Protective Effect of Hemin Against Experimental Chronic Fatigue Syndrome in Mice: Possible Role of Neurotransmitters, 2020, Kumar et al

Andy

Andy

Retired committee member
Mouse model = mice they have exhausted through over exercising. Therefore this is of dubious use to us.
Chronic fatigue syndrome (CFS) is a disorder characterized by persistent and relapsing fatigue along with long-lasting and debilitating fatigue, myalgia, cognitive impairment, and many other common symptoms. The present study was conducted to explore the protective effect of hemin on CFS in experimental mice.

Male albino mice were subjected to stress-induced CFS in a forced swimming test apparatus for 21 days. After animals had been subjected to the forced swimming test, hemin (5 and 10 mg/kg; i.p.) and hemin (10 mg/kg) + tin(IV) protoporphyrin (SnPP), a hemeoxygenase-1 (HO-1) enzyme inhibitor, were administered daily for 21 days. Various behavioral tests (immobility period, locomotor activity, grip strength, and anxiety) and estimations of biochemical parameters (lipid peroxidation, nitrite, and GSH), mitochondrial complex dysfunctions (complexes I and II), and neurotransmitters (dopamine, serotonin, and norepinephrine and their metabolites) were subsequently assessed.

Animals exposed to 10 min of forced swimming session for 21 days showed a fatigue-like behavior (as increase in immobility period, decreased grip strength, and anxiety) and biochemical alteration observed by increased oxidative stress, mitochondrial dysfunction, and neurotransmitter level alteration. Treatment with hemin (5 and 10 mg/kg) for 21 days significantly improved the decreased immobility period, increased locomotor activity, and improved anxiety-like behavior, oxidative defense, mitochondrial complex dysfunction, and neurotransmitter level in the brain. Further, these observations were reversed by SnPP, suggesting that the antifatigue effect of hemin is HO-1 dependent. The present study highlights the protective role of hemin against experimental CFS-induced behavioral, biochemical, and neurotransmitter alterations.
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Paywall, https://link.springer.com/article/10.1007/s12640-020-00231-y
Open access PDF paper, https://sci-hub.tw/10.1007/s12640-020-00231-y
 
Indeed, torturing mice with forced swims might cause fatigue, but it certainly isn't CFS or ME.

Side note: Heme oxygenase is HSP32. Heme is broken down into biliverdin (ultimately bilirubin) and Fe2+
Gilbert's syndrome is not uncommon in CFS patients, suggesting this pathway has increased activity in many patients...
 
This is very interesting ( cc : @wigglethemouse ), Thank you @Andy


Upon searching for hemin i found that hemin is a TSPO ligand :


This is consistent with previous evidences obtained with the endogenous TSPO ligand, hemin (iron protoporphyrin IX), which limits mitochondrial Ca2+ accumulation in isolated mitochondria by reducing VDAC conductance.16 Synthetic TSPO ligands can also affect mitochondrial Ca2+ handling.15

TSPO leaves unaltered communication and connectivity between the ER and mitochondria (Figures 3d–g) consistently with previous data on mitofusin 1 and 2 levels that also remain constant.17
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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5520880/



TSPO has been identified by Machine Learning since 2018. To be fair, there was no connection of its function with mitochondrial Calcium metabolism but rather with Cholesterol metabolism. Recall that Prusty also discussed about dysregulated calcium metabolism in one of his slides in his latest presentation.

So, it could be of interest.
 
This is about as valid and ethical as experiments where someone takes participants into a room and tell them that their parents were gruesomely murdered and use that state as a proxy for depression.

Which, in mice, would be quite a feat.

But, no, ME, or even CFS, is not the same as a healthy person (or mouse) exercising excessively. The big tell is right there in the name. Chronic. Chro-nic. Words. Mean. Things.
 
mariovitali said:
This is very interesting ( cc : @wigglethemouse ), Thank you @Andy


Upon searching for hemin i found that hemin is a TSPO ligand :

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5520880/


TSPO has been identified by Machine Learning since 2018. To be fair, there was no connection of its function with mitochondrial Calcium metabolism but rather with Cholesterol metabolism. Recall that Prusty also discussed about dysregulated calcium metabolism in one of his slides in his latest presentation.

So, it could be of interest.
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@mariovitali Hi Mario, Themos pointed me here after a twitter discussion of TSPO (also with @wigglethemouse)

I find TSPO very interesting for its link to both mitochondrial enzymes and neuroinflammation. The connection to hemin is further intriguing for a number of reasons. I'll be brief here since TSPO perhaps deserves it's own separate thread (if there isn't one already on this site. I don't see one).

I wonder if there are any (tenuous) lines to be drawn between hemin & some of the OMF blood studies, i.e. the RBC deformability study and the "something in healthy serum restores ME-cellular function under stress"-study. It seems too much to hope that hemin is this key factor but it's maybe worth consideration. I'd like to do some digging on how hemin arises endogenously in the body.



Regarding the primary topic of this thread - yeah, what an atrocious mouse study. Mice studies tend to be that way, sadly.
 
Basic biology is very conserved in mammals (and all eukaryotes) so research which tells us how normal biological functions work could lead to benefits finding what is wrong in ME, but animal models of disease are not very useful nowadays.

They worked out what hormones are and how they function in animals and then used that knowledge to treat humans with endocrine diseases saving millions of lives but they did not start by trying to feed sugar into mice to give them diabetes.
 
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