Why immunoexcitoxicity is the basis of most neurodegenerative diseases and systemic immune activation: An analysis
- Theoretical Neuroscience Research, LLC, Ridgeland, Mississippi, United States.
Russell L. Blaylock, Retired Neurosurgeon, Theoretical Neuroscience Research, LLC, Ridgeland, Mississippi, United States.
DOI:10.25259/SNI_626_2023Copyright: © 2023 Surgical Neurology International This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-Share Alike 4.0 License, which allows others to remix, transform, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.
How to cite this article: Blaylock RL. Why immunoexcitoxicity is the basis of most neurodegenerative diseases and systemic immune activation: An analysis. Surg Neurol Int 04-Aug-2023;14:281
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Immunoexcitotoxicity simply means a connection between immune activation in the body and enhancement of excitotoxicity in tissues containing glutamate receptors. This series of reactions occurs principally by the number of systems at play. It has been demonstrated, for example, that the glutamate transporters are inhibited by reactive oxygen species (ROS) as well as activation of cell systems that make up the various glutamate (excitotoxic) receptors, basically their subunits.[
In the first instance, ROS are known to inactivate the main glutamate transporters, GLT1, and GLAST.[
In most cases, the most destructive excitotoxic reaction occurs by opening a cell membrane calcium pore.[
In the immunoexcitotoxic reaction, ROS are massively generated and consequently the transporters are inactivated [
Demonstration of various mechanisms used by the immune system to enhance excitotoxicity. EAATs: Excitatory Amino Acid Transporters, TNFα:Tumor Necrosis Factor alpha, TNFR1:Tumor necrosis factor receptor 1, AMPA:α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid, (GABAA):γ-Aminobutyric acid type A (GABAA).
Inflammatory cytokines generate several free radicals (especially interleukin-1 beta [IL-1ß] and tumor necrosis factor-alpha [TNF-alpha]). A second reaction that has been recently recognized is the ability of some inflammatory cytokines (IL-1ß and TNF-alpha) to enhance particular excitotoxic subunits, for example, the NR1 subunit of the N-methyl-D-aspartate (NMDA) receptor [
Illustration demonstrating the various glutamate receptors and the effect of activating TNFR1 and well as calcium channels in this process. NMDA: N-methyl-D-aspartate, PKA: cAMP-dependent protein kinase A, PKC: Protein kinase C, cAMP: Cyclic adenosine monophosphate, MAPK:Mitogen-activated protein kinase, CREB: cAMP-response element binding protein, CaMkII: Ca2+/calmodulin-dependent protein kinase-II.
Like NMDA receptors, they are calcium permeable and are responsible for greatly enhanced excitotoxicity. The AMPA receptor normally makes up the fast transmission system. With inflammation, anywhere in the body, they become more destructive within the CNS. Unlike NMDA receptors, they are not controlled by magnesium.[
The metabotropic receptors control the sensitivity of the main glutamate receptors, (NMDAR, AMPAR, and kainate receptors). By enhancing the sensitivity of metabotropic receptor 1 (an activator), the inflammatory cytokines can enhance the sensitivity of the main receptors, especially NMDA receptors [
There are other systems at play in excitotoxicity, such as the Xc system, which exchanges external cystine for internal glutamate.[
Recent research indicates that there are hemichannels that move glutamate out of the cell in massive amounts and that inflammatory cytokines can activate these hemichannels worsening excitotoxicity.[
In addition, TNF-alpha suppresses glutamine synthetase, an enzyme which protects the neuron by converting glutamate to glutamine [
In essence, we see a very intimate connection between glutamate receptors and the immune system mediators. It has been shown that this enhancement is present even with minor surgical operations systemically. The length of this enhancement varies from a few days to decades (in the case of head trauma and autism).[
The views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Journal or its management. The information contained in this article should not be considered to be medical advice; patients should consult their own physicians for advice as to their specific medical needs.
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