Myelin Switch
Re: Myelin Switch
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.
-
- Newbie
- Posts: 8
- Joined: Sun Mar 03, 2019 4:35 pm
Re: Myelin Switch
Re: Myelin Switch
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?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."
If it's already FDA approved, then why do preclinical animal studies? Why not jump straight to Phase I?
Re: Myelin Switch
https://www.drugs.com/mtm/vorapaxar.html
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3860775/
-
- Similar Topics
- Replies
- Views
- Last post
-
- 13 Replies
- 1591 Views
-
Last post by Petr75
Tue Jan 19, 2021 7:06 am
-
- 0 Replies
- 774 Views
-
Last post by Petr75
Tue Oct 22, 2019 10:33 am
-
-
new biomarker for citrullination (myelin degeneration)
by frodo » Wed Apr 29, 2020 2:18 am » in MS Etiology and Pathogenesis - 0 Replies
- 161 Views
-
Last post by frodo
Wed Apr 29, 2020 2:18 am
-
-
-
Myelin disruption precedes autoimmunity in NAWM
by NHE » Wed Feb 10, 2021 2:52 pm » in MS Etiology and Pathogenesis - 1 Replies
- 200 Views
-
Last post by frodo
Sat Feb 20, 2021 3:41 am
-
-
-
Sugar Molecule May Be Potential Myelin-repairing Therapy
by tzootsi » Tue Dec 22, 2020 7:39 am » in General Discussion - 2 Replies
- 226 Views
-
Last post by Scott1
Tue Dec 22, 2020 4:05 pm
-
-
-
New Compound Promotes Healing of Myelin in Nervous System Disorders
by seeva » Mon Sep 09, 2019 1:21 am » in Drug Pipeline - 7 Replies
- 1740 Views
-
Last post by NHE
Tue Jan 12, 2021 12:15 pm
-
-
-
Re: Higher Vitamin D Levels May Promote Myelin Integrity in PMS Study Suggests
by seeva » Sat Aug 31, 2019 1:42 am » in Natural Approach - 0 Replies
- 6195 Views
-
Last post by seeva
Sat Aug 31, 2019 1:42 am
-
-
-
New compound promotes healing of myelin in nervous system disorders by Oregon Health & Science University
by catmandu » Fri Sep 06, 2019 6:14 pm » in General Discussion - 0 Replies
- 552 Views
-
Last post by catmandu
Fri Sep 06, 2019 6:14 pm
-