I also hope that a cure will be found as soon as possible. I don’t really know anyone who has it personally, but it deeply concerns me and I do believe it is one of the worst illnesses out there. I am so sorry about the things that had happened to your family, and I wish you all the best, keep strong <3
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.
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.
OVERVIEW
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.
Outside the community of biomedical scientists, glutamate is probably best known as “monosodium glutamate” or “MSG” which is used as a flavor or taste enhancer in food. It is usually available together with other food additives and spices in most large food stores. Some people may also have heard the term “Chinese restaurant syndrome” which is a sudden fall in blood pressure with subsequent fainting after ingestion of very spicy food. Excessive use of MSG has been suggested to be the cause, but this is controversial. The use of glutamate as a food additive, however, is not the reason for the enormous scientific interest in glutamate.
The main motivation for the ongoing World Wide research on glutamate is due to the role of glutamate in the signal transduction in the nervous systems of apparently all complex living organisms, including man. Glutamate is considered to be the major mediator of excitatory signals in the mammalian central nervous system and is involved in most aspects of normal brain function including cognition, memory and learning.
Glutamate does not only mediate a lot of information, but also information which regulates brain development and information which determines cellular survival, differentiation and elimination as well as formation and elimination of nerve contacts (synapses). From this it follows that glutamate has to be present in the right concentrations in the right places for the right time. Both too much and too little glutamate is harmful. This implies that glutamate is both essential and highly toxic at the same time.
It may sound astonishing, but it took the scientific community a long time to realize that glutamate is a neurotransmitter although it was noted already 70 years ago that glutamate is abundant in the brain and that it plays a central role in brain metabolism. Ironically, the reason for the delay seems to have been its overwhelming importance. Brain tissue contains as much as 5 - 15 mmol glutamate pr kg, depending on the region, more than of any other amino acid. Glutamate is one of the ordinary 20 amino acids which are used to make proteins and takes parts in typical metabolic functions like energy production and ammonia detoxification in addition to protein synthesis. It was hard to believe that a compound with so many functions and which is present virtually everywhere in high concentrations could play an additional role as transmitter.
Like other signaling substances (neurotransmitters and hormones) the signaling effect of glutamate is not dependent on the chemical nature of glutamate, but on how cells are programmed to respond when exposed to glutamate. Only cells with glutamate receptor proteins (“glutamate receivers”) on their surfaces are sensitive to glutamate. Glutamate exerts its signaling function by binding to and thereby activating these receptor proteins. Several subtypes of glutamate receptors have been identified: NMDA, AMPA/kainate and metabotropic receptors (mGluR).
Although the individual receptor subtypes show specific (restricted) localizations, glutamate receptors of one type or another are found virtually everywhere. Most of the nerve cells, and even glial cells, have glutamate receptors.
At first glance this looks like an impossible system. A closer look, however, reveals that glutamate is not present everywhere. It is almost exclusively located inside the cells. The intracellular location of some 99.99 % of brain glutamate is the reason why this system can work. This is essential because glutamate receptors can only be activated by glutamate binding to them from the outside. Hence, glutamate is relatively inactive as long as it is intracellular.
The volume of brain cells and of the meshwork formed by their intermingled extensions, constitute about 80 % of brain tissue volume. This network is submerged in a fluid, the extracellular fluid which represents the remaining 20 % of brain tissue volume. The normal (resting) concentration of glutamate in this fluid is low, in the order of a few micromolar. In contrast, the glutamate concentration inside the cells is several thousand times higher, at around 1 - 10 millimolar. The highest glutamate concentrations are found in nerve terminals and the concentration inside synaptic vesicles may be as high as 100 millimolar.
It follows from the description above that the mechanisms which can maintain low extracellular concentrations of glutamate are essential for brain function. The only (significant) mechanism for removal of glutamate from the extracellular fluid is cellular uptake of glutamate; the so called “glutamate uptake”. This uptake is mediated by a family of special transporter proteins which act as pumps. These proteins bind glutamate, one molecule at the time, and transfer them into the cells. In agreement with the abundance of glutamate and the ubiquity of glutamate receptors, brain tissue displays a very high glutamate uptake activity. This was noted already in 1949, although its true importance was not recognized until after the excitatory action of glutamate was discovered in the 1950s and 1960s.
Glutamate is taken up into both glial cells and nerve terminals. The former is believed to be the more important from a quantitative point of view. Glutamate taken up by astroglial cells is converted to glutamine. Glutamine is inactive in the sense that it cannot activate glutamate receptors, and is released from the glial cells into to extracellular fluid. Nerve terminals take up glutamine and convert glutamine back to glutamate. This process is referred to as the glutamate-glutamine, and is important because it allows glutamate to be inactivated by glial cells and transported back to neurons in an inactive (non-toxic) form.
Bensimon, et al. (1994) hypothesized that riluzole may have beneficial effects on people with diseases such as amyotrophic lateral sclerosis (ALS) which involve overactivation of glutamate receptors. ALS is a progressive and fatal disorder affecting nerve cells. The cause of the disease is unknown, and no treatment is available that influences survival.
Many hypotheses about the cause of the disease are currently being studied. One of these hypotheses involves glutamate. Studies have reported that increased glutamate concentrations in the brain result in nerve cell death. Given this possible role of glutamate in ALS progression, the researchers sought to assess the effects of riluzole in people with ALS.
The researchers conducted a trial in 155 participants with ALS in France for one year. The participants were given either 50-mg of riluzole twice a day or a placebo. Survival and changes in ability to function were used as tests for the drug’s effectiveness. A secondary test used to examine the drug’s effectiveness was change in muscle strength.
After 12 months, 58 percent in the placebo group were still alive, compared with 74 percent in the riluzole group. The deterioration of muscle strength and functional ability was significantly slower in the riluzole group than in the placebo group.
Side effects of riluzole included stiffness, mild increase in blood pressure, and increase in the levels of the enzyme aminotransferase, which sometimes result in elevations of toxic ammonia. High levels of ammonia have been associated with brain damage, although the reason for ammonia toxicity is still unknown. While aminotransferase elevations were more frequent with riluzole treatment, the elevations were well tolerated and did not cause severe adverse effects in most of the participants in this study. More studies need to be conducted to understand this side effect of riluzole.
On the whole, it appears that these reported side effects may worsen the quality of life, but such consequences may be outweighed by the effect of the drug in improving muscle function and survival rates. The mechanism by which riluzole improves muscle function and survival rates is still unknown. However, the results of this study indicate that riluzole may have a beneficial effect in people with diseases that involve glutamate toxicity such as ALS and HD.
Rosas, et al. (1999) hypothesized that riluzole treatment may have beneficial effects in people with HD. The researchers conducted a 6-week trial of riluzole in eight participants with HD. The participants were treated with 50 mg of riluzole twice a day and were observed for changes in chorea (involuntary dance-like movements), dystonia (prolonged muscle contractions), and total functional capacity(TFC) scores. TFC is a standardized scale used to assess the capacity to work, handle finances, perform domestic chores and self-care tasks, and live independently. The brain lactate levels of the participants were also studied. Lactate is a by-product of anaerobic metabolism that is often used as a measure of energy metabolism efficiency in cells. Low lactate levels would indicated high aerobic respiration and high energy yields. High lactate levels on the other hand, would indicate that cells are unable to perform aerobic respiration and had to resort to the less-efficient anaerobic respiration instead. Changes in lactate levels were then used by the researchers to test the effects of riluzole on energy metabolism.
The researchers found that the chorea rating score of the participants who took riluzole improved by 35% compared to their scores before treatment. Discontinuation of treatment resulted in worsened chorea, indicating that riluzole was indeed associated with the improved chorea. No significant changes were seen on the dystonia or TFC scores.
Lactate levels were lower in the riluzole-treated participants compared to their levels before treatment. However, the researchers reported concerns about inaccuracies in lactate measurements due to limitations in their instruments and measuring methods. Whether or not the decreased lactate levels associated with riluzole indicate improved energy metabolism remains to be determined.
In this study, no significant adverse effects were observed after 6 weeks of treatment. The most frequent side effect was diarrhea; other symptoms quickly resolved without the need for medical intervention.
The results of this study also suggest a possible role for riluzole in the treatment of chorea in people with HD. However, the mechanism by which riluzole might alter or prevent disease progression is still ambiguous. More studies need to be conducted to determine whether and how riluzole can slow the progression of HD and protect nerve cells.
