Back Clinic Nerve Injury Team. Nerves are fragile and can be damaged by pressure, stretching, or cutting. Injury to a nerve can stop signals to and from the brain, causing muscles not to work properly and losing feeling in the injured area. The nervous system manages a great majority of the body’s functions, from regulating an individual’s breathing to controlling their muscles as well as sensing heat and cold. But, when trauma from an injury or an underlying condition causes nerve injury, an individual’s quality of life may be greatly affected. Dr. Alex Jimenez explains various concepts through his collection of archives revolving around the types of injuries and condition which can cause nerve complications as well as discuss the different form of treatments and solutions to ease nerve pain and restore the individual’s quality of life.
The information herein is not intended to replace a one-on-one relationship with a qualified healthcare professional or licensed physician and is not medical advice. We encourage you to make your own health care decisions based on your research and partnership with a qualified health care professional. Our information scope is limited to chiropractic, musculoskeletal, physical medicines, wellness, sensitive health issues, functional medicine articles, topics, and discussions. We provide and present clinical collaboration with specialists from a wide array of disciplines. Each specialist is governed by their professional scope of practice and their jurisdiction of licensure. We use functional health & wellness protocols to treat and support care for the injuries or disorders of the musculoskeletal system. Our videos, posts, topics, subjects, and insights cover clinical matters, issues, and topics that relate to and support, directly or indirectly, our clinical scope of practice.* Our office has made a reasonable attempt to provide supportive citations and has identified the relevant research study or studies supporting our posts. We provide copies of supporting research studies available to regulatory boards and the public upon request.
We understand that we cover matters that require an additional explanation of how it may assist in a particular care plan or treatment protocol; therefore, to further discuss the subject matter above, please feel free to ask Dr. Alex Jimenez or contact us at 915-850-0900.
MSG is a food additive which is found in the majority of the industrial foods. It boosts the taste of the food hence attracting customers. There is no value in terms of nutrition and it really does nothing to the eater, however, it can have many effects on foods. MSG is known as an “excitotoxin” or neurotoxin. Research studies have found that it has devastating and degenerative effects on the brain and the nervous system. The neurons or brain cells overstimulate and fatigue to their death. MSG enters the brain through the membranes in the mouth and the throat. It also enters the blood-stream through the digestion of food in the gastrointestinal (GI) tract. MSG “tricks” the human body into believing that it is getting value from these foods. �
MSG is not a natural substance found in nature. It’s a man-made chemical from glutamic acid, an amino acid found in proteins. Amino acids do happen naturally in animal cells and in several plant cells. The kinds of amino acids have been processed through the change of this pure form of glutamate. Some of the materials used for this purpose include starches, molasses, and corn. The manipulation procedure generates this type of glutamate. The d-glutamate is not found naturally. The free glutamates can enter the body about eight to ten times faster compared to natural glutamates. Natural glutamate is found in foods such as tomatoes, mushrooms, and milk. Techniques used to manufacture glutamate were not in use before the 1960s. The MSG in use now is not natural. In the article, we will discuss how MSG is associated with neurological diseases. �
Research Studies on MSG and Neurological Diseases
Research studies indicate that MSG is the reason for neurological diseases like Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, and Amyotrophic lateral sclerosis. Neuroscientists have explained that MSG attacks the blood-brain barrier of the neurons which is responsible for the regulation of the fragile chemical exchange inside the brain cells. The chemical exchange process is well balanced and its performance is unquestionable. Under normal conditions, the brain and the entire immune system manage all sorts of toxins, health issues, and stress. A very small amount of poisonous substances can actually make the brain overreact, ultimately resulting in excessive exhaustion and death, according to research studies. �
MSG is a leading “excitotoxin” and it is widely known to cause harm to the brain region which governs or controls additional systems from the human body. The damage will seem like a disease in the endocrine system and the immune system. This can be shown in the cases of food cravings, persistent hunger, and unusual sleeping patterns. This normally leads to obesity. MSG is also known to cause migraine headaches, behavioral disorders, depression, asthma attacks, heart problems, arthritis, sinus issues, and digestive issues. �
MSG is a neurotoxin which requires an extremely brief time to create a broadly diverse and dramatic effect on the human body. An individual may have a mild dose of a prescription drug and also have favorable effects. However, another individual might take the prescription drug and get sad, have a swollen tongue, stomach disorders, and joint problems. The different parts of the brain affected do govern various body functions. The part which is attacked will depend on the individual. If by way of instance, an individual has had a headache, a genetic pinch in a given portion of the brain, has had a fever that’s attacking regions of the brain, or has had a stroke, then it’s certain that the component of the brain that has been affected will be due to the toxins. �
A number of the foods sold are ultimately sold as weight loss promotions to the people. MSG, along with aspartame, is added when food substances, such as fat and sugar, are eliminated from the meals. These excitotoxins have been known to cause obesity and irregular heartbeats. FDA generally allows the labeling of MSG’S as natural flavors, hydrolyzed proteins, and autolyzed yeast, when used as just a partial ingredient in an additive rather than only MSG. Americans now are consuming 160 million lbs of MSG per year. Author and toxicologist Dr, George Schwartz asserts that two tablespoons of MSG on bread could kill a medium-sized dog within a moment. The FDA in 1995 claimed that no one can respond to less than 3 grams of MSG per meal. In spite of their confirmation, they’ve warned that children, pregnant or lactating women, and the elderly should avoid MSG. An extremely sensitive individual can also ultimately react even to under a gram of MSG. �
Effects of MSG and Neurological Diseases
Research studies have shown that from the late 1950s, an estimated amount of 12 grams per person of MSG was utilized by most Americans each year. These days, taking a look at precisely the same health issue, the quote is between 400 and 500 g per person each year. This is an amount which requires evaluation. The wide usage of MSG arrived in the mid-1970s. It gained much popularity throughout the 1980s with manufacturers of food. Two powerful excitotoxic food additives which took the food sector by storm have been the use of MSG and aspartame. MSG has been broadly associated with a wide assortment of symptoms and health issues. As previously stated, it affects the human body’s neurological system. The same ailments are being reported to be on their rise. The ailments are absolutely unexpected and difficult to describe. �
Neurological diseases associated with MSG and numbers of interest released by federal organizations have been recorded in fibromyalgia, which is a growing epidemic. Its patients eliminated aspartame and MSG during the research study conducted by the Florida University which reported complete relief of symptoms. On the other hand, the most cognitive research study was conducted to prove the connection between fibromyalgia and MSG along with several different additives as a common rheumatologic disorder. In this case, 4 patients had been diagnosed for 2 to 17 years with fibromyalgia syndrome. They had undergone various methods of therapy whilst failing to consider MSG as the causative agent. After eliminating aspartame and MSG in their diets, complete or near complete resolution of symptoms diagnosed was listed within months. The subjects were women who had recurring symptoms and multiple comorbidities. It’s therefore indicative that the excitotoxins, present in compounds, such as aspartate and MSG, become excitatory neurotransmitters once ingested and when consumed in excess may lead to neurotoxicity. These 4 patients may, therefore, signify this fibromyalgia syndrome and act as a link to conclusively establish a link to MSG. Therefore, persistent research studies, if carried out on a larger sample, might serve to connect the fibromyalgia syndrome into MSG and aspartame more concretely. Further research studies are required. �
Moreover, a research study connected MSG to adrenal adenomas. The hypothalamus which leads damage on the nerves is overstimulated by MSG. The hypothalamus is responsible for directing the pituitary gland’s actions, which can be known as the endocrine gland since it in turn directs the rest of the glands in the human body and their activities such as metabolism, development of reproductive and sex organs and other essential development functions. Statistics have demonstrated that 25 percent of Kenyans have a pituitary adenoma. However, research studies linking pituitary adenomas to MSG have ultimately been inconclusive. Some research studies had depicted this as a disease but have been proven wrong. �
About half of the pituitary adenomas secrete prolactin. These can become large over time in the optic nerve, thus, affecting vision. It also prevents ovulation and menses. This prevents pregnancy or conception generally. Furthermore, since prolactin is responsible for lactation, lactation can be caused by secretion in the individual even if they’re male or even when they were not pregnant. Men with these adenomas grow breasts. Since the tumor can only be discovered when it’s big and dangerous unlike in women that are forewarned by the effects on vision or related headaches, this problem is deadly in men. There’s a further need to sponsor more research studies so as to ultimately associate MSG and brain tumors, among others. �
Other effects which were attributed to MSG and neurological diseases are headaches and migraines, asthma, and obesity amongst others. In headaches and migraines, an approximate amount of $2.2 billion each year are being spent on drugs and/or medicines that treat head pain. This chronic condition has received a 74 percent increase. Second, asthma associated with the brain was connected to MSG. According to data, there was a decrease of asthma before the mid-eighties. Since then, however, there’s been a 100 percent gain in the rate of death among children and seniors. This prevalence has increased by 600 percent in the last 10 years. FDA has identified that uncontrollable asthma can be caused by MSG, sadly, no measures are taken to take care of the situation. In defects of birth and disorders of production, MSG was identified as a mutagen i.e. mutates fetuses. It’s reputed to cause damage to the development, reproduction, and growth patterns as well as the functions. Such research studies have not been concrete. Other consequences include emotional or neurological disorders. Laboratory research studies demonstrate devastating effects on brain development, including dyslexia, attention deficit, autism, hyperactivity, violent episodes or rage, panic attacks, depression, paranoia, seizures and cerebral palsy. Rats were utilized with this research study. However, human beings are five times more sensitive to MSG than rats. �
This topic of ailments in behavior for children is becoming a frequent discussion amongst professionals. These have associated attention deficits, behaviour, and instability to chemical imbalances occurring in the brain. It is now becoming an intense possibility that there’ll be damage caused by excitotoxins in the blood-brain barrier of young brains. �
In April 1994, a magazine article confirmed the rising problem of behavioral disorders. The magazine stated that the attention deficit hyperactivity disorder wasn’t in existence. It’s however said that it is currently affecting 3.3 million American kids. This magazine article estimates prominent research studies which 10 years ago stated that symptoms of ADHD and ADD vanished with maturity. Nowadays, however, ADD is the fastest growing diagnostic category for adults. The combination of both excitotoxins i.e. MSG and aspartame came into wide utilization in the 1980s. �
In the medical field, a controversy as to whether MSG is associated with neurological diseases has been determined. Monosodium glutamate, or MSG, has been utilized as a flavorant in the food industry for approximately 100 years and it is consumed by the masses on a regular basis today. Although the FDA, or the Food and Drug Administration, categorizes MSG as a safe food ingredient, many research studies have determined that it can cause a variety of health issues, including neurodegenerative diseases, among others. – Dr. Alex Jimenez D.C., C.C.S.T. Insight – Dr. Alex Jimenez D.C., C.C.S.T. Insight
Metabolic Assessment Form
The following Metabolic Assessment Form can be filled out and presented to Dr. Alex Jimenez. Symptom groups listed on this form are not intended to be utilized as a diagnosis of any type of disease, condition, or any other type of health issue. �
In honor of Governor Abbott’s proclamation, October is Chiropractic Health Month. Learn more about the proposal. � MSG is a food additive. It boosts the taste of food, attracting customers. There is no nutrition and it really does nothing to the eater, however, it can have many effects on foods. MSG is known as an “excitotoxin” or neurotoxin. Research studies have found that it has devastating and degenerative effects on the brain and the nervous system. The scope of our information is limited to chiropractic, musculoskeletal and nervous health issues as well as functional medicine articles, topics, and discussions. We use functional health protocols to treat injuries or chronic disorders of the musculoskeletal system. To further discuss the subject matter above, please feel free to ask Dr. Alex Jimenez or contact us at 915-850-0900 . �
Curated by Dr. Alex Jimenez �
Additional Topic Discussion: Chronic Pain
Sudden pain is a natural response of the nervous system which helps to demonstrate possible injury. By way of instance, pain signals travel from an injured region through the nerves and spinal cord to the brain. Pain is generally less severe as the injury heals, however, chronic pain is different than the average type of pain. With chronic pain, the human body will continue sending pain signals to the brain, regardless if the injury has healed. Chronic pain can last for several weeks to even several years. Chronic pain can tremendously affect a patient’s mobility and it can reduce flexibility, strength, and endurance.
Neural Zoomer Plus for Neurological Disease
� �
Dr. Alex Jimenez utilizes a series of tests to help evaluate neurological diseases. The Neural ZoomerTM Plus is an array of neurological autoantibodies which offers specific antibody-to-antigen recognition. The Vibrant Neural ZoomerTM Plus is designed to assess an individual�s reactivity to 48 neurological antigens with connections to a variety of neurologically related diseases. The Vibrant Neural ZoomerTM Plus aims to reduce neurological conditions by empowering patients and physicians with a vital resource for early risk detection and an enhanced focus on personalized primary prevention. �
Formulas for Methylation Support
XYMOGEN�s Exclusive Professional Formulas are available through select licensed health care professionals. The internet sale and discounting of XYMOGEN formulas are strictly prohibited.
Proudly,�Dr. Alexander Jimenez makes XYMOGEN formulas available only to patients under our care.
Please call our office in order for us to assign a doctor consultation for immediate access.
If you are a patient of Injury Medical & Chiropractic�Clinic, you may inquire about XYMOGEN by calling 915-850-0900.
�
For your convenience and review of the XYMOGEN products please review the following link.*XYMOGEN-Catalog-Download �
* All of the above XYMOGEN policies remain strictly in force.
When compared to other central nervous system (CNS) health issues, chronic neurodegenerative diseases can be far more complicated. Foremostly, because the compromised mitochondrial function has been demonstrated in many neurodegenerative diseases, the resulting problems in energy sources are not as severe as the energy collapse in ischemic stroke. Therefore, if excitotoxicity contributes to neurodegeneration, a different time of chronic excitotoxicity needs to be assumed. In the following article, we will outline what is known about the pathways that may cause excitotoxicity in neurodegenerative diseases. We will specifically discuss that in amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD) and Huntington’s disease (HD) as fundamental examples with sufficiently validated animal models in research studies. �
Huntington’s Disease
Huntington’s disease (HD) is as an inherited, fatal neurodegenerative disease which is caused by a trinucleotide (CAG) repeat expansion in the coding region of the huntingtin (htt) gene which is associated with the degeneration of the GABAergic medium-sized spiny neurons (MSN) in the striatum, although other brain regions can also ultimately be affected as the health issue progresses. HD is identified as a movement disorder with co-morbid cognitive and psychiatric symptomatology. Both mutant htt RNA together with the encoded protein which includes a polyglutamine repeat expansion is believed to cause the complicated changes in cellular metabolism which occurs in mitochondrial dysfunction and oxidative stress. �
Early research study findings which demonstrated that excitotoxicity may play a fundamental role in HD were based upon the observation that an injection of their KYN metabolite and NMDA receptor agonist QUIN, in addition to L-glutamate and kainate, in the striatum of rats caused neuronal degeneration. Another research study determined that QUIN, as compared to NMDA and kainate, causes selective degeneration of the MSNs instead of neuronal death, which tremendously resembles the pathology of HD. Moreover, NMDA receptors have been shown to be hyperactive and striatal neurons from different HD mouse models, such as a yeast artificial chromosome (YAC) which leads to over-expression of full-length htt with elongated polyglutamine repeats as well as R6/2 mice over-expressing htt exon 1 with elongated polyglutamine repeats in addition to in knock-in mice with greater CAG repeats inserted from the mouse htt gene, were demonstrated to be sensitized to excitotoxicity in vitro. Furthermore, in vivo, a sensitization to an excitotoxin injection into the striatum was only demonstrated in the transgenic YAC model of HD, whereas mice overexpressing mutant htt exon 1, R6/1 and R6/2 mice, or N171-82Q mice overexpressing mutant exon 1 and components of exon 2 or the so-called “shortstop” mouse expressing human N-terminal htt encoded by exon 1 and 2 with a 128 CAG repeat below the htt promoter, produced somewhat of a resistance to striatal excitotoxin injection during the aging process. This neuroprotection isn’t necessarily for NMDA receptor agonists, however, it can help different neurotoxic insults and may be an adaptive response to cellular stress. �
Rat MSN release increased levels of NR2A- and NR2B-containing NMDA receptors compared to interneurons in the striatum. NR1 and NR2B mRNA expression in the neostriatum of HD patients has been demonstrated to considerably decrease which is associated with the loss of these neurons. In addition, NMDA receptor-mediated pathways in MSN were determined to be tremendously sensitive to the NR2B-specific inhibitor ifenprodil. In HEK293 cells, overexpression of mutant htt increased NMDA receptor-mediated pathways and aggravated NMDA-induced cell release only when NR2B- but not when NR2A-containing NMDA receptors were co-expressed. One possible explanation for the increase in NR2B-containing NMDA receptor expression from HD models is that an extended polyglutamine repeat in htt decreases its connection to PSD95, a postsynaptic density protein included in NMDA and kainate receptor clustering, ultimately causing a greater response of PSD95 together with the NR2B subunit. Recently, research study findings suggest that not only does the subunit composition but also the localization of NMDA receptors may play a fundamental role in the NMDA receptor activity. Another research study showed that in severe striatal slice preparations from YAC transgenic mice utilizing 128 CAG repeats, extrasynaptic NMDA receptors, especially those with NR2B, are considerably increased compared to pieces from wild-type mice and YAC mice expressing htt with 18 CAG repeats. As expected from in vitro research studies, this change was associated with decreased CREB phosphorylation. The increased percentage of NR2B-containing extrasynaptic NMDA receptors was demonstrated to be associated with increased extrasynaptic localization of PSD95. One pathway which may cause the sensitization to excitotoxic stimulation downstream of the activation of extrasynaptic NMDA receptors was identified as activation of p38 MAPK. Taken multilayered evidence suggests that mutant htt results in sensitization of MSN into glutamate excitotoxicity through the redistribution of NMDA receptors from subunits to extrasynaptic sites. �
The activation of extrasynaptic NMDA receptors in acute striatal brain slices can be effectively shown in YAC mice utilizing 128 CAG repeats through spillover of synaptic glutamate by restricting EAATs. As a result, it may be determined that decreased EAAT expression may increase the activation of NMDA receptors. Surprisingly, within situ-hybridization, research studies discovered a decrease in astrocytic EAAT2 mRNA expression in the neostriatum of all HD patients. As compared to wild-type mice, however, no changes in protein expression were found to be decreased in synaptosomes of YAC mice overexpressing human htt utilizing 128 CAG repeats. The researchers determined that a decrease in EAAT2 activity from the YAC model of HD was caused by decreased palmitoylation of the transporter. In R6/2 mice, others discovered decreased EAAT2 mRNA and protein expression associated with decreased EAAT2 in synaptosomes or acute cortico-striatal pieces. However, extracellular striatal glutamate concentrations have been shown to be similar to those of wild-type control mice and a decreased glutamate clearance capability in the R6/2 mice demonstrated by therapy with EAAT inhibitors or glutamate. A putative explanation for this finding could be a decrease in glutamate release through system x?c and in xCT, the subunit of system x?c which has been demonstrated at the striatum of R6/2 mice in the mRNA and protein levels. �
As previously mentioned, the injection of the KYN metabolite QUIN in supraphysiological concentrations was utilized as an early animal model of HD. This caused further research studies of KYN metabolism in HD. Surprisingly, the QUIN precursor 3HK aggravates neurodegeneration from the QUIN HD version while KYNA is protective. Research studies discovered that in early-stage HD, compared to control and end-stage HD, neostriatal 3HK and QUIN concentrations were considerably upregulated. Another research study discovered that KYNA levels decreased in autopsied HD striata with the CSF of HD patients when compared with controls. The first enzyme of this KYN pathway, IDO, is triggered from the striatum of both YAC mice with 128 CAG repeats. Mice deficient in IDO are less sensitive to intrastriatal QUIN injection. Evaluation of KYN metabolites from three different mouse models of HD, R6/2 mice, YAC128 mice as well as HdhQ92 and HdhQ111 knock-in mice in various brain regions, suggested age-dependent activation of their KYN pathway. However, the detailed pattern of metabolite changes was different among the versions with increased 3HK in cortex, striatum, and cerebellum in R6/2 mice whereas mice expressing full-size mutant htt demonstrated an extra cortical and striatal upregulation of QUIN. Moreover, treatment of R6/2 mice with a non-blood brain barrier permeable KMO inhibitor, JM6, which indirectly improved cerebral extracellular KYNA concentrations by 50 percent, has been associated with a decrease in extracellular cerebral L-glutamate, decreased neurodegeneration and prolonged survival. Further research studies are still required for further evidence. �
Taken collectively, the research studies support the view that in HD there is a redistribution of both NMDA receptors, especially those containing NR2B, which can activate signaling pathways which boost neurodegeneration, as shown in Figure 5. There is not any evidence that cerebral L-glutamate levels are grossly increased in HD. This might be explained by the fact that even though EAAT2 and KYNA may be downregulated, there is also a downregulation of system x?c action. As only very high levels of QUIN activated NMDA receptors, this KYN metabolite is unlikely to contribute to the excitotoxic load. �
In many research studies, evidence and outcome measures have demonstrated that glutamate dysregulation and excitotoxicity in many neurological diseases, including AD, HD, and ALS, ultimately lead to neurodegeneration and a variery of symptoms associated with the health issues. The purpose of the following article is to discuss and demonstrate the role that glutamate dysregulation and excitotoxicity plays on neurodegenerative diseases. The mechanisms for excitotoxicity are different for every health issue. – Dr. Alex Jimenez D.C., C.C.S.T. Insight – Dr. Alex Jimenez D.C., C.C.S.T. Insight
Metabolic Assessment Form
[wp-embedder-pack width=”100%” height=”1050px” download=”all” download-text=”” attachment_id=”72423″ /] � The following Metabolic Assessment Form can be filled out and presented to Dr. Alex Jimenez. Symptom groups listed on this form are not intended to be utilized as a diagnosis of any type of disease, condition, or any other type of health issue. �
In honor of Governor Abbott’s proclamation, October is Chiropractic Health Month. Learn more about the proposal. �
In the article above, we outlined what is known about the pathways which may cause excitotoxicity in neurodegenerative diseases. We also discussed that in amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD) and Huntington’s disease (HD) as fundamental examples with sufficiently validated animal models in research studies. The scope of our information is limited to chiropractic, musculoskeletal and nervous health issues as well as functional medicine articles, topics, and discussions. We use functional health protocols to treat injuries or chronic disorders of the musculoskeletal system. To further discuss the subject matter above, please feel free to ask Dr. Alex Jimenez or contact us at 915-850-0900 . �
Curated by Dr. Alex Jimenez �
References
Lewerenz, Jan, and Pamela Maher. �Chronic Glutamate Toxicity in Neurodegenerative Diseases-What Is the Evidence?� Frontiers in Neuroscience, Frontiers Media S.A., 16 Dec. 2015, www.ncbi.nlm.nih.gov/pmc/articles/PMC4679930/.
Additional Topic Discussion: Chronic Pain
Sudden pain is a natural response of the nervous system which helps to demonstrate possible injury. By way of instance, pain signals travel from an injured region through the nerves and spinal cord to the brain. Pain is generally less severe as the injury heals, however, chronic pain is different than the average type of pain. With chronic pain, the human body will continue sending pain signals to the brain, regardless if the injury has healed. Chronic pain can last for several weeks to even several years. Chronic pain can tremendously affect a patient’s mobility and it can reduce flexibility, strength, and endurance.
Neural Zoomer Plus for Neurological Disease
Dr. Alex Jimenez utilizes a series of tests to help evaluate neurological diseases. The Neural ZoomerTM Plus is an array of neurological autoantibodies which offers specific antibody-to-antigen recognition. The Vibrant Neural ZoomerTM Plus is designed to assess an individual�s reactivity to 48 neurological antigens with connections to a variety of neurologically related diseases. The Vibrant Neural ZoomerTM Plus aims to reduce neurological conditions by empowering patients and physicians with a vital resource for early risk detection and an enhanced focus on personalized primary prevention. �
Formulas for Methylation Support
XYMOGEN�s Exclusive Professional Formulas are available through select licensed health care professionals. The internet sale and discounting of XYMOGEN formulas are strictly prohibited.
Proudly,�Dr. Alexander Jimenez makes XYMOGEN formulas available only to patients under our care.
Please call our office in order for us to assign a doctor consultation for immediate access.
If you are a patient of Injury Medical & Chiropractic�Clinic, you may inquire about XYMOGEN by calling 915-850-0900.
�
For your convenience and review of the XYMOGEN products please review the following link.*XYMOGEN-Catalog-Download �
* All of the above XYMOGEN policies remain strictly in force.
When compared to other central nervous system (CNS) health issues, chronic neurodegenerative diseases can be far more complicated. Foremostly, because the compromised mitochondrial function has been demonstrated in many neurodegenerative diseases, the resulting problems in energy sources are not as severe as the energy collapse in ischemic stroke. Therefore, if excitotoxicity contributes to neurodegeneration, a different time of chronic excitotoxicity needs to be assumed. In the following article, we will outline what is known about the pathways that may cause excitotoxicity in neurodegenerative diseases. We will specifically discuss that in amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD) and Huntington’s disease (HD) as fundamental examples with sufficiently validated animal models in research studies. �
Alzheimer’s Disease
Alzheimer’s disease (AD) is one of the main causes of dementia among older adults in the United States. Neuropathologically, AD is characterized as neurodegeneration with extracellular senile plaques made up of ? amyloid (A?) and intraneuronal neurofibrillary tangles of aggregated tau, which initially appear in the hippocampus than then spread as the health issue progresses. Prominent microglial cell activation can also be associated with AD. Hereditary types of AD occur due to mutations in the A? precursor protein, A?PP, or in the presenilins, which are part of the multi-protein complex involved in A? generation. The pathophysiology of AD is complicated and a variety of pathways are included in the synaptic and the cellular degeneration in AD, such as abnormalities in signaling pathways through glycogen synthase kinase-3 beta or mitogen-activated protein kinases, cell cycle re-entry, oxidative stress, or decreased transport of trophic factors and adrenal dysregulation. However, evidence suggests that L-glutamate dysregulation plays a critical role in Alzheimer’s disease. �
Research studies demonstrated that primary neurons from transgenic mice overexpressing mutant presenilin are far more sensitive to excitotoxic stimulation in vitro. In vitro, aggregated A? increases both NMDA and kainate receptor-mediated L-glutamate toxicity, perhaps by interrupting neuronal calcium homeostasis. Others have demonstrated that A? can increase neuronal excitability by changing the capacity of glycogen synthase kinase 3? inhibition to decrease NMDA receptor-mediated pathways. Soluble A? oligomers were demonstrated to cause L-glutamate release from astrocytes resulting in dendritic spine loss through over-activation of extrasynaptic NMDA receptors. Moreover, extracellular L-glutamate concentrations were demonstrated to increase in a triple transgenic mouse model of AD, in which a 3-month treatment with the NMDA receptor inhibitor ultimately affected synapse loss. However, further research studies are still required. �
Numerous mouse research studies have demonstrated the consequences of AD-like pathology on EAAT expression and/or function. In acute hippocampal slice preparations, A? was shown to interrupt the clearance of synaptically released L-glutamate by diminishing membrane insertion of EAAT2, a result perhaps mediated by oxidative stress. In aged A?PP23 mice, research studies revealed the downregulation of EAAT2 expression in the frontal cortex and hippocampus, which in the frontal cortex was associated with an increase in xCT expression. These changes were associated with a strong tendency toward improved extracellular L-glutamate amounts as measured by microdialysis. In triple transgenic AD mice expressing the amyloid precursor protein mutations K670N and M671L, the presenilin 1 mutation M146V and the tau P301L mutation, a strong and age-dependent decrease of EAAT2 expression was demonstrated. Restoration of EAAT2 activity in the AD mice following treatment with all the ?-lactam antibiotic Cef was associated with a decrease in cognitive impairment and reduced tau pathology. In human AD brains, decreased expression of EAAT2 protein and a decrease in EAAT action was determined. However,� this outcome measure could not be replicated by other researchers. On the transcriptome level, research studies discovered exon-skipping splice variations of EAAT2 which reduce glutamate transport activity to be upregulated in human AD brains. From the CSF, several groups demonstrated an increase in glutamate concentrations in AD patients where other groups demonstrated absolutely no change or even diminished levels of L-glutamate associated with Alzheimer’s disease. �
In vitro, A? causes L-glutamate discharge from primary microglia through the upregulation of program x?c. Others discovered that it also triggered L-glutamate release from astrocytes through the activation of the ?7 nicotinic acetylcholine receptor. Additionally, xCT, the specific subunit of system x?c is upregulated at the region of senile plaques, possibly in microglial cells, in Thy1-APP751 mice (TgAPP) expressing human APP bearing the Swedish (S: KM595/596NL) and London (L: V6421) mutations after A? injection in the hippocampus. Semiquantitative immunoblot evaluations revealed an upregulation of xCT protein expression in the frontal cortex in elderly A?PP23 mice compared to wild-type controls. �
Postmortem research studies show that KYN metabolism affects AD elevated concentrations of KYNA while also discovered in the basal ganglia of both AD sufferers. Utilizing immunohistochemistry, research studies demonstrated immunoreactivity for both IDO and QUIN upregulated in AD brains, particularly in the vicinity of plaques. A? causes IDO expression in human primary macrophages and microglia. Systemic inhibition of KMO ultimately increases brain KYNA levels and ameliorated the phenotype of a mouse model of AD, indicating an upregulation of KYNA may be an endogenous protective reaction, including the IDO inhibitor, coptisine, decreased microglial, astrocytic activation and cognitive impairment in AD mice. �
Taken together, along with many other harmful changes, there is evidence for chronic excitotoxicity in AD which can be driven by numerous variables, including the central sensitization of both NMDA receptors, a decrease in L-glutamate and L-aspartate reuptake capacity and an increase in glutamate release through system x?c, as shown in Figure 4. Although the KYN pathway seems to be upregulated in AD, no specific conclusions can be drawn regarding glutamatergic neurotransmission from the upregulation of the two QUIN which was neurotoxic and neuroprotective KYNA. �
�
In many research studies, evidence and outcome measures have demonstrated that glutamate dysregulation and excitotoxicity in many neurological diseases, including AD, HD, and ALS, ultimately lead to neurodegeneration and a variery of symptoms associated with the health issues. The purpose of the following article is to discuss and demonstrate the role that glutamate dysregulation and excitotoxicity plays on neurodegenerative diseases. The mechanisms for excitotoxicity are different for every health issue. – Dr. Alex Jimenez D.C., C.C.S.T. Insight – Dr. Alex Jimenez D.C., C.C.S.T. Insight
In the article above, we outlined what is known about the pathways which may cause excitotoxicity in neurodegenerative diseases. We also discussed that in amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD) and Huntington’s disease (HD) as fundamental examples with sufficiently validated animal models in research studies. The scope of our information is limited to chiropractic, musculoskeletal and nervous health issues as well as functional medicine articles, topics, and discussions. We use functional health protocols to treat injuries or chronic disorders of the musculoskeletal system. To further discuss the subject matter above, please feel free to ask Dr. Alex Jimenez or contact us at 915-850-0900 . �
Curated by Dr. Alex Jimenez �
References �
Lewerenz, Jan, and Pamela Maher. �Chronic Glutamate Toxicity in Neurodegenerative Diseases-What Is the Evidence?� Frontiers in Neuroscience, Frontiers Media S.A., 16 Dec. 2015, www.ncbi.nlm.nih.gov/pmc/articles/PMC4679930/.
Additional Topic Discussion: Chronic Pain
Sudden pain is a natural response of the nervous system which helps to demonstrate possible injury. By way of instance, pain signals travel from an injured region through the nerves and spinal cord to the brain. Pain is generally less severe as the injury heals, however, chronic pain is different than the average type of pain. With chronic pain, the human body will continue sending pain signals to the brain, regardless if the injury has healed. Chronic pain can last for several weeks to even several years. Chronic pain can tremendously affect a patient’s mobility and it can reduce flexibility, strength, and endurance.
Neural Zoomer Plus for Neurological Disease
Dr. Alex Jimenez utilizes a series of tests to help evaluate neurological diseases. The Neural ZoomerTM Plus is an array of neurological autoantibodies which offers specific antibody-to-antigen recognition. The Vibrant Neural ZoomerTM Plus is designed to assess an individual�s reactivity to 48 neurological antigens with connections to a variety of neurologically related diseases. The Vibrant Neural ZoomerTM Plus aims to reduce neurological conditions by empowering patients and physicians with a vital resource for early risk detection and an enhanced focus on personalized primary prevention. �
Formulas for Methylation Support
XYMOGEN�s Exclusive Professional Formulas are available through select licensed health care professionals. The internet sale and discounting of XYMOGEN formulas are strictly prohibited.
Proudly,�Dr. Alexander Jimenez makes XYMOGEN formulas available only to patients under our care.
Please call our office in order for us to assign a doctor consultation for immediate access.
If you are a patient of Injury Medical & Chiropractic�Clinic, you may inquire about XYMOGEN by calling 915-850-0900.
�
For your convenience and review of the XYMOGEN products please review the following link.*XYMOGEN-Catalog-Download �
* All of the above XYMOGEN policies remain strictly in force.
When compared to other central nervous system (CNS) health issues, chronic neurodegenerative diseases can be far more complicated. Foremostly, because the compromised mitochondrial function has been demonstrated in many neurodegenerative diseases, the resulting problems in energy sources are not as severe as the energy collapse in ischemic stroke. Therefore, if excitotoxicity contributes to neurodegeneration, a different time of chronic excitotoxicity needs to be assumed. In the following article, we will outline what is known about the pathways that may cause excitotoxicity in neurodegenerative diseases. We will specifically discuss that in amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD) and Huntington’s disease (HD) as fundamental examples with sufficiently validated animal models in research studies. �
Amyotrophic Lateral Sclerosis
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease associated with the degeneration of motor neurons which ultimately determine the length of the health issue. ALS is considered fatal several years after it begins. It is hypothesized that L-glutamate excitotoxicity plays a role in the motor neuron death in ALS because cells demonstrate increased levels of calcium-permeable AMPA receptors and low levels of calcium-binding proteins. Compared to the utilization of AMPA and kainate, and L-HCA, in the spinal cord of rats, treatment with NMDA spared motor neurons suggests that NMDA excitotoxicity may actually not play a fundamental role in ALS. However, NMDA receptor-mediated excitotoxicity in motor neurons was demonstrated in chick embryo organotypic slice cultures. Electrophysiological research studies suggested that transient hyperexcitability of motor nerves in the presymptomatic phase of ALS in mice transgenic for the G93A mutation of human SOD1 is associated with hereditary ALS. Additionally, cortical hyperexcitability was recorded in familial and sporadic ALS patients with the onset of symptoms in familial ALS mutation carriers. Moreover, the only approved drug and/or medication utilized for ALS, which increases survival by 2 to 3 months, acts as an inhibitor of both NMDA and kainate receptors together with quickly upregulating EAAT activity in synaptosomes, according to several research studies. �
In autopsied spinal cords from patients with ALS, several groups demonstrated a decrease in EAAT2 and not in EAAT1 protein expression in the gray matter of regions with considerable motor neuron loss. In addition, both L-glutamate uptake and EAAT2 immunoreactivity, as demonstrated by Western blotting, were demonstrated to be quantitatively decreased in postmortem tissue of ALS patients, particularly in the spinal cord, the tissue which is most commonly affected by the health issue. Additionally, it has been demonstrated that as a possible effect of EAAT2 downregulation, L-glutamate amounts are increased in the CSF in patients with ALS. However, this outcome measure couldn’t be replicated by other research studies. �
The downregulation of EAAT2 in human ALS is demonstrated in several animal models of ALS, including transgenic mice expressing human SOD1 containing the G93A mutation which causes hereditary ALS or transgenic rats expressing the same mutation. Surprisingly, “whereas Bendotti demonstrated a late decrease in EAAT2 expression at the time when the mice had already become symptomatic,” research studies demonstrated fluctuations in EAAT2 expression at the presymptomatic stage. The ?-lactam antibiotic ceftriaxone (Cef) promotes the production of EAAT2 in cultured murine spinal cord slices and in neuron/astrocyte co-cultures. In addition, it caused EAAT2 expression from the spinal cords of wild-type and mutant G93A mSOD1 Tg mice, which has been associated with a decrease in motor neuron loss, weight reduction, and other ALS-like symptoms as well as an increase in survival, compatible with the hypothesis that EAAT2 loss contributes to chronic excitotoxicity in this mouse model. Just recently, a significant decrease in EAAT2 immunoreactivity had been demonstrated in a separate bark model for ALS, rats expressing ALS-inducing mutant TAR DNA binding protein 43 in astrocytes only. Surprisingly, the research studies demonstrated that when measured by microdialysis, the extracellular L-glutamate and L-aspartate concentrations increase while the L-glutamate clearance capability decrease in the cerebral cortex of G93A mSOD1 Tg mice, however, this region doesn’t show overt pathology nor downregulation of EAAT1 when evaluated. �
Taken together these research studies support the view that there is a downregulation of EAAT2 in both human ALS patients and animal models of ALS. However, while some animal research studies suggest that EAAT2 downregulation occurs before motor neuron loss, others are compatible with the hypothesis that the downregulation of EAAT2, the astroglial expression of which is associated with the existence of neurons, is a consequence of neurodegeneration in neurological diseases. �
Furthermore, EAATs decrease extracellular L-glutamate, extracellular cerebral L-glutamate is upregulated in a variety of brain regions from the cystine/glutamate antiporter system x?c. XCT, one particular subunit of program x?c, was demonstrated to be differentially regulated and maintained in mouse models of ALS. Research studies demonstrated that the uptake of radiolabelled cystine was upregulated in spinal cord slices of presymptomatic G93A mSOD1 Tg mice at the age of 70 days but not in 55 or 100 days and not in symptomatic 130 day-old mice which also determined that the upregulation of cystine uptake at day 70 was because of system x?c activity utilizing the system x?c inhibitor sulfasalazine (SSZ). It needs to be considered, however, that cystine can also be hauled by EAATs. Therefore, as evidence about the SSZ-sensitivity of cystine uptakes were not demonstrated for days 100 and 130, the differential cystine uptake demonstrated in this research study at the older ages could rather be a result of decreased EAAT action. By comparison, research studies with rtPCR demonstrated a strong growth in xCT mRNA levels in G37R mSOD1 Tg mice on the beginning of symptoms, which has been further increased as symptoms improved. Moreover, it was demonstrated that xCT was primarily demonstrated in spinal cord microglial cells. Microglia revealed xCT mRNA upregulation in the presymptomatic stage. Taken together, these outcome measures suggest the system x?c is upregulated in animal models of ALS. However, the evidence is lacking about whether this is true for human cases of ALS. Nevertheless, further research studies revealed that the mRNA levels of CD68, a marker of microglial activation, were associated with xCT mRNA expression in postmortem spinal cord tissue of individuals with ALS, demonstrating that neuroinflammation in humans is also ultimately associated with xCT upregulation. �
Beyond the dysregulation of L-glutamate and L-aspartate levels by EAAT downregulation or system x?c upregulation, pathways that indirectly regulate and maintain glutamatergic neurotransmission also have been suggested to participate in motor neuron degeneration in ALS. D-Serine levels have been shown to become considerably increased from the spinal cord of G93A mSOD1 Tg mice. Starting at disease onset and ongoing during the course of this symptomatic phase, D-serine increases NMDA excitotoxicity in motor neurons. The upregulation of D-serine at the spinal cord was duplicated by other research studies. Downregulation of this D-serine metabolizing enzyme DAO in the reticulospinal tract has been demonstrated as the main mechanism for D-serine upregulation in the spinal cord in ALS mice. In addition, genetic inactivation of DAO in mice has been associated with motor neuron degeneration and a deficiency in the D-serine generating enzyme serine racemase prolonged survival in G93A mSOD1 Tg mice although it hastened neurodegenerative disease onset. A heterozygous mutation of DAO has been demonstrated to be separate from the ALS phenotype in a large family with hereditary ALS. However, this continues to be the only family determined where a DAO mutation is associated with ALS. �
Concerning the other amino acid co-agonist of the NMDA receptor, glycine, an increase in the CSF levels in patients with ALS was demonstrated by one group, however, it couldn’t be replicated by other research studies. Several research studies also determined that KYNA levels are upregulated in the CSF of bulbar ALS patients as well as those in end-stage ALS. Independently, it was revealed that tryptophan and KYN levels are increased in the CSF from ALS patients as compared to controls. Additionally, IDO was proven to be expressed in neurons and spinal cord microglia from patients with ALS, indicating that microglial activation may increase the conversion of tryptophan in ALS into KYN, among others. �
Multilayered evidence suggests that increased glutamatergic neurotransmission is within ALS and may ultimately cause neurodegeneration in neurodegenerative diseases, as shown in Figure 3. Downregulation of EAAT2 in astrocytes and upregulation of program x?forecast in the context of microglial activation was repeatedly documented. NMDA receptors by D-serine may also play a role in dysregulation. Moreover, the kynurenine pathway seems to be triggered in ALS. �
�
In many research studies, evidence and outcome measures have demonstrated that chronic excitotoxicity may be associated with a variety of neurodegenerative diseases, including AD, HD, and ALS, ultimately causing neurodegeneration and a variery of symptoms associated with the health issues. The purpose of the following article is to outline what may cause excitotoxicity in neurodegenerative diseases. We will discuss these in amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD) and Huntington’s disease (HD). – Dr. Alex Jimenez D.C., C.C.S.T. Insight – Dr. Alex Jimenez D.C., C.C.S.T. Insight
In the article above, we outlined what is known about the pathways which may cause excitotoxicity in neurodegenerative diseases. We also discussed that in amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD) and Huntington’s disease (HD) as fundamental examples with sufficiently validated animal models in research studies. The scope of our information is limited to chiropractic, musculoskeletal and nervous health issues as well as functional medicine articles, topics, and discussions. We use functional health protocols to treat injuries or chronic disorders of the musculoskeletal system. To further discuss the subject matter above, please feel free to ask Dr. Alex Jimenez or contact us at 915-850-0900 . �
Curated by Dr. Alex Jimenez �
References �
Lewerenz, Jan, and Pamela Maher. �Chronic Glutamate Toxicity in Neurodegenerative Diseases-What Is the Evidence?� Frontiers in Neuroscience, Frontiers Media S.A., 16 Dec. 2015, www.ncbi.nlm.nih.gov/pmc/articles/PMC4679930/.
Additional Topic Discussion: Chronic Pain
Sudden pain is a natural response of the nervous system which helps to demonstrate possible injury. By way of instance, pain signals travel from an injured region through the nerves and spinal cord to the brain. Pain is generally less severe as the injury heals, however, chronic pain is different than the average type of pain. With chronic pain, the human body will continue sending pain signals to the brain, regardless if the injury has healed. Chronic pain can last for several weeks to even several years. Chronic pain can tremendously affect a patient’s mobility and it can reduce flexibility, strength, and endurance.
Neural Zoomer Plus for Neurological Disease
�
Dr. Alex Jimenez utilizes a series of tests to help evaluate neurological diseases. The Neural ZoomerTM Plus is an array of neurological autoantibodies which offers specific antibody-to-antigen recognition. The Vibrant Neural ZoomerTM Plus is designed to assess an individual�s reactivity to 48 neurological antigens with connections to a variety of neurologically related diseases. The Vibrant Neural ZoomerTM Plus aims to reduce neurological conditions by empowering patients and physicians with a vital resource for early risk detection and an enhanced focus on personalized primary prevention. �
Formulas for Methylation Support
XYMOGEN�s Exclusive Professional Formulas are available through select licensed health care professionals. The internet sale and discounting of XYMOGEN formulas are strictly prohibited.
Proudly,�Dr. Alexander Jimenez makes XYMOGEN formulas available only to patients under our care.
Please call our office in order for us to assign a doctor consultation for immediate access.
If you are a patient of Injury Medical & Chiropractic�Clinic, you may inquire about XYMOGEN by calling 915-850-0900.
�
For your convenience and review of the XYMOGEN products please review the following link.*XYMOGEN-Catalog-Download �
* All of the above XYMOGEN policies remain strictly in force.
Excitotoxicity is characterized as an acute insult which causes nerve cell death due to the excessive activation of iGluRs. Acute excitotoxicity plays a fundamental role in a variety of central nervous system (CNS) health issues, including cerebral ischemia, TBI, and status epilepticus. The mechanisms for acute excitotoxicity are different for every health issue. �
With brain ischemia, L-glutamate-associated and L-aspartate-associated excitotoxicity happen within minutes due to the growth in extracellular cerebral L-glutamate as well as L-aspartate. Because these are also energy-dependent, the abrupt loss of energy due to the shut down of blood flow can ultimately breakdown the neuronal and astroglial membrane. In neurons, membrane depolarization contributes to vesicular discharge. Additionally, energy degradation may even cause a change in their action, therefore, causing L-glutamate and L-aspartate to activate and affect ionic homeostasis which can interrupt EAAT action. The activation of L-glutamate/L-aspartate contributes to excitotoxicity through the over-activation of iGluRs of the NMDA type as demonstrated by the efficiency of NMDA antagonists in animal models of transient cerebral ischemia. �
In TBI, the mechanical tissue damage and the disruption of the blood-brain barrier can trigger acute secondary neurodegeneration, which, together with neuroinflammation and oxidative stress, is associated with L-glutamate activation from intracellular compartments and, therefore, by acute excitotoxicity. Moveover, acute application of the NMDA antagonist MK801 following TBI ameliorates neuronal loss and long-term behavioral abnormalities, among others. �
In status epilepticus, continuing the synchronized activity of excitatory neuronal networks as well as the continuous breakdown of restricting mechanisms is the main source of L-glutamate and L-aspartate activation. As the severity of synchronous activity depends upon the involvement of nerve cells into a neuronal system as well as the capability of a neural cell to withstand excess glutamate mainly depends on the expression pattern of iGluRs, a somewhat restricted and maturation-associated degeneration of neuronal populations which is ultimately caused by prolonged epileptic seizures. The significance of excitotoxicity in status epilepticus is shown as NMDA antagonists, such as ketamine, decrease adrenal loss. �
Excitotoxicity in Neurological Diseases
Because EAATs were discovered to be down-regulated in a variety of central nervous system (CNS) health issues and L-glutamate, as well as L-aspartate, clearance can ultimately affect the excitotoxicity of neurological diseases, many healthcare professionals have decided to determine substances which cause EAAT2, or the main EAAT in the brain and most commonly shown to be downregulated. This has demonstrated substances which shows astrocytic EAAT2 expression both in vitro and in vivo research studies. Several of these have also demonstrated protective properties in animal models of neurological diseases. Cef is one of the most evaluated compounds and it has been analyzed in AD, HD, and ALS models with positive outcomes. However, none of the substances has been extensively researched for its capability to interact with other neuroprotective pathways. Cef has also been demonstrated to promote EAAT2 expression but also to trigger the transcription factor Nrf2, which results in the transcription of a wide array of genes involved in cytoprotection and antioxidant protection. Because oxidative stress is believed to play an essential role in many, if not all, neurological diseases, this pathway may account for the neuroprotection caused by Cef. Furthermore, xCT, which can be one of the downstream targets of Nrf2, has been demonstrated to be upregulated by Cef in vitro and in vivo. Another in vitro EAAT2-promoting substance, MS-153, efficiently protected against secondary neurodegeneration after traumatic brain injury as well as through mechanisms other than EAAT2 upregulation. Evidence of concept experiments which demonstrate the increased stimulation through iGluRs in neurodegenerative diseases needs manipulations of their neurotransmitter physiology. �
Glud1 Tg mice demonstrate a model of excitotoxicity associated with enhanced synaptic L-glutamate activation with restricted neuronal loss. However, this animal model of glutamatergic neurotransmission has not yet been utilized to analyze if Glud1 over-expression aggravates the phenotype of mouse models in neurological diseases. Another version involves the EAAT2-deficient mouse. Homozygous EAAT2 knock-out mice have health issues associated with premature death because of epilepsy as well as hippocampal and focal cortical atrophy. Heterozygous EAAT2 knock-out mice, however, develop normally and show only mild behavioral abnormalities. This mouse model of moderate glutamate hyperfunction has been utilized in a collection of evidence of principle research studies which demonstrated the fundamental role of glutamate. ALS mice, which have both the G93A mSOD1 mutation and a decreased quantity of EAAT2 (SOD1(G93A)/EAAT2�), revealed an increase in the speed of motor decline accompanied by earlier motor neuron loss when compared with single mutant G93A mSOD1 Tg mice. A decrease in survival was also demonstrated in these mutant mice. When crossed with transgenic mice expressing mutations of the human amyloid-? protein precursor and presenilin-1 (A?PPswe/PS1?E9), partial loss of EAAT2 unmasked spatial memory deficits in 6-month-old mice expressing A?PPswe/PS1?E9. These mice demonstrated an increase in the ratio of detergent-insoluble A?42/A?40 demonstrating that shortages in glutamate transporter function ultimately cause premature pathogenic processes associated with AD. By comparison, the phenotype of the R6/2 HD mouse model wasn’t changed in mice which had only one EAAT2 allele. Further research studies are still necessary for further evidence. �
As a complement to these research studies, transgenic mice which over-express EAAT2 in astrocytes through the GFAP promoter has also been developed. EAAT2/G93A mSOD1 double Tg mice demonstrated moderate amelioration of their ALS-like phenotype with a statistically significant (14 times ) delay in grip power decrease and loss of motor neurons as well as a decrease in other occasions, such as caspase-3 activation and SOD1, although not at the beginning of paralysis, weight loss or an extended life span when compared with monotransgenic G93A mSOD1 littermates. Exactly the same EAAT2 transgenic mouse model was utilized to evaluate the effect of improved astrocytic L-glutamate and L-aspartate uptake by cross-breeding with an animal model of AD, A?PPswe/Ind mice. Increased EAAT2 protein levels considerably increased and improved overall cognitive functioning, restored synaptic ethics, and decreased amyloid plaques in those AD mice. �
In mice in which genetically engineered regulation and management of xCT causes a lack in the glutamate/cystine antiporter system x?c, the obvious decrease of extrasynaptic L-glutamate is associated with the tremendous resistance of dopaminergic neurons against 6-hydroxydopamine-induced neurodegeneration, perhaps as a consequence of reduced excitotoxicity. However, microglial activation has also been demonstrated to be modulated by system x?c deficiencies leading to a more neuroprotective phenotype which offers an explanation for the protective effect of xCT deletion in this circumstance. �
Therefore, genetic variations encourage the role of chronic excitotoxicity in neurodegenerative diseases, particularly AD and ALS. These models all represent life-long changes in glutamatergic neurotransmission. These models can’t determine if the utilization of drugs and/or medications can directly affect glutamate levels throughout the neurodegenerative process and/or be protective. Both evaluation and analysis of EAAT2-inducing medicine for the progression of inducible mouse models and their interaction with other signaling pathways is still warranted by researchers and healthcare professionals. �
In many research studies, evidence and outcome measures have demonstrated that glutamate dysregulation and excitotoxicity in many neurological diseases, including AD, HD, and ALS, ultimately lead to neurodegeneration and a variery of symptoms associated with the health issues. The purpose of the following article is to discuss and demonstrate the role that glutamate dysregulation and excitotoxicity plays on neurodegenerative diseases. The mechanisms for excitotoxicity are different for every health issue. – Dr. Alex Jimenez D.C., C.C.S.T. Insight – Dr. Alex Jimenez D.C., C.C.S.T. Insight
Metabolic Assessment Form
The following Metabolic Assessment Form can be filled out and presented to Dr. Alex Jimenez. Symptom groups listed on this form are not intended to be utilized as a diagnosis of any type of disease, condition, or any other type of health issue. �
Excitotoxicity is characterized as an acute insult which causes cell death due to the excess activation of iGluRs. Excitotoxicity plays a fundamental role in a variety of central nervous system (CNS) health issues, including cerebral ischemia, TBI, and status epilepticus. The mechanisms for acute excitotoxicity are different for every health issue. The scope of our information is limited to chiropractic, musculoskeletal and nervous health issues as well as functional medicine articles, topics, and discussions. We use functional health protocols to treat injuries or chronic disorders of the musculoskeletal system. To further discuss the subject matter above, please feel free to ask Dr. Alex Jimenez or contact us at 915-850-0900 . �
Curated by Dr. Alex Jimenez �
References �
Lewerenz, Jan, and Pamela Maher. �Chronic Glutamate Toxicity in Neurodegenerative Diseases-What Is the Evidence?� Frontiers in Neuroscience, Frontiers Media S.A., 16 Dec. 2015, www.ncbi.nlm.nih.gov/pmc/articles/PMC4679930/.
Additional Topic Discussion: Chronic Pain
Sudden pain is a natural response of the nervous system which helps to demonstrate possible injury. By way of instance, pain signals travel from an injured region through the nerves and spinal cord to the brain. Pain is generally less severe as the injury heals, however, chronic pain is different than the average type of pain. With chronic pain, the human body will continue sending pain signals to the brain, regardless if the injury has healed. Chronic pain can last for several weeks to even several years. Chronic pain can tremendously affect a patient’s mobility and it can reduce flexibility, strength, and endurance.
Neural Zoomer Plus for Neurological Disease
�
Dr. Alex Jimenez utilizes a series of tests to help evaluate neurological diseases. The Neural ZoomerTM Plus is an array of neurological autoantibodies which offers specific antibody-to-antigen recognition. The Vibrant Neural ZoomerTM Plus is designed to assess an individual�s reactivity to 48 neurological antigens with connections to a variety of neurologically related diseases. The Vibrant Neural ZoomerTM Plus aims to reduce neurological conditions by empowering patients and physicians with a vital resource for early risk detection and an enhanced focus on personalized primary prevention. �
Formulas for Methylation Support
XYMOGEN�s Exclusive Professional Formulas are available through select licensed health care professionals. The internet sale and discounting of XYMOGEN formulas are strictly prohibited.
Proudly,�Dr. Alexander Jimenez makes XYMOGEN formulas available only to patients under our care.
Please call our office in order for us to assign a doctor consultation for immediate access.
If you are a patient of Injury Medical & Chiropractic�Clinic, you may inquire about XYMOGEN by calling 915-850-0900.
�
For your convenience and review of the XYMOGEN products please review the following link.*XYMOGEN-Catalog-Download �
* All of the above XYMOGEN policies remain strictly in force.
Previous research studies suggest that L-aspartate, like L-glutamate, triggers excitatory activity on neurons. L-aspartate functions with L-glutamate in the synaptic vesicles of asymmetric excitatory synapses. But, the total concentration of these in the human brain (0.96-1.62 ?mol/gram wet weight), their extracellular concentrations in the cortex as measured by microdialysis (1.62 ?M for L-aspartate and 9.06 ?M for L-glutamate) and their supply according to immunohistochemistry suggest that L-aspartate is significantly less abundant than L-glutamate. Moreover, L-aspartate is a powerful agonist for NMDA receptors but not for other iGluRs with an EC50 just eight-fold higher than that of L-glutamate. EAATs which play a fundamental role in the uptake of all vesicular released L-glutamate in the central nervous system (CNS) also requires the utilization of L-aspartate. L-aspartate is perhaps as less essential as L-glutamate connected to the total excitatory activity associated with iGluRs. Along with its role as a neurotransmitter, as previously mentioned, L-aspartate is also necessary as a substrate for aspartate amino-transferase which turns into 2-oxoglutarate and L-glutamate to transport to the cortical vesicles of glutamatergic neurons which may also consequently and indirectly increase L-glutamate release. �
Other Molecules in Glutamate Signaling
One characteristic which distinguishes NMDA receptors from different iGluRs is that the activation of NMDA receptors needs the connection of a co-agonist to the glycine binding region of the receptor. By way of instance, in the retina and in the spinal cord, the origin of glycine may spillover out of glycinergic inhibitory synapses. But, in different regions of the brain with increased NMDA receptor expression, such as the hippocampal formation, reactions associated with strychnine-sensitive glycine receptors are missing, at least in adult neurons, demonstrating the absence of glycinergic inhibitory neurotransmissions. But, glycine is found in the extracellular fluid of the hippocampus at baseline amounts of roughly 1.5 ?M, which is similar to the saturation of the glycine binding region of the NMDA receptor, although these may be up- and down-regulated. The origin of extracellular glycine in the hippocampus can be neurons which release glycine through the alanine-serine-cysteine amino acid transporter 1 (asc-1). But, glycine release by astrocytes that is stimulated by depolarization and kainate, has also been demonstrated. Further research studies are required to ultimately show these outcome measures. �
Even in previous research studies of the NMDA receptor and its co-activation by glycine revealed that D-amino acids, particularly D-serine, are nearly as powerful as glycine. Only several years after, it became obvious that D-serine is found in rat and human brains at roughly one-third of their concentration of L-serine having an absolute concentration of more than 0.2 ?mol/g brain tissue. Utilizing an antiserum for D-serine, research studies demonstrated that D-serine from the brain is only found in astrocytes and its supply fits the expression of NMDA receptors. In addition, the same researchers demonstrated that D-serine is released from cultured astrocytes when exposed to L-glutamate or kainate. The abundance of D-serine is found by the degrading enzyme D-amino acid oxidase (DAO) which reveals increased expression in the hindbrain where D-serine levels are reduced as well as the synthetic enzyme serine racemase which creates D-serine from L-serine. D-Serine appears to be stored in cytoplasmic vesicles in astrocytes and it can be released by exocytosis. Long-term potentiation is dependent upon D-serine release from astrocytes in hippocampal slices, suggesting that this amino acid definitely plays a fundamental role in glutamatergic neurotransmission through NMDA receptors. Additionally in hippocampal slices, research studies found, utilizing D-serine and glycine degrading enzymes, which D-serine functions as a co-transmitter for synaptic NMDA receptors on CA1 neurons likewise which glycine functions as the endogenous co-agonist for extrasynaptic NMDA receptors. Synaptic NMDA receptors of dentate gyrus neurons utilize glycine rather than D-serine as the co-agonist. �
Taken collectively, multilayered outcome measures show that L-aspartate doesn’t simply function as an agonist on NMDA receptors but also glycine and D-serine play fundamental roles in glutamatergic neurotransmission in the human brain. But, other molecules also have been demonstrated to be relevant modulators of glutamatergic neurotransmission. �
Glutamate Activated by Other Molecules
L-homocysteate (L-HCA) has structural similarities with L-glutamate. The non-protein amino acid is an oxidation product of homocysteine that is biosynthesized from methionine in the elimination of its own terminal methyl group and it is also an intermediate of the transsulfuration pathway by which methionine may be converted to cysteine through cystathionine. Early research studies demonstrated that this amino acid can cause calcium influx in cultured neurons as safely and effectively as L-glutamate. Moreover, L-HCA revealed an increased affinity for NMDA receptors when compared to other iGluRs in binding assays associated with its capacity to cause NMDA receptor antagonist-inhibitable excitotoxicity and sodium influx. Additionally, L-HCA can trigger mGluR5 as efficiently as L-glutamate. L-HCA is found in the brain, however, the concentrations were demonstrated to be approximately 500-fold lesser than those of L-glutamate and even 100-fold lesser when compared to those of L-aspartate in different regions of the rat brain. Throughout potassium-induced stimulation, L-HCA discharge is triggered from brain slice preparations as demonstrated for L-aspartate and L-glutamate although the absolute release of HCA is approximately 50-fold lesser. Surprisingly, HCA is a very efficient competitive inhibitor of cystine and L-glutamate uptake through the cystine/glutamate antiporter system x?c, the activity that regulates and manages the extracellular extrasynaptic L-glutamate concentrations in the brain. Therefore, the impact of L-HCA on the activation of NMDA and other L-glutamate receptors may also rely on the L-HCA-induced trigger of L-glutamate through system x?c. L-HCA may play an important role in the overall stimulation of L-glutamate receptors. Nevertheless, this can change tremendously under certain conditions, e.g., in patients with high-dose methotrexate therapy, an anticancer drug which, by restricting dihydrofolate reductase, limits the tetrahydrofolate-catalyzed recycling of methionine from homocysteine. Here, L-HCA concentrations of more than 100 ?M have been demonstrated from the cerebrospinal fluid whereas L-HCA was undetectable in control subjects. Further research studies are still required to determine these outcome measures. �
Further endogenous small molecules which are believed to affect L-glutamate signaling include several intermediates of tryptophan metabolism, as shown in Figure 2. Through the activity of indoleamine 2,3-dioxygenase (IDO) or tryptophan 2,3-dioxygenase (TDO), tryptophan is turned into N-formyl-L-kynurenine which is later turned into kynurenine (KYN) by formamidase. Three pathways, two of which connect at a subsequent step, result in further metabolism. First, through the activity of kynurenine aminotransferase (KAT), KYN is converted into kynurenic acid (KYNA). KYN can also be converted to 3-hydroxykynurenine (3HK) by kynurenine monooxygenase (KMO), which can subsequently be utilized as a substrate by kynureninase for the synthesis of 3-hydroxyanthranilic acid (3HANA). Additionally, utilizing KYN as a substrate, kynureninase develops anthranilic acid (ANA), which by non-specific hydroxylation may also be converted to 3HANA. According to research studies, 3HANA finally functions as a substrate for the generation of quinolinic acid (QUIN). �
The tryptophan concentration in the rat brain is roughly 25 nmol/g wet weight and approximately 400-fold less than L-glutamate and 100-fold less than L-aspartate. The demonstrated brain levels of kynurenines are even lower with 0.4-1.6 nmol/g for QUIN, 0.01-0.07 nmol/ml for KYNA, and 0.016 nmol/g for 3HANA. Approximately 40 percent of brain KYN is locally synthesized. The metabolites of tryptophan demonstrate differential binding to plasma proteins and their transport through the barrier which is quite different. KYN and 3HK are carried through the large neutral amino acid carrier system L. Kynurenines seem to penetrate the human brain by passive diffusion. Additionally, KYNA, 3HANA, and especially ANA bind to serum proteins which then ultimately restrict and limit their diffusibility across the blood-brain barrier. �
Research studies demonstrated that QUIN, when ionophoretically utilized in rat cells, caused neuronal firing which has been prevented by an NMDA receptor antagonist, suggesting that QUIN may function as an NMDA receptor agonist. However, the EC50 for QUIN to trigger NMDA receptor currents has been shown to be roughly 1000-fold higher than the EC50 of L-glutamate. Intracerebral injection of QUIN was proven to cause ultrastructural, neurochemical, and behavioral changes similar to those caused by NMDA receptor agonists. The fact that QUIN concentrations are about 5000- to 15,000-fold lower than cerebral L-glutamate concentrations makes it unlikely that modulation of NMDA receptor signaling by QUIN plays an essential role. KYNA was demonstrated to function as an NMDA receptor antagonist. But, although infusion with the KMO inhibitor Ro 61-8048 improved cerebral extracellular KYNA concentrations 10-fold, this didn’t result in an inhibition of NMDA-mediated neuronal depolarization, a finding which challenges the belief that KYNA at near-physiological amounts directly modulates NMDA receptors. In comparison, increased KYNA in the brain induced from the KMO inhibitor JM6 decreased the extracellular cerebral L-glutamate concentration. Additionally, KYNA levels from the extracellular cerebral fluid have been associated with L-glutamate levels suggesting that even at physiological or near physiological levels, KYNA modulates L-glutamate metabolism. Both the activation of the G-protein-coupled receptor GPR35 and the inhibition of presynaptic ?7 nicotinic acetylcholine receptors are suggested in the KYNA-induced reduction in L-glutamate release. To summarize, although QUIN and L-HCA are present in the human brain, their concentrations discuss against them with roles in regulating and maintaining neurotransmission. In contrast, even though the pathways have to be defined in greater detail, evidence supports levels and the opinion that discharge can be modulated by KYNA and neurotransmission. �
Glutamate, together with aspartate and other molecules, are several of the main excitatory neurotransmitters in the human brain. Although these play a fundamental role in the overall structure and function of the central nervous system, including the brain and the spinal cord, excessive amounts of other molecules can ultimately trigger glutamate receptors. Excess glutamate can cause excitotoxicity which may lead to a variety of health issues, such as Alzheimer’s disease and other types of neurological diseases. The following article describes how other molecules can activate glutamate receptors. – Dr. Alex Jimenez D.C., C.C.S.T. Insight – Dr. Alex Jimenez D.C., C.C.S.T. Insight
Research studies suggest that L-aspartate, like L-glutamate, triggers excitatory activity. L-aspartate functions with L-glutamate in the synaptic vesicles of asymmetric excitatory synapses. But, the total concentration of these in the human brain suggest that L-aspartate is significantly less abundant than L-glutamate. Moreover, L-aspartate is a powerful agonist for NMDA receptors but not for other iGluRs with an EC50 just eight-fold higher than that of L-glutamate. The scope of our information is limited to chiropractic, musculoskeletal and nervous health issues as well as functional medicine articles, topics, and discussions. We use functional health protocols to treat injuries or chronic disorders of the musculoskeletal system. To further discuss the subject matter above, please feel free to ask Dr. Alex Jimenez or contact us at 915-850-0900 . �
Curated by Dr. Alex Jimenez �
References �
Lewerenz, Jan, and Pamela Maher. �Chronic Glutamate Toxicity in Neurodegenerative Diseases-What Is the Evidence?� Frontiers in Neuroscience, Frontiers Media S.A., 16 Dec. 2015, www.ncbi.nlm.nih.gov/pmc/articles/PMC4679930/.
Additional Topic Discussion: Chronic Pain
Sudden pain is a natural response of the nervous system which helps to demonstrate possible injury. By way of instance, pain signals travel from an injured region through the nerves and spinal cord to the brain. Pain is generally less severe as the injury heals, however, chronic pain is different than the average type of pain. With chronic pain, the human body will continue sending pain signals to the brain, regardless if the injury has healed. Chronic pain can last for several weeks to even several years. Chronic pain can tremendously affect a patient’s mobility and it can reduce flexibility, strength, and endurance.
Neural Zoomer Plus for Neurological Disease
�
Dr. Alex Jimenez utilizes a series of tests to help evaluate neurological diseases. The Neural ZoomerTM Plus is an array of neurological autoantibodies which offers specific antibody-to-antigen recognition. The Vibrant Neural ZoomerTM Plus is designed to assess an individual�s reactivity to 48 neurological antigens with connections to a variety of neurologically related diseases. The Vibrant Neural ZoomerTM Plus aims to reduce neurological conditions by empowering patients and physicians with a vital resource for early risk detection and an enhanced focus on personalized primary prevention. �
Formulas for Methylation Support
XYMOGEN�s Exclusive Professional Formulas are available through select licensed health care professionals. The internet sale and discounting of XYMOGEN formulas are strictly prohibited
Proudly,�Dr. Alexander Jimenez makes XYMOGEN formulas available only to patients under our care.
Please call our office in order for us to assign a doctor consultation for immediate access.
If you are a patient of Injury Medical & Chiropractic�Clinic, you may inquire about XYMOGEN by calling 915-850-0900.
�
For your convenience and review of the XYMOGEN products please review the following link.*XYMOGEN-Catalog-Download �
* All of the above XYMOGEN policies remain strictly in force.
The term excitotoxicity was first employed to demonstrate the capability of L-glutamate, in addition to structurally-associated amino acids, to destroy nerve cells, a process which has been suggested to occur in acute and chronic health issues of the central nervous system (CNS). Excitotoxicity is caused by the excess stimulation of iGluRs into a characteristic loss of cell bodies and dendrites as well as post-synaptic structures. There is a substantial degree of variation in the sensitivity of nerve cells compared to the variety of iGluRs which is associated with the specific receptors demonstrated on the nerve cells and their metabolisms. The susceptibility of neurons to excitotoxicity can be affected with age. �
Acute excitotoxic nerve cell death is believed to occur in reaction to a number of severe insults, including cerebral ischemia, traumatic brain injury (TBI), hypoglycemia, and status epilepticus. However, what about neurodegenerative diseases, such as Alzheimer’s disease? Does chronic excitotoxicity also occur? Could exposure of nerve cells to low but above-average concentrations of L-glutamate, or even glutamatergic neurotransmission through a variety of molecules be involved as previously mentioned, within an extended time period also significantly result in neural cell death? The purpose of the article below is to demonstrate the concepts of acute and chronic glutamate toxicity on the health and wellness of the brain. �
Acute and Chronic Glutamate Toxicity
Excitotoxicity was initially studied in animals, however, so as to comprehend the mechanisms underlying this procedure, cell culture models were developed. The basic cell culture model of acute excitotoxicity involves the treatment of principal neurons in accordance with L-glutamate or particular iGluRs for a brief time interval (min) and then analyzing downstream events in the time point which is most relevant for the research study. By way of instance, cell death is frequently determined after 24 hours. While these types of research studies are proven to be quite useful for understanding the pathways involved in acute excitotoxicity, it has demonstrated to be far more difficult to evaluate chronic excitotoxicity in culture partially because it is not completely clear how to specify “chronic” in the context of cell culture. Does consistent imply a minimal dose supplied for 24 hours instead of a maximum dose supplied for 5 to 10 minutes or is it more complicated than that? �
Among the few research studies which tried to come up with a model of chronic excitotoxicity, it was revealed that it is indeed more complicated with acute and chronic excitotoxicity appearing to be different processes. In this research study, the researchers utilized pure cultures of primary cortical neurons developed from day 14 mouse embryos and treated them after seven and 14 days in culture (DIV). For constant excitotoxicity, the neurons were exposed to L-glutamate or NMDA for 24 hours and for severe excitotoxicity for 10 minutes. In both circumstances, cell death was measured after 24 hours. Surprisingly, the EC50s in their toxicity of L-glutamate were lower for acute toxicity, particularly in the 7 DIV cultures, when compared with the EC50s for chronic toxicity. Additionally, it was discovered that a high cell culture density increased the cells’ sensitivity into excitotoxicity that was acute but not chronic. Further research studies indicated that the lower sensitivity of these neurons to L-glutamate in the chronic excitotoxicity paradigm was due to the stimulation of mGluR1, associated with earlier data on the neuroprotective effects of mGluR1 stimulation, among other important processes. �
Further Research Studies for Glutamate Toxicity
An alternative approach for understanding chronic glutamate toxicity used organotypic spinal cord cultures in conjunction with L-glutamate uptake inhibitors. These spinal cord cultures, which had been prepared from 8-day-old rat pups, were kept in culture for up to 3 months. Persistent inhibition of L-glutamate uptake utilizing two varieties of uptake inhibitors caused a consistent increase of L-glutamate in the cell culture medium and time period as well as a concentration of dependent motor neuron cell death. The highest concentration of uptake inhibitor increased extracellular L-glutamate levels at least 25-fold and began to kill the cells within 1 week whereas a five-fold lower concentration raised extracellular L-glutamate levels eight-fold and cell death only began after 2 to 3 weeks of treatment. The toxicity was obstructed with non-NMDA but not NMDA receptors as well as by inhibitors of L-glutamate synthesis or release. These research studies ultimately indicate that moderately increased L-glutamate concentrations can also induce toxicity as well as a variety of other health issues. �
In vivo approaches to studying excitotoxicity have relied on an approach analogous to that utilized with the spinal cord cultures. In the wide variety of the research studies, a single or multiple EAATs were transiently or permanently genetically eliminated and the effects on brain function were evaluated. During the first few research studies, which utilized rats, chronic intraventricular administration of antisense RNA was utilized to eliminate every one of the 3 primary EAATs (EAAT1, EAAT2, and EAAT3). The loss of either of the glial L-glutamate transporters (EAAT1 and EAAT2) but not the neuronal transporter (EAAT3) caused large increases in extracellular L-glutamate concentrations in the striatum following 7 days as demonstrated by microdialysis (EAAT2, 32-fold increase; EAAT1, 13-fold increase). Treatment with the EAAT1 or EAAT2 antisense oligonucleotides caused a progressive motor impairment whereas epilepsy was produced by the EAAT3 antisense oligonucleotide. The loss of any of the 3 transporters demonstrated clear evidence of neuronal damage in the striatum and hippocampus after 7 days of treatment although the effects of the EAAT1 and EAAT2 antisense oligonucleotides were far more dramatic, consistent with the substantial increases in extracellular L-glutamate brought about by treatment. �
Particularly different results were demonstrated with homozygous mice deficient in EAAT2 or EAAT1. Mice deficient in EAAT2 demonstrated sudden and normally deadly seizures with 50 percent dead by 6 weeks of age. Approximately 30 percent of these mice demonstrated selective degeneration in the CA1 area at 4 to� 8 weeks of age. L-glutamate amounts in the CA1 region of the hippocampus measured by microdialysis were three-fold greater in the mutant mice as compared with the wild type mice. In contrast, heterozygous EAAT2 knock-out mice have an average lifespan and do not reveal hippocampal CA1 atrophy. However, they exhibit several behavioral abnormalities suggestive of moderate glutaminergic hyperactivity. While mice deficient in EAAT1, that is expressed in cerebellar astrocytes, didn’t reveal changes in cerebellar arrangement or obvious indicators of cerebellar impairment, such as ataxic gait, they had not been able to adapt to difficult motor tasks like rapidly running the rotorod. When taken collectively, these results imply that disruptions in homeostasis which are glutamatergic have a greater impact when they occur in the animal rather than when they are found from conception. �
Other Health Issues in Glutamate Toxicity
Tuberous sclerosis complex (TSC) is a multi-system genetic disease caused by the mutation of both TSC1 or TSC2 genes, where it is characterized by severe neurodegenerative diseases. Mice with inactivation of the TSC1 gene in glia have a less than 75 percent reduction in the expression and function of EAAT1 and EAAT2 as well as to cause seizures. At 4 weeks of age, prior to the development of seizures in these mice, there was a 50 percent increase in extracellular L-glutamate in the hippocampus of the mutant mice, as determined by microdialysis, which correlated with increases in markers of cell death in neurons in both hippocampus and cortex. Utilizing slices from mice that were 2 to 4 week old, impairments in long-term potentiation were determined, which translated into deficits when mice were analyzed for contextual and spatial memory in the Morris water maze and fear conditioning assays. Further research studies are still necessary for outcome measures. �
In the majority of the research studies described above, there was a large increase in extracellular L-glutamate that, when analyzed, caused adverse effects on the role of specific neuronal populations. To ascertain the long-term effects of more moderate increases in extracellular glutamate, further research studies created transgenic (Tg) mice with extra copies of this gene for Glud1, especially in neurons. Mitochondrial 2-oxoglutarate from Glud1 is transported into the cytoplasm of nerve terminals in which it’s converted back into L-glutamate and kept in synaptic vesicles thus leading to the pool of synaptically releasable L-glutamate. Nine-month-old Glud1 Tg mice demonstrated a 10 percent boost in L-glutamate in the hippocampus and striatum relative to wild type mice as determined to utilize magnetic resonance spectroscopy. In addition, 50 percent caused increased L-glutamate release in the striatum. At 12 to 20 months of age, the Glud1 Tg mice revealed significant decreases in the numbers of neurons in the CA1 area of the hippocampus and granule cell layer of the dentate gyrus in addition to an age-dependent loss of the two dendrites and dendritic spines in the hippocampus. There was also a drop in long-term potentiation after high frequency stimulation in hippocampal slices in the mice when compared with the wild type mice. Evaluation of the transcriptome of those Glud1 Tg mice in comparison with wild type mice indicated that long-term moderate increases in cerebral L-glutamate ultimately caused both rapid aging in the level of gene expression combined with compensatory reactions which protected against pressure and/or promoted recovery, among other capabilities. �
Conclusion
Brain function and nerve cell survival can be affected by excitotoxicity. The results appear to be highly dependent on the degree of L-glutamate increase, however, even a 10 percent growth appears to influence nerve cell survival, particularly in the context of aging indicating that chronic excitotoxicity may be associated with neurodegenerative diseases. �
Several toxins which connect to iGluRs and that have also been demonstrated to cause excitotoxicity in cell culture may cause slowly growing neurological health issues in both animals and humans. Surprisingly, each toxin appears to target a particular type of neuron, an effect which may be associated with the pharmacokinetics and ADME properties of the toxins, which have not been analyzed to any great extent. The data from these types of toxins supports the idea that excitotoxicity may play a fundamental role in neurodegenerative diseases as well as in other health issues which exist in humans. �
Because iGluRs are demonstrated both from the synapse and in extra-synaptic locations, there has been a great deal of effort devoted to discovering if the region of the receptors impacts the toxicity of molecules. An influential research study with primary neuronal cultures indicated that synaptic and extrasynaptic NMDA receptors have counteracting effects on cell survival with neural cell death being primarily controlled by extrasynaptic NMDA receptors. Nonetheless, these outcome measures have not been reproduced in brain slices or in vivo. Furthermore, many more recent research studies utilizing the exact same primary neuronal culture preparation protocol as the prior research study found either no difference between synaptic and extrasynaptic NMDA receptors in boosting excitotoxicity or discovered that both receptors were needed for cell death. Finally, a variety of research studies that supported the idea that extrasynaptic NMDA receptors promote excitotoxicity relied on the NMDA receptor inhibitor memantine that was originally believed to specifically act on extrasynaptic NMDA receptors. However, more recent research studies demonstrate that memantine can inhibit both synaptic and extrasynaptic NMDA receptors. These results strongly imply that synaptic and extrasynaptic NMDA receptors may contribute to excitotoxicity but the contribution of each depends on the experimental and/or pathological conditions. �
Glutamate is the primary excitatory neurotransmitter in the brain. Although it plays a fundamental role in the overall structure and function of the central nervous system, excessive amounts of glutamate can ultimately cause excitotoxicity which may lead to a variety of health issues, such as Alzheimer’s disease and other types of neurodegenerative diseases. Acute and chronic excitotoxicity treatment currently focuses on decreasing or restricting glutamate receptors or extracellular glutamate. The article above summarizes the available research studies for glutamate toxicity in neurodegenerative diseases. – Dr. Alex Jimenez D.C., C.C.S.T. Insight
Excitotoxicity demonstrates the capability of L-glutamate, as well as structurally-associated amino acids, processes which have been suggested to occur in acute and chronic excitotoxicity. Excitotoxicity is caused by the excess stimulation of iGluRs in cell bodies and dendrites as well as post-synaptic structures. There is a substantial degree of variation in nerve cells compared to iGluRs associated with the receptors demonstrated on the nerve cells and their metabolisms. The scope of our information is limited to chiropractic, musculoskeletal and nervous health issues as well as functional medicine articles, topics, and discussions. We use functional health protocols to treat injuries or chronic disorders of the musculoskeletal system. To further discuss the subject matter above, please feel free to ask Dr. Alex Jimenez or contact us at 915-850-0900 . �
Curated by Dr. Alex Jimenez �
References �
Lewerenz, Jan, and Pamela Maher. �Chronic Glutamate Toxicity in Neurodegenerative Diseases-What Is the Evidence?� Frontiers in Neuroscience, Frontiers Media S.A., 16 Dec. 2015, www.ncbi.nlm.nih.gov/pmc/articles/PMC4679930/.
Additional Topic Discussion: Chronic Pain
Sudden pain is a natural response of the nervous system which helps to demonstrate possible injury. By way of instance, pain signals travel from an injured region through the nerves and spinal cord to the brain. Pain is generally less severe as the injury heals, however, chronic pain is different than the average type of pain. With chronic pain, the human body will continue sending pain signals to the brain, regardless if the injury has healed. Chronic pain can last for several weeks to even several years. Chronic pain can tremendously affect a patient’s mobility and it can reduce flexibility, strength, and endurance.
Neural Zoomer Plus for Neurological Disease
�
Dr. Alex Jimenez utilizes a series of tests to help evaluate neurological diseases. The Neural ZoomerTM Plus is an array of neurological autoantibodies which offers specific antibody-to-antigen recognition. The Vibrant Neural ZoomerTM Plus is designed to assess an individual�s reactivity to 48 neurological antigens with connections to a variety of neurologically related diseases. The Vibrant Neural ZoomerTM Plus aims to reduce neurological conditions by empowering patients and physicians with a vital resource for early risk detection and an enhanced focus on personalized primary prevention. �
Formulas for Methylation Support
XYMOGEN�s Exclusive Professional Formulas are available through select licensed health care professionals. The internet sale and discounting of XYMOGEN formulas are strictly prohibited.
Proudly,�Dr. Alexander Jimenez makes XYMOGEN formulas available only to patients under our care.
Please call our office in order for us to assign a doctor consultation for immediate access.
If you are a patient of Injury Medical & Chiropractic�Clinic, you may inquire about XYMOGEN by calling 915-850-0900.
�
For your convenience and review of the XYMOGEN products please review the following link.*XYMOGEN-Catalog-Download �
* All of the above XYMOGEN policies remain strictly in force.
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