In April of 2024 results of a scientific study were released showing that the presence of glutamate was much higher in Restless Legs patients than in the normal population. As you'll read below, excessive glutamate makes your brain start churning. Not helpful if you're trying to fall asleep before your legs start acting up.
This (as well as the discovery of increased histamine levels in RLS patients) is hard evidence of why so many RLS sufferers have a racing mind at night when they are trying to sleep.
Fortunately, there are remedies to help lessen your glutamate level. I'll touch on those later.
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from Johns Hopkins Medicine
The small new study, headed by Richard P. Allen, Ph.D., an associate professor of neurology at the Johns Hopkins University School of Medicine, used MRI to image the brain and found glutamate ? a neurotransmitter involved in arousal - in abnormally high levels in people with RLS. The more glutamate the researchers found in the brains of those with RLS, the worse their sleep.
For the study, Allen and his colleagues examined MRI images and recorded glutamate activity in the thalamus, the part of the brain involved with the regulation of consciousness, sleep and alertness. They looked at images of 28 people with RLS and 20 people without. The RLS patients included in the study had symptoms six to seven nights a week persisting for at least six months, with an average of 20 involuntary movements a night or more.
The researchers then conducted two-day sleep studies in the same individuals to measure how much rest each person was getting. In those with RLS, they found that the higher the glutamate level in the thalamus, the less sleep the subject got. They found no such association in the control group without RLS.
Previous studies have shown that even though RLS patients average less than 5.5 hours of sleep per night, they rarely report problems with excessive daytime sleepiness. Allen says the lack of daytime sleepiness is likely related to the role of glutamate, too much of which can put the brain in a state of hyperarousal ? day or night. |
from the Vitality & Wellness Centre
Your body has two sorts of neurotransmitters; one that excites you (keeps you awake) called Glutamate and one that relaxes you called GABA.
GABA is your body's main relaxing neurotransmitter. Your body's main excitatory neurotransmitter (Glutamate) is most active during your waking hours. So when you fall asleep your brain Glutamate levels should drop and your brain GABA levels should rise. This facilitates a great restful nights sleep.
People who have trouble sleeping, or more specifically are unable to switch their minds off, generally have lower than normal levels of GABA with elevated Glutamate levels. These people generally make the comment that their minds are always racing and that they are unable to fall asleep or when they wake up they are always thinking and are unable to get back to sleep.
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Below is an excerpt from a highly informative article by Dr. Nancy Mullan that gives a great overview of glutamate. I'll also be posting information from the same article about how to lower your glutamate level.
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from Nancy Mullan MD
Glutamate is an excitatory neurotransmitter. While I am thinking, talking, processing and sharing with you, the glutamate receptors in my neurons are functioning actively to take glutamate into the cell.
You need glutamate for learning, attending, and functioning. In fact, the more intelligent you are, the more glutamate receptors you have on your cells. But too much glutamate being taken in to your nerve cells will burn them out. It would be like turning a light switch on and off continuously until it breaks.
A number of other substances related to glutamate will also act as excitatory neurotransmitters at glutamate receptor sites. They include glutamate, glutamic acid, glutamine, alpha ketoglutarate, and monosodium glutamate or MSG. The aspartate family of molecules will do this also. They include aspartate, aspartic acid, and aspartame, commonly known as NutraSweet.
For the aficionados among you, cysteine can also act as a mild excitatory neurotransmitter, but N-acetyl cysteine does not. However, N-acetyl cysteine contains an acetyl and a sulfur group and so must be used thoughtfully.
Glycine is also a special case neurotransmitter. If the balance in your body is towards glutamate, glycine will be excitatory. If the balance is toward GABA, it will be inhibitory. So if you tend toward glutamate excess, avoid glycine.
The number of glutamate receptor sites on your neuron surfaces are an important determinant of the level of glutamate in your cells. The more glutamate receptor sites you have, the more glutamate you take in. Your resting level of glutamate is higher. Your balance tips to favor excitotoxicity. Glutamate excitotoxicity produces nerve damage or death. It does this by setting off inflammation.
Increased numbers of glutamate receptors have been associated with certain neurologic disorders. Lou Gehrig's Disease or Amyotrophic Lateral Sclerosis (ALS), Fragile X, schizophrenia, and seizure disorder are among them.
Increased glutamate produces insomnia, decreased eye contact and may lead to too much acetyl-choline which can lead to bladder contraction and abnormal eye movements called strabismus. And increased glutamate causes an increase in self-stimulatory behavior (stims).
One of the ways your brain deals with excitotoxin damage is to increase the level of opioids that are produced. Opioids are opium-like substances. Obviously they will interfere with your ability to function.
Elevated levels of glutamate deplete your levels of glutathione (GSH). GSH is a central antioxidant and metal detox agent in your body. Depleted GSH leads to increased inflammatory mediators, including TNF alpha, and helps to exacerbate leaky gut. |
from Wikipedia - Excitotoxicity
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Excitotoxicity is the pathological process by which nerve cells are damaged and killed by excessive stimulation by neurotransmitters such as glutamate and similar substances. This occurs when receptors for the excitatory neurotransmitter glutamate (glutamate receptors) such as the NMDA receptor and AMPA receptor are overactivated by Glutamatergic Storm. |
Pictorial Review of Glutamate Excitotoxicity: Fundamental Concepts for Neuroimaging."
Leighton P. Marka, Robert W. Prosta, John L. Ulmera, Michelle M. Smitha, David L. Danielsa, James M. Strottmanna, W. Douglas Browna and Lotfi Hacein-Beya. From the Neuroradiology Section, Department of Diagnostic Radiology, Medical College of Wisconsin, Froedtert Hospital, 9200 W Wisconsin Ave, Milwaukee, WI 53226. AJNR 2001 22: 1813-1824
There is a growing list of neurologic disorders are now understood to share a final common destructive metabolic pathway called excitotoxicity, which has been the focus of intense investigative efforts in the neurosciences over the past several decades (3?31). Excitotoxicity refers to an excessive activation of neuronal amino acid receptors. The specific type of excitotoxicity triggered by the amino acid glutamate is the key mechanism implicated in the mediation of neuronal death in many disorders.
Glutamate excitotoxicity is the final common pathway resulting in neuronal injury for many seemingly unrelated disorders, including ischemia, trauma, seizures, hypoglycemia, hypoxia, and even some neural degenerative disorders. Familiarity with this process is important for neuroradiologists because of its central position in many of the disorders encountered in daily practice. This area has been one of the most intensely investigated fields in the neurosciences over the past several decades, and the information generated from this work will clearly influence our basic understanding of many neurologic disorders. |
When I see a report like results of the John Hopkins study, I am 100% certain that if I do a bit of digging, there will be an undeniable bond between whatever the agent happens to be (in this case glutamate) and inflammation.
Sure enough, the evidence is OVERWHELMING that inflammation is directly involved with the excessive glutamate levels.
Here are some examples:
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from Russell L. Blaylock, M.D. on the Vaccine Risk Awareness Network
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Neuroscientists have known for some time that inflammatory cytokines cause the brain to release higher levels of glutamate -- the more intense the inflammation, the higher the brain glutamate level. The highest levels are found in the prefrontal lobes and limbic system, the areas most related to mood control. MSG also increases brain inflammation.
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from Emily Deans, M.D. in Evolutionary Psychiatry
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Inflammatory cytokines interfere with the regulation ofthe neurotransmitter, glutamate. Glutamate is an excitatory neurotransmitter that, if left to go wild, can pound our NMDA receptors in the brain and wreak major havoc. No one wants overexcited NMDA receptors, and clinical depression is one among many nasty brain issues that can be caused by overexcitement. Astrocytes, little clean-up cells in the brain, are supposed to mop up excess glutamate to keep it from going nutso on the NMDA. Turns out inflammatory cytokines interfere with the clean-up process. The horse tranquilizer (and club drug) ketamine, when administered IV, can eliminate symptoms of severe depression pretty much immediately in some cases (do NOT try this at home) (2). Ketamine helps the astrocytes mop up glutamate, and it is assumed that this is how ketamine instantly cures depression. Unfortunately, the effects of ketamine don't last, otherwise it would be a nifty tool, indeed.
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"Effect of glutamate on inflammatory responses of intestine and brain after focal cerebral ischemia."
Xu L, Sun J, Lu R, Ji Q, Xu JG. Department of Anesthesiology, Jinling Hospital, 305 East Zhongshan Road, Nanjing 210002, Jiangsu Province, China.
CONCLUSION: Glutamate is involved in the mechanism of intestinal and cerebral inflammation responses. The effects of glutamate on cerebral and intestinal inflammatory responses after ischemia are up-regulated at the transcriptional level, through the NF-kappaB signal transduction pathway.
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"Inflammation-induced changes in peripheral glutamate receptor populations." Carlton SM, Coggeshall RE. Brain Res. 1999 Feb 27;820(1-2):63-70. Department of Anatomy and Neurosciences, Marine Biomedical Institute, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX, 77555-1069
The ionotropic glutamate receptors N-methyl-d-aspartate (NMDA), a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate (KA) have been localized on subpopulations of unmyelinated and myelinated sensory axons in normal skin. Behavioral studies indicate that activation of these receptors results in nociceptive behaviors and contributes to inflammatory pain. The goal of the present study was to determine if these glutamate receptors might contribute to the peripheral hypersensitivity observed in inflammation.
These data indicate that the number of sensory axons containing ionotropic glutamate receptors increases during inflammation, and this may be a contributing factor to peripheral sensitization in inflammation.
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Andy McGlashen on AAAS, the Science Society
Brundin and colleagues examined glutamate activity by measuring quinolinic acid -- which flips a chemical switch that makes glutamate send more signals to nearby cells.
In the spinal fluid of 100 patients in Sweden. About two-thirds of the participants were admitted to a hospital after attempting suicide and the rest were healthy. They found that suicide attempters had more than twice as much quinolinic acid in their spinal fluid as the healthy people, which indicated increased glutamate signaling between nerve cells. Those who reported the strongest desire to kill themselves also had the highest levels of the acid.
The results also showed decreased quinolinic acid levels among a subset of patients who came back six months later, when their suicidal behavior had ended.
The findings explain why earlier research has pointed to inflammation in the brain as a risk factor for suicide. The body produces quinolinic acid as part of the immune response that creates inflammation.
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"Factors in glutamate excitotoxicity, inflammation and epilepsy."
Zhu, Shanshan, Doctor of Philosophy - PhD, B.Sc., Peking University, P. R. China, 2003
Studying the mechanisms underlying glutamate excitotoxicity and inflammatory responses provides hints to the pathology of neurological diseases such as epilepsy. In this dissertation I investigated the expression and function of Kr?ppel-like factor 4 (KLF4) in glutamate excitotoxicity. I also studied the distribution and the role of progranulin (PGRN) in inflammatory stimulation, in epilepsy and in astrocytes subjected to glutamate excitotoxicity.
Our findings suggest that PGRN may be involved in glutamate-evoked increase of glycolysis in cultured astrocytes. In conclusion, our findings provide insights into factors involved in glutamate excitotoxicity, inflammation, and epilepsy.
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from CEMO Seminar "Chronic administration of SNV regulates the glutamate handling, the inflammation and shows behaviour benefits in a rat model of ALS"
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Glutamate uptake is a key activity exerted by astrocytes, protecting neurons from excitotoxic insults. At the molecular level, the adaptive response of astrocytes against glutamate toxicity in pathological conditions is characterized by changes in the expression, cell trafficking and activity of glutamate transporters, which to some extent may transiently preserve or even enhance the glutamate clearance capacity. The concept of a relationship between inflammatory process and neuroprotection against glutamate toxicity has recently received growing attention. Activated microglia releases various inflammatory substances modifying expression of the glutamate transporters and uptake of the neurotransmitter in astrocytes.
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"L-glutamate released from activated microglia downregulates astrocytic L-glutamate transporter expression in neuroinflammation: the 'collusion' hypothesis for increased extracellular L-glutamate concentration in neuroinflammation"
Junpei Takaki1,2, Koki Fujimori1,2, Marie Miura1,2, Takeshi Suzuki2, Yuko Sekino1 and Kaoru Sato1* Journal of Neuroinflammation 2012, 9:275 doi:10.1186/1742-2094-9-275
L-glutamate (L-Glu) is one of the most important excitatory neurotransmitters in the mammalian central nervous system (CNS). However, high concentrations of L-Glu cause excessive stimulation of L-Glu receptors and lead to neurotoxicity.
Accordingly, the impairment of L-Glu transporters has been suggested to contribute to elevated extracellular L-Glu concentrations in inflammation; however, the specific role of such transporters remains unknown, as some inflammation models also cause cell death.
In this study, we aimed to clarify the interaction between activated microglia and astrocyte L-Glu transporters in inflammation.
Our findings suggest that activated microglia trigger the elevation of extracellular L-Glu through their own release of L-Glu, and astrocyte L-Glu transporters are downregulated as a result of the elevation of astrocytic intracellular L-Glu levels, causing a further increase of extracellular L-Glu. Our data suggest the new hypothesis that activated microglia collude with astrocytes to cause the elevation of extracellular L-Glu in the early stages of neuroinflammation.
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Local Glutamate Level Dictates Adenosine A 2A Receptor Regulation of Neuroinflammation and Traumatic Brain Injury."
Shuang-Shuang Dai, Yuan-Guo Zhou, Wei Li, Jian-Hong An, Ping Li, Nan Yang, Xing-Yun Chen, Ren-Ping Xiong, Ping Liu, Yan Zhao, Hai-Ying Shen, Pei-Fang Zhu and Jiang-Fan Chen. Molecular Biology Center, State Key Laboratory of Trauma, Burn, and Combined Injury, Research Institute of Surgery and Daping Hospital, Third Military Medical University, Chongqing 400042, China, Department of Neurology, Boston University School of Medicine, Boston, MA 02118, and Department of Biochemistry and Molecular Biology, Third Military Medical University, Chongqing 400038, China
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According to the well documented role of extracellular glutamate in excitotoxicity, we reasoned that the interplay of extrasynaptic glutamate and adenosine in CNS inflammatory cells (e.g., microglial cells) may be critical to how A 2A R activation impacts neuroinflammation and brain damage. We hypothesized that local increase of glutamate level switches the effect of A 2A R activation from antiinflammatory effect and neuroprotection to proinflammatory effect and cytotoxicity.
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"Inflammation, glutamate, and glia in depression: a literature review."
Leah McNally, Zubin Bhagwagar, Jonas Hannestad. Yale University School of Medicine, New Haven, CT 06519. CNS spectrums (impact factor: 2.2). 07/2008; 13(6):501-10.
Multiple lines of evidence suggest that inflammation and glutamate dysfunction contribute to the pathophysiology of depression. Peripheral inflammation leads to microglial activation which could interfere with excitatory amino acid metabolism leading to inappropriate glutamate receptor activation.
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CLICK HERE to learn how you can lower your glutamine levels
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