An Adrenalectomy Mouse Model Reflecting Clinical Features for Chronic Fatigue Syndrome, 2020, Lee et al

Andy

Andy

Senior Member (Voting rights)
Another dubious mouse model, this time from Korea.
Chronic fatigue syndrome (CFS) is one of the most intractable diseases and is characterized by severe central fatigue that impairs even daily activity. To date, the pathophysiological mechanisms are uncertain and no therapies exist. Therefore, a proper animal model reflecting the clinical features of CFS is urgently required.

We compared two CFS animal models most commonly used, by injection with lipopolysaccharide (LPS from Escherichia coli O111:B4) or polyinosinic: polycytidylic acid (poly I:C), along with bilateral adrenalectomy (ADX) as another possible model. Both LPS- and poly I:C-injected mice dominantly showed depressive behaviors, while ADX led to fatigue-like performances with high pain sensitivity. In brain tissues, LPS injection notably activated microglia and the 5-hydroxytryptamine (HT)1A receptor in the prefrontal cortex and hippocampus. Poly I:C-injection also remarkably activated the 5-HT transporter and 5-HT1A receptor with a reduction in serotonin levels in the brain. ADX particularly activated astrocytes and transforming growth factor beta (TGF-β) 1 in all brain regions.

Our results revealed that LPS and poly I:C animal models approximate depressive disorder more closely than CFS. We suggest that ADX is a possible method for establishing a mouse model of CFS reflecting clinical features, especially in neuroendocrine system.
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Open access, https://www.mdpi.com/2218-273X/10/1/71
 
Cut, cut, cut. NO WAY.

Why would you want to activate astrocytes and transforming growth factor beta (TGF-β) ?????

Ain't astrocytes not already activated in ME patients?
 
lansbergen said:
Cut, cut, cut. NO WAY.

Why would you want to activate astrocytes and transforming growth factor beta (TGF-β) ?????

Ain't astrocytes not already activated in ME patients?
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They are not suggesting removal of adrenal glands as treatment for ME, they are suggesting that removing them in mice leads to similar symptoms as in humans with ME - creating a possible mouse model of ME that can then be used in research about ME.
 
Trish said:
They are not suggesting removal of adrenal glands as treatment for ME, they are suggesting that removing them in mice leads to similar symptoms as in humans with ME - creating a possible mouse model of ME that can then be used in research about ME.
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Yes, but what will that tell????
 
They are saying that removal of adrenal glands appears to create an illness that is closer to ME/CFS than the illness created by injecting mice with compounds that the immune system interprets as bacterial and viral infection.

Of course adrenal insufficiency is not ME/CFS and mice are not humans but I thought this was interesting.
 
My impresssion from a quick read is that they have rejected previous mouse models of ME created by injecting various things that set up an inflammatory reaction, or that stress the mice. They say these mimic depression, fibromyalgia and chronic fatigue, but not CFS.

Their model is be based on research that showed low cortisol in ME, so they induced that in the mice by adrenalectomy. They say this led to various test results that matched those in ME better than the previous models had, and that this mouse model could therefore potentially be used for things like drug testing for possible ME treatments.

From the discussion section:
As expected, ADX completely depleted the serum corticosterone level, but it was considerably elevated in both the LPS and poly I:C models (Figure 2C). Hypocortisolism is an endocrinological hallmark of CFS, which is diametrically opposed to fibromyalgia and depressive disorder [53]. In patients with CFS, the low cortisol awakening response is believed to affect chronic pain [54] and cause impairment in sleep-wake cycles [55] and PEM symptoms [56].
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These are the references they base this on:

53. Morris, G.; Anderson, G.; Maes, M. Hypothalamic-pituitary-adrenal hypofunction in Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS) as a consequence of activated immuneinflammatory and oxidative and nitrosative pathways. Mol. Neurobiol. 2017, 54, 6806–6819, doi:10.1007/s12035-016-0170-2.

54. Fries, E.; Hesse, J.; Hellhammer, J.; Hellhammer, D.H. A new view on hypocortisolism. Psychoneuroendocrinology 2005, 30, 1010–1016, doi:10.1016/j.psyneuen.2005.04.006.

55. Torres-Harding, S.; Sorenson, M.; Jason, L.; Maher, K.; Fletcher, M.A.; Reynolds, N.; Brown, M. The associations between basal salivary cortisol and illness symptomatology in chronic fatigue syndrome. J. Appl. Biobehav. Res. 2008, 13, 157–180.

56. Hall, D.L.; Lattie, E.G.; Antoni, M.H.; Fletcher, M.A.; Czaja, S.; Perdomo, D.; Klimas, N.G. Stress management skills, cortisol awakening response, and post-exertional malaise in Chronic Fatigue Syndrome. Psychoneuroendocrinology 2014, 49, 26–31, doi:10.1016/j.psyneuen.2014.06.021.
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strategist said:
They are saying that removal of adrenal glands appears to create an illness that is closer to ME/CFS than the illness created by injecting mice with compounds that the immune system interprets as bacterial and viral infection.
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Yes, but I do not see what it can tell.

Why create an Addison-patiënt? Addison is very difficult to control.
 
An idea that came to me in the days when I gave up animal model work was:

If there are 100 models of illness X, each based on a different causal mechanism, then 99 of them must be the wrong mechanism. That makes it statistically highly likely that 100 of them are the wrong mechanism.
 
I think its a bit premature to do these kind of animal studies. We don't know if hypocortisolism really has something to do with the pathology of ME/CFS or if its just a consequence of it and findings for TGF beta are rather conflicting. So I don't think these could be seen as indicators wether an animal model resembles ME/CFS or not.

It thought it was interesting that they thought the immune model (injecting mice with compounds that the immune system interprets as bacterial and viral infection) looked more like depression than CFS, cause this theory is quite popular among CFS researchers. Then again I'm not sure if the tests they made the mouse do would be able to show a clear difference between depression or CFS. If mise can have CFS, i think they would look pretty depressed.
 
Jonathan Edwards said:
An idea that came to me in the days when I gave up animal model work was:

If there are 100 models of illness X, each based on a different causal mechanism, then 99 of them must be the wrong mechanism. That makes it statistically highly likely that 100 of them are the wrong mechanism.
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Isn't that going to be true of any models for illness X, animal models or otherwise? Presumably research is primarily about trying to find the right illness model, even if it turns out to be the 999th, whatever? (I suspect I may be missing your point here).
 
strategist said:
They are saying that removal of adrenal glands appears to create an illness that is closer to ME/CFS than the illness created by injecting mice with compounds that the immune system interprets as bacterial and viral infection.

Of course adrenal insufficiency is not ME/CFS and mice are not humans but I thought this was interesting.
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Feeds into the cortisol resistance narrative ? @alex3619
 
Several years ago I felt so horrible and I begged my dr to ‘do something’. She is a bunch of blood tests, one of which was the AM and PM cortisol. It came back flagged at a critical low. Something like 45 when the normal range would be 180-800. I was sent to the endocrinologist, which was delayed because of the holiday season, but in the meantime was started on Cortef, which did not seem to do anything for me. Usually people feel a little jolt (a burst of energy) when given cortico-steroids. Not me. A month later, i had my consultation. My AM Cortisol still flagged as critical low, though a bit higher this time in the 80’s, i still did not feel better. I had the Corticotropin stimulation test (not sure if it’s the right name for it) which showed i did not have Addison. I was (very painfully) weaned off the Cortef and that was that.

i would welcome animal study of the Korean kind, because I believe the HPA axis hormones are involved, but with the caution that it may represent a subset of the patients and that it may explain one event in time, without explaining all of the symptomatology.
 
Barry said:
Isn't that going to be true of any models for illness X, animal models or otherwise? Presumably research is primarily about trying to find the right illness model, even if it turns out to be the 999th, whatever? (I suspect I may be missing your point here).
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If there was only one, or maybe three models based on different causal mechanisms then the chance that one of them was the right mechanism could be fair. The only model for tuberculosis was injecting animals with Mycobacterium tuberculosis - and that turned out to be the right model.

But if there are 100 models each based on a different explanation then it looks very much as if people are struggling.

As an example, animal models of rheumatoid arthritis included immunising mice with cartilage collagen, immunising rabbits to milk by diet, injecting mycobacterial cell wall into rats, introducing trangenes encoding for absence of lymphocyte death in mice, intruding transcends for unregulated secretion of TNF, injecting mice with pristine oil, injecting ovalbumin into rat knees, and so on... None had any relevance at all to the aetiology of the illness (except that TNF turns out to be involved for other reasons).
 
I suspect that feeling horrible when waking up might could have something to do with cortisol awakening response not working well. By the time blood is typically drawn, the cortisol levels would however already be fairly normal.

I did a diurnal salivary cortisol curve once and the first sample in the morning was well below the norm.
 
Milo said:
i would welcome animal study of the Korean kind, because I believe the HPA axis hormones are involved, but with the caution that it may represent a subset of the patients and that it may explain one event in time, without explaining all of the symptomatology.
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They remove the whole glands. Look at all the things you have to compensate for.
 
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