T-Cell Modulation - Mdivi-1 and FGIN-1-27

mitoMAN

Senior Member
Messages
607
Likes
1,162
Location
Germany/Austria
Two very promising treatment approaches that modulate T helper cells and have been proposed to be effective in animal models of autoimmune encephalomyelitis.

Mdivi-1 also greatly works on mitochondria and DRP1 Proteins which might be toxic at too high dosages as an inhibitor.

FGIN-1-27 seems to lack this inhibitory property. Our Chemist proposed this treatment when trying to synthesize another TSPO lingand Empanuil.


Mdivi-1, a mitochondrial fission inhibitor, modulates T helper cells and suppresses the development of experimental autoimmune encephalomyelitis. https://jdc.jefferson.edu/cgi/viewcontent.cgi?article=1201&context=neurologyfp
Background: Unrestrained activation of Th1 and Th17 cells is associated with the pathogenesis of multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). While inactivation of dynamin-related protein 1 (Drp1), a GTPase that regulates mitochondrial fission, can reduce EAE severity by protecting myelin from demyelination, its effect on immune responses in EAE has not yet been studied.

Results: Mdivi-1 effectively suppressed EAE severity by reducing demyelination and cellular infiltration in the CNS. Mdivi-1 treatment decreased the phosphorylation of Drp1 (ser616) on CD4+ T cells, reduced the numbers of Th1 and Th17 cells, and increased Foxp3+ regulatory T cells in the CNS. Moreover, Mdivi-1 treatment effectively inhibited IFN-γ +, IL-17+, and GM-CSF+ CD4+ T cells, while it induced CD4+ Foxp3+ regulatory T cells in splenocytes by flow cytometry.
Conclusions: Together, our results demonstrate that Mdivi-1 has therapeutic potential in EAE by modulating the balance between Th1/Th17 and regulatory T cells.



A similar effect seems to be archieved by fgin-1-27



FGIN-1-27 ameliorates Autoimmunity by TH17 modulation
Another very interesting compound John can synthesize https://pubmed.ncbi.nlm.nih.gov/32111885/
He said it is a TSPO ligand similar to Emapunil but much easier to synthesize.

Abstract Th17 cells are critical drivers of autoimmune diseases and immunopathology. There is an unmet need to develop therapies targeting pathogenic Th17 cells for the treatment of autoimmune disorders. Here, we report that anxiolytic FGIN-1-27 inhibits differentiation and pathogenicity of Th17 cells in vitro and in vivo using the experimental autoimmune encephalomyelitis (EAE) model of Th17 cell-driven pathology. Remarkably, we found that the effects of FGIN-1-27 were independent of translocator protein (TSPO), the reported target for this small molecule, and instead were driven by a metabolic switch in Th17 cells that led to the induction of the amino acid starvation response and altered cellular fatty acid composition. Our findings suggest that the small molecule FGIN-1-27 can be re-purposed to relieve autoimmunity by metabolic reprogramming of pathogenic Th17 cells.
 

Hoosierfans

Senior Member
Messages
264
Likes
667
@mitoMAN do you know if either Ron Davis or Prusty is looking at Mdivi-1? It hasn't been tested in humans yet, has it?

There were some folks on my peptides FB group asking about Mdivi-1 but no one was answering. :zippit:
 

mitoMAN

Senior Member
Messages
607
Likes
1,162
Location
Germany/Austria
Mdivi-1 is investigated by Dr Prusty and he said its one of the most promising treatments BUT has been shown to be toxic in wrong dosages! So its nothing one should mindlessly play with!

In December 2020 Dr. Prusty also noted in an Email, that he still believes SS-31 is very helpful for a subset of patients. The subset being those strongly affected by mitochondrial dsysfunction (he didnt state the exact subset)