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Molecular Mechanisms of Neuroinflammation in ME/CFS and Long COVID to Sustain Disease and Promote Relapses (Tate et al, 2022)

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600
Abstract

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disease now well-documented as having arisen commonly from a viral infection, but also from other external stressors, like exposure to agricultural chemicals, other types of infection, surgery, or other severe stress events. Research has shown these events produce a systemic molecular inflammatory response and chronic immune activation and dysregulation. What has been more difficult to establish is the hierarchy of the physiological responses that give rise to the myriad of symptoms that ME/CFS patients experience, and why they do not resolve and are generally life-long. The severity of the symptoms frequently fluctuates through relapse recovery periods, with brain-centered symptoms of neuroinflammation, loss of homeostatic control, “brain fog” affecting cognitive ability, lack of refreshing sleep, and poor response to even small stresses. How these brain effects develop with ME/CFS from the initiating external effector, whether virus or other cause, is poorly understood and that is what our paper aims to address. We propose the hypothesis that following the initial stressor event, the subsequent systemic pathology moves to the brain via neurovascular pathways or through a dysfunctional blood-brain barrier (BBB), resulting in chronic neuroinflammation and leading to a sustained illness with chronic relapse recovery cycles. Signaling through recognized pathways from the brain back to body physiology is likely part of the process by which the illness cycle in the peripheral system is sustained and why healing does not occur. By contrast, Long COVID (Post-COVID-19 condition) is a very recent ME/CFS-like illness arising from the single pandemic virus, SARS-CoV-2. We believe the ME/CFS-like ongoing effects of Long COVID are arising by very similar mechanisms involving neuroinflammation, but likely with some unique signaling, resulting from the pathology of the initial SARS-CoV-2 infection. The fact that there are very similar symptoms in both ongoing diseases, despite the diversity in the nature of the initial stressors, supports the concept of a similar dysfunctional CNS component common to both.

The study: https://www.frontiersin.org/articles/10.3389/fneur.2022.877772/full
 

Wishful

Senior Member
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5,808
Location
Alberta
I skimmed the paper, and there's not much in the way of hard evidence to support it. While I agree with the basic hypothesis, the support seems to be cherry-picked results from other studies. If you look long enough, you can find results--possibly from questionable studies--that will support all sorts of hypotheses. They do propose some further research to look for evidence, so that's a good thing. I expect that ME won't show a definite 'smoking gun' in the form of drastically abnormal levels of anything; it will more likely be a combination of minor abnormalities in specific locales, that all conspire to hold us in this abnormal state.
 
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600
I tend to like this type of theory quite a bit. Basically neuroinflammation in a vicious cycle.

My problem with mitochondrial ideas is that for me walking an hour in the woods wouldnt necessarily cost me too much energy but a 40 minute drive in my car could lead to PEM. I dont see how driving the car would cost more ATP than walking in the woods for a even longer duration. Im sure the mitochondria is affected in mecfs but i suspect its more like a downstream effect. Also ppl that have mitochondrial disease doesnt necessarily look too similar to mecfs even if some elements are similar, from what im reading.

Also there are all the metabolic alterations reported by e.g Hanson et al but many of these things seem a bit like a mess in my view. Im not hearing anyone talking about any clear patterns basically.

So im basically thinking that prolonged neuroinflammation is causing brain dysfunction and with it comes a whole slew of metabolic alterations as a result.

Also i think that neuroinflammation has the potential to explain the sound/light/screen sensitivities that many ppl experience and the brain fog, not convinced that too many other theories can explain these things.

And then there is the intraday energy fluctuation that many ppl experience. I can be totally drained early in the day and later in the day go for a one hour walk or more in the woods. Sounds more consistent with fluctuating neuroinflammation than mitochondrial dysfunction or autoimmunity.

But ye, thats what im thinking atm...
 

Rufous McKinney

Senior Member
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13,460
The fact that there are very similar symptoms in both ongoing diseases, despite the diversity in the nature of the initial stressors, supports the concept of a similar dysfunctional CNS component common to both.

I don't think we have yet have ruled out that some aspects of long covid are related to reactivation of Eppstein Barr or perhaps some other virus one already was carrying.

A friend's doctor current intends to treat her long COVID with antivirals to go after EB.
 

SWAlexander

Senior Member
Messages
1,960
Prof Tate delivers a comprehensive paper that explains how a virus and/or bacteria cause (neuro)inflammation and how the hypothalamus connects the nervous system to the endocrine system.
The question how we can stop inflammation remains open.
 

Violeta

Senior Member
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3,009

Violeta

Senior Member
Messages
3,009
To continue, from @Manuel, "Quinolinic acid (QUIN) stimulates glutamate (GLU) release by activating the NMDA glutamate receptor in the presynaptic neuron. On the other hand, in astrocytes it decreases the expression of glutamate transporters and increases their release, thus increasing extracellular glutamate levels. Thus, quinolinic acid can increase glutamate levels in the brain and decrease brain cells' ability to eliminate excess glutamate. Moreover, quinolinic acid has neurotoxic properties by binding to the neurons' NMDA receptor, followed by sustained calcium (Ca2+) influx leading to increased oxidative and nitrosative stress. This increase in nitrosative and oxidative stress leads to the activation of PARP-1 polymerase to prevent DNA damage. But continuous overactivation of PARP-1 leads to depletion of intracellular reserves of nicotinamide adenine dinucleotide (NAD) and ATP, with the consequent alteration in energy production and mitochondrial function. The binding of glutamate to extrasynaptic NMDA receptors can lead to a reduction in the levels of neurotrophic factors such as brain-derived neurotrophic factor (BDNF), leading to a decrease in synaptic plasticity and increased vulnerability to excitotoxicity..."

Epstein–Barr virus-acquired immunodeficiency in myalgic encephalomyelitis—Is it present in long COVID?


https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-023-04515-7
 

Wishful

Senior Member
Messages
5,808
Location
Alberta
Niacin used to make my ME symptoms much worse. My theory was that there's a mechanism for converting QUIN to niacin, and the exogenous niacin reduced the amount of QUIN being converted, leading to the nasty neurological effects of excess QUIN.
 

Violeta

Senior Member
Messages
3,009

Violeta

Senior Member
Messages
3,009
Glutamate decarboxylase or glutamic acid decarboxylase is an enzyme that catalyzes the decarboxylation of glutamate to gamma-aminobutyric acid (GABA) and carbon dioxide. GAD uses pyridoxal-phosphate as a cofactor.

Pyridoxine (vitamin B6) is a cofactor for both glutamic acid decarboxylase and GABA transaminase, the enzymes required for the synthesis and metabolism of GABA in the brain.

At physiological concentrations, zinc stimulates the activity of pyridoxal kinase, enhancing the formation of pyridoxal phosphate, which in turn enhances the activity of glutamic acid decarboxylase.
 
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