A molecular switch has the ability to turn on a substance in animals that repairs neurological damage in disorders such as multiple sclerosis (MS), Mayo Clinic researchers discovered.
The early research in animal models could advance an already approved Food and Drug Administration therapy and also could lead to new strategies for treating diseases of the central nervous system.
Research by Isobel Scarisbrick, Ph.D., published in the Journal of Neuroscience finds 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,” says Dr. Scarisbrick, principal investigator and senior author. “This sets the stage for development of new clinically relevant myelin regeneration strategies.”
Myelin, Thrombin and the Nervous System
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 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). BDNF is like a fertilizer for brain cells that keeps them healthy, functioning and growing.
“These oligodendroglia fail to differentiate into mature myelin regenerating cells for reasons that remain poorly understood,” says Dr. Scarisbrick.
“Our research identifies PAR1 as a molecular switch of myelin regeneration. In this study, we demonstrate that blocking the function of the PAR1, also referred to as the thrombin receptor, promotes myelin regeneration in two unique experimental models of demyelinating disease.”
The Research
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). BDNF is like a fertilizer for brain cells that keeps them healthy, functioning and growing.
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.”
Additional research is needed to verify and advance the findings toward clinical practice.
Funding: The study was made possible by a grant from the National Multiple Sclerosis Society with support from the Mayo Clinic Rehabilitation Medicine Research Center, the Center for Multiple Sclerosis and Autoimmune Neurology and the Mayo Clinic Center for Regenerative Medicine.
The complex physiological process of hemostasis involves several pathways in which procoagulant and anticoagulant forces are maintained in a constant equilibrium by autoregulation. In fact, hemostasis allows the vascular wall to provide anticoagulant blood containment until damage causes significant activation of coagulation, the confined formation of blood clot with hemorrhage cessation, and removal of that clot after the restoration of vascular integrity (1).
Increased blood-brain-barrier (BBB) permeability is a feature of several neurological diseases, and one of the first events that characterizes multiple sclerosis (MS) pathogenesis (2–5), leading to the irruption of coagulation/hemostasis factors into the central nervous system (CNS) (6). This, in turn, potentially triggers leakage of hemostasis components into the brain parenchyma, which potentially triggers the coagulation cascade. Besides their cytotoxic deposition, hemostasis components cause an inflammatory response and immune activation, sustaining neurodegenerative processes in MS (Figure 1) (6–12). Coagulation and inflammation are characterized by multiple links, and coagulation proteins and their fragments may promote neurodegeneration (12, 13).
Preclinical models provide (albeit with some limitations) an informative means to investigate the pathophysiology of human diseases, and those mimicking MS have received attention in the last 3 decades. In particular, an increasing number of studies, largely based on animal models (14), have provided insights into the tight relationship among vasculature alterations, neuroinflammation, neuroimmunology, and neurodegeneration. Nevertheless, they only partially contribute to the relation between hemostasis components and experimental evidence in MS patients.
This review article focuses on coagulation pathways in MS patients and related animal models. Current knowledge of how coagulation factors, coagulation inhibitors, and components of the fibrinolytic pathway are (dys)regulated in MS patients is reviewed and missing or inconsistent information is highlighted to guide future research.
Coagulation Cascade Essentials
Before exploring the contribution of coagulation components in the pathophysiology of MS, it is important to consider the basic physiology of coagulation. Coagulation occurs as a complex network of overlapping reactions tightly localized on specific cell surfaces. It is often still represented as a one-way Y-shaped model as proposed in the 1960s (15, 16).
Although an oversimplification, this model posits two distinct pathways, so-called “extrinsic” and “intrinsic,” that converged into a “common” one. Here, the interactions of inactive procoagulant mediators enable a sequential cascade of proteolytic events leading to their activation and the final fibrin and blood clot formation.
The extrinsic pathway was so named because it requires an external factor (from the extravascular tissue), while the intrinsic pathway includes factors that are already present in the blood. In contrast to this commonly cited model, in the actual in-vivo process, extrinsic, and intrinsic pathways do not work independently and the pro-coagulant mediators, once activated, support the exponential amplification and propagation of the system with several interactions and feedback loops (17, 18).
Although the activity in plasma of pro-coagulant factors of extrinsic and intrinsic pathways can be measured separately using clinically available coagulation tests such as partial thromboplastin time (PT) and activated partial thromboplastin time (aPTT), respectively (19), these laboratory tests do not accurately reflect the in-vivo situation (17). In fact, they force the system into a controlled condition on platelet-poor plasma through the exogenous supply of reagents (tissue factor/thromboplastin, phospholipids, calcium, and micronized silica) to assess the activity level of a certain factor.
In order to form a blood clot in-vivo, platelets and coagulation factors must communicate and support each other (20). Tissue factor (TF), the main trigger of the process responsible for the initial acceleration of cascade activation, is kept hidden on subendothelial cells until vascular damage exposes it (18). Once exposed, it promotes the activation of platelets and their recruitment into the clot (21). In turn, platelets mediate pro-coagulant functions through the release of additional coagulation factors and by the release of negatively charged phospholipids that are required cofactors for the proteolytic reactions of coagulation factors (22).
The procoagulant mediators that initiate, amplify, and propagate this cascade exist as proenzymes (also known as zymogens) in the blood (22). Under normal conditions, a basal activation of coagulation factors takes place, but it leads to an “idling” coagulation (18), which does not escalate to full clot formation. This occurs because the biochemical reactions are several orders of magnitude less efficient without the procoagulant mediators.
In summary, (1) fibrin can be produced only as a result of the complex interplay of coagulation factors, and (2) to productively trigger coagulation, cell surface exposure is necessary (TF-bearing membranes and platelets).
Based on the above, one of the main questions relevant to MS is how the coagulation cascade is triggered in the CNS.
Source:
Mayo Clinic
