PAR1 Inhibition Activates Remyelination

Myelin is the sheathing of nerves, essential to their function. Excessive loss produces disabling and ultimately fatal conditions such as multiple sclerosis, but we all lose myelin integrity to some degree as a consequence of the damage and dysfunction of degenerative aging. This most likely contributes to cognitive decline and other age-related issues. A number of different approaches have been identified to boost the operation of the normal maintainance processes that remyelinate nerves, such as FGF21 upregulation, or increasing the size of remyelinating cell populations. Here, researchers discover another possible trigger that might force greater remyelination. While the work aims at treatment of conditions such as multiple sclerosis, successful remyelination therapies should in principle be useful for anyone in the later stages of aging.

Researchers have found that by genetically switching off a receptor activated by blood proteins, named Protease Activated Receptor 1 (PAR1), the body switches on regeneration of myelin, a fatty substance that coats and protects nerves. "Myelin regeneration holds tremendous potential to improve function. We showed when we block the PAR1 receptor, neurological healing is much better and happens more quickly. In many cases, the nervous system does have a good capacity for innate repair. This sets the stage for development of new clinically relevant myelin regeneration strategies."

Myelin acts like a wire insulator that protects electrical signals sent through the nervous system. Demyelination, or injury to the myelin, slows electrical signals between brain cells, resulting in loss of sensory and motor function. Sometimes the damage is permanent. Demyelination is found in disorders such as MS, Alzheimer's disease, Huntington's disease, schizophrenia, and spinal cord injury. Thrombin is a protein in blood that aids in healing. However, too much thrombin triggers the PAR1 receptor found on the surface of cells, and this blocks myelin production. Oligodendrocyte progenitor cells capable of myelin regeneration are often found at sites of myelin injury, including demyelinating injuries in multiple sclerosis.

The research focused on two mouse models. One was an acute model of myelin injury and the other studied chronic demyelination, each modeling unique features of myelin loss present in MS, Alzheimer's disease, and other neurological disorders. Researchers genetically blocked PAR1 to block the action of excess thrombin. The research not only discovered a new molecular switch that turns on myelin regeneration, but also discovered a new interaction between the PAR1 receptor and a very powerful growth system called brain derived neurotropic factor (BDNF).

Significantly, the researchers found that a current FDA-approved drug, vorapaxar, 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. 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."

Link: https://newsnetwork.mayoclinic.org/discussion/mayo-clinic-research-discovers-a-molecular-switch-for-repairing-central-nervous-system-disorders/

Comments

Study shows promise in repairing damaged myelin
https://www.sciencedaily.com/releases/2019/04/190418141614.htm

'Myelin repair with minimal side effects: The study demonstrated that the compound -- known as sobetirome -- promotes remylenation without the severe side effects of thyroid hormone therapy. Thyroid hormone therapy has not been tried in people because chronic elevated exposure known as hyperthyroidism harms the heart, bone, and skeletal muscle.
Efficient delivery: Researchers developed a new derivative of sobetirome (Sob-AM2) that penetrates the blood brain barrier, enabling a tenfold increase in infiltration to the central nervous system'

Posted by: Jones at January 21st, 2020 2:14 AM

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