Excitotoxicity is an acute insult that causes nerve cell death due to the excessive activation of iGluRs. Acute excitotoxicity plays a fundamental role in various 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 shutdown of blood flow can ultimately break down the neuronal and astroglial membranes. In neurons, membrane depolarization contributes to vesicular discharge. Energy degradation may also cause a change in their action, 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 blood-brain barrier disruption 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. Moreover, acute application of the NMDA antagonist MK801 following TBI ameliorates neuronal loss and long-term behavioral abnormalities.
In status epilepticus, continuing the synchronized activity of excitatory neuronal networks and 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 in 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.
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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 that cause EAAT2, or the main EAAT in the brain and most commonly shown to be downregulated. This has demonstrated substances that show astrocytic EAAT2 expression in 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 their capability to interact with other neuroprotective pathways. Cef has also been demonstrated to promote EAAT2 expression and 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 that 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 and 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 from principal research studies that 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 APPswe/PS1E9. 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 that had only one EAAT2 allele. Further research studies are still necessary for further evidence.
To complement these research studies, transgenic mice that over-express EAAT2 in astrocytes through the GFAP promoter have 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 xc, 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 modulated by system xc deficiencies leading to a more neuroprotective phenotype, which explains 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 are 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
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Excitotoxicity is characterized as an acute insult that causes cell death due to the excess activation of iGluRs. Excitotoxicity plays a fundamental role in various central nervous system (CNS) health issues, including cerebral ischemia, TBI, and status epilepticus. The mechanisms for acute excitotoxicity are different for every health issue.
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 differs from average 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 reduce flexibility, strength, and endurance.
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