Myelin Switch

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hargarah
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Myelin Switch

Post by hargarah » Mon Jan 13, 2020 6:46 am


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NHE
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Re: Myelin Switch

Post by NHE » Tue Jan 14, 2020 5:33 am

Blocking the Thrombin Receptor Promotes Repair of Demyelinated Lesions
in the Adult Brain.
J Neurosci. 2020 Jan 7. pii: 2029-19.
  • Myelin loss limits neurological recovery and myelin regeneration and is critical for restoration of function. We recently discovered that global knockout of the thrombin receptor, also known as Protease Activated Receptor 1 (PAR1), accelerates myelin development. Here we demonstrate that knocking out PAR1 also promotes myelin regeneration. Outcomes in two unique models of myelin injury and repair, that is lysolecithin or cuprizone-mediated demyelination, showed that PAR1 knockout in male mice improves replenishment of myelinating cells and remyelinated nerve fibers and slows early axon damage. Improvements in myelin regeneration in PAR1 knockout mice occurred in tandem with a skewing of reactive astrocyte signatures towards a pro-repair phenotype. In cell culture, the pro-myelinating effects of PAR1 loss-of-function are consistent with possible direct effects on the myelinating potential of oligodendrocyte progenitor cells (OPCs), in addition to OPC-indirect effects involving enhanced astrocyte expression of pro-myelinating factors, such as BDNF. These findings highlight previously unrecognized roles of PAR1 in myelin regeneration, including integrated actions across the oligodendrocyte and astroglial compartments that are at least partially mechanistically linked to the powerful BDNF-TrkB neurotrophic signaling system. Altogether findings suggest PAR1 may be a therapeutically tractable target for demyelinating disorders of the CNS.

    SIGNIFICANCE STATEMENT: Replacement of oligodendroglia and myelin regeneration holds tremendous potential to improve function across neurological conditions. Here we demonstrate Protease Activated Receptor 1 (PAR1) is an important regulator of the capacity for myelin regeneration across two experimental murine models of myelin injury. PAR1 is a G-protein coupled receptor densely expressed in the CNS, however there is limited information regarding its physiological roles in health and disease. Using a combination of PAR1 knockout mice, oligodendrocyte monocultures and oligodendrocyte-astrocyte co-cultures, we demonstrate blocking PAR1 improves myelin production by a mechanism related to effects across glial compartments and linked in part to regulatory actions towards growth factors such as BDNF. These findings set the stage for development of new clinically relevant myelin regeneration strategies.

HarbourBoy
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Re: Myelin Switch

Post by HarbourBoy » Tue Jan 14, 2020 6:01 am

Hopefully they are on to something that actually repairs our disease damage

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NHE
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Re: Myelin Switch

Post by NHE » Tue Jan 14, 2020 9:14 am

MedicalExpress wrote:Significantly, the researchers found that a current Food and Drug Administration-approved drug that inhibits the PAR1 receptor also showed ability to improve myelin production in cells tested in the laboratory.

"It is important to say that we have not and are not advocating that patients take this inhibitor at this time," says Dr. Scarisbrick. "We have not used the drug in animals yet, and it is not ready to put in patients for the purpose of myelin repair. Using cell culture systems, we are showing that this has the potential to improve myelin regeneration."
Really? If there's already an FDA approved drug that's now found to promote myelin repair, then I would probably take it as long as the side effects are moderate. I took Avonex for 10 years. That was a bust (with awful side effects to boot). Why not?

If it's already FDA approved, then why do preclinical animal studies? Why not jump straight to Phase I?

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Re: Myelin Switch

Post by NHE » Tue Jan 14, 2020 10:22 am

Well, that was easy to find. It seems that the only FDA approved PAR1 antagonist is Vorapaxar. It's used as an antiplatelet drug commonly co-prescribed with aspirin. The side effects might be a problem. One of the phase III trials for Vorapaxar was terminated early due to a significant increase of intracranial hemorrhage. Maybe that was due to the combination with aspirin?

https://www.drugs.com/mtm/vorapaxar.html

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3860775/

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