Novel therapy corrects mito dysfunction AND neuroinflammation

[natasa778]

purinergic antagonist Suramin used to address mitochondrial dysfunction-neuroinflammation,


ATP signaling modulates immune responses and chronic inflammation, as well as anti-viral signaling, microglial activation, gut motility and permeability, and sensitivity to food allergens. Suramin inhibits purinergic signaling and has been used for treating African Sleeping Sickness (Trypanosomiasis) since the early 1900s. Treating the offspring of maternal immune activated mice weekly with suramin normalizes their social behavior, motor coordination, body temperature, mitochondrial respiratory function and other metabolic measures. Most impressively, this treatment also corrects a neuropathology ...

since mitochondria are located at the hub of the wheel of metabolism and play a central role in non-infectious cellular stress, innate immunity, inflammasome activation, and the stereotyped antiviral response [17], we searched for a signaling system that was both traceable to mitochondria and critical for innate immunity. Purinergic signaling via extracellular nucleotides like ATP and ADP satisfied these requirements.

... Excess extracellular ATP (eATP) is an activator of innate and adaptive immunity, is a danger signal and damage-associated molecular pattern (DAMP) that is chemotactic for neutrophils, and a potent regulator of microglial activation, death, and survival

... Antipurinergic therapy appears to provide a novel means for upregulating the expression of this receptor pharmacologically in disorders associated with innate immune dysregulation and inflammation.

I feel MITOKINES and purinergic signalling is a huge unexplored area in ME, spanning across mito, neuroinflammatory, gut and infection/immune areas and so has a big treatment potential ...

Full paper

 

[natasa778]

this is also very interesting

Suramin is a drug used in the therapy of Rhodesian trypanosomiasis and onchocerciasis, and it is known to inhibit the reverse transcriptase of a number of retroviruses. Suramin has now been found to block in vitro the infectivity and cytopathic effect of HTLV-III at doses that are clinically attainable in human beings.


with good, albeit temporary inhibitiory effects in humans!

Suramin was given to ten outpatients with acquired immunodeficiency syndrome (AIDS) presenting as Kaposi's sarcoma (KS) or as an AIDS-related complex (ARC). ... The detectable virus level fell in each case by the time of the last dose, and in three cases it became undetectable at the end of therapy. In each case, viral replication was again detected in the weeks or months following the administration of suramin.

 

[Ema]

this is also very interesting

Suramin is a drug used in the therapy of Rhodesian trypanosomiasis and onchocerciasis, and it is known to inhibit the reverse transcriptase of a number of retroviruses. Suramin has now been found to block in vitro the infectivity and cytopathic effect of HTLV-III at doses that are clinically attainable in human beings.


with good, albeit temporary inhibitiory effects in humans!

Suramin sounds like a disaster with more than 50% getting damage to the adrenal cortex...but hopefully this pathway can continue to be explored further and possibly safer drugs developed.

I also think the purinergic pathway is likely of crucial importance.

 

[wastwater]

Looks interesting, I saw suramin trialled for autism

 

[anciendaze]

Just want to warn people that the HTLV-III mentioned in the paper on Suramin is now called HIV-I. There was a nasty dispute about terminology that went along with the fight for the Nobel Prize.

Like Ema, I am also concerned about anything causing damage to the adrenal cortex when there is evidence of damage to the HPA axis, plus immunological abnormalities, in the disease. This treatment is not ready for prime time, and should never be done carelessly.

The MIA model is about Maternal Immune Activation. A recent publication which concluded autism is 90% genetic downplayed the fact that homozygous twins not only share the same genes for innate immune response, but also the same maternal environment. They also receive their initial acquired immunity from the same mother via nursing. This takes place at a time when their systems are immunologically naive, making them especially vulnerable to infections the mother's immune system can control, but a naive immune system cannot. They may also pick up inappropriate immune activation via this route.

The business of "too much" vs. "too little" of particular chemicals is also confusing here. The problem they were dealing with came from extra-cellular purines used in signalling, not purines being used up within cells. Exactly what was going on inside cells is less clear. In many other cases of purinergic signalling these mitokines serve to confirm other cell signals present in the blood stream as being local to a particular microenvironment around cells emitting these signals. Not only are nearby cells indicating something unusual is going on, they are also showing that they are taking action involving expenditure of cellular energy.

This takes place at many immunological boundaries, not just in the brain. I believe this is behind reports of reversal of symptoms of autism associated with change of diet. The inflammation in those cases originates largely in the gut rather than the brain.

This is a promising lead on better understanding of autism, not "the answer".

 

[natasa778]

Like Ema, I am also concerned about anything causing damage to the adrenal cortex when there is evidence of damage to the HPA axis, plus immunological abnormalities, in the disease. This treatment is not ready for prime time, and should never be done carelessly.

Small scale, or better to say short duration human trial is hopefully starting very soon. The idea is to give one or two doses only, to see if there is any positive effect at all. If yes, the big picture plan is to get big pharma/big money interested into developing similar purinergic agents minus dangerous side effects. Lots of Ifs and Buts (including the question of whether this trial will be well designed and sensitive enough) and the whole thing could take many, many years, but has great potential ...