percent of sporadic cases of ALS are characterized by this elevated glutamate in cerebrospinal fluid (CSF). Abundant evidence points to glutamate as a destructive factor in ALS. The first and so far only approved specific treatment for ALS is riluzole, a drug that modulates glutamate.

The transporter that clears glutamate is called EAAT2 (an “excitatory amino acid transporter;” as glutamate is one of the amino acids that serve as transmitters). In ALS, transport of glutamate is slowed into the glial cells that surround the junctions of motor neurons. Indeed, a mutation has been identified in an ALS patient that prevented the transporter from working properly.

Researchers are working towards gene therapy approaches to deliver the glutamate transporter molecule to cells affected by ALS. Other avenues towards control of glutamate in ALS are also under active investigation.

What is homocysteine?

According to Patrick Holford, author of The New Optimum Nutrition Bible, one of the best ways to extending a healthy lifespan is by reducing overall homocysteine levels.

Homocysteine is a type of protein found in the blood which should, ideally, be present in very low quantities. First investigated by Dr. Kilmer McCully in the late 1960s, homocysteine plays a role in many normal body processes such as cell and tissue growth, bone growth, and insulin formation. The proper metabolization of homocysteine relies on the adequate supply of vitamin B6, vitamin B12, and folate. When these vitamins become deficient in the body, homocysteine cannot be converted into substances such as glutathione, the body's most important antioxidant, and a methyl donor called S-adenosylmethionine (or SAMe).

Important for understanding why this conversion from homocysteine to other beneficial substances in the body is the process of methylation. Methylation is how the body maintains its chemical balance through the addition or subtraction of molecules called methyl groups from one substance in order to turn it into another. For example, when stressed, the body responds by adding a methyl group to noradrenaline to produce adrenalin. In reverse, when stress is reduced, the body automatically removes a methyl group from adrenaline, converting it into noradrenaline. This type of chemical reaction occurs billions of times per second and is crucial for the proper functioning of the human body.

 

With this knowledge, when the body cannot convert homocysteine into these two important substances, it builds up in the blood, and these elevated homocysteine levels have now been linked with over fifty diseases including atherosclerosis, certain cancers, diabetes, depression, and Alzheimer's disease. While most Americans have homocysteine levels above 10 units, experts generally believe that a level of 6 units or below is optimal for avoiding the increased risk of diseases associated with high levels.

 

An article written by Dr. Siamak T. Nabili and posted on MedicineNet.com, recommends that healthy adults eat more fresh fruits and vegetable, eat less saturated fat and cholesterol, and take one multivitamin daily. Daily supplementation for the standard' homocysteine level of 10 is as follows: Folic acid (1,200 mcg) / Vitamin B12 (1,000 mcg) / Vitamin B6 (75 mg) / Vitamin B2 (20 mg).

Additional supplementation with zinc (15 mg) and trimethyl glycine, or TMG (1.5-3g), has produced even greater reductions in homocysteine levels. TMG, especially, helps to lower homocysteine levels because it can immediately donate a methyl group to homocysteine, working to immediately detoxify the protein.

Additional recommendations for reducing homocysteine levels include eating a clove of garlic every day, avoiding the addition of salt to foods, cutting back on tea and coffee, limiting alcohol consumption, and quitting smoking.

While Dr. Elson M. Hass believes that routine checks on homocysteine levels and paying close attention to the intake of the vitamins necessary for its conversion, through both diet and supplementation, can help to effectively reduce the risk of having high homocysteine in the blood, it is important to note that there is presently no consensus as to the optimal dose of folic acid and other B vitamins for the treatment of elevated blood homocysteine levels. Additionally, certain risk factors which should be brought to the attention of your healthcare professional, also contribute to varying methods of reducing homocysteine levels.

Among these risk factors are:

- Family history of heart disease, strokes, cancer, Alzheimer's disease, schizophrenic, or diabetes,
- Increasing age,
- Male sex,
- Estrogen deficiency,
- Lack of exercise,
- Hostility and repressed anger,
- Inflammatory bowel diseases,
- Pregnancy, and
- Being a strict vegetarian or vegan.

Ultimately, decisions regarding both testing for high homocysteine levels as well as a lifestyle program to reduce high levels should be individualized after consulting with your doctor. After consultation, testing, and doctor-advised measures are discussed and implemented, a marked reduction in homocysteine levels can usually be achieved within weeks.

References

Hass, E.M., MD, & Levin, B., PhD, RD. (2006). Staying healthy with nutrition: The complete guide to diet and nutritional medicine. Berkeley, California: Celestial Arts.

Holford, P. (1999). The optimum nutrition bible. Berkeley, California: Crossing Press.

Nabili, S., MD, MPH. (2008). Homocysteine. Medicine.net: We Bring Doctors' Knowledge To You. Retrieved March 19, 2009, from http://www.medicinenet.com/hom ocysteine/article.htm.