Abstract
Interest in the role of coagulation and fibrinolysis in the nervous system was active in several laboratories dating back before cloning of the functional thrombin receptor in 1991. As one of those, our attention was initially on thrombin and plasminogen activators in synapse formation and elimination in the neuromuscular system, with orientation towards diseases such as amyotrophic lateral sclerosis (ALS) and how clotting and fibrinolytic pathways fit into its pathogenesis. This perspective is on neuro-thromboinflammation, emphasizing this emerging concept from studies and reports over more than three decades. It underscores how it may lead to novel therapeutic approaches to treat the ravages of neurotrauma and neurodegenerative diseases, with a focus on PAR1, ALS, and parmodulins.
Highlights
Introduction to NeuroThromboinflammation and Historical BackgroundOur initial concept began with visualizing synapse formation, such as the formation of blood clots, which involved thrombin-mediated coagulation
The hypothesis predicted that as with clot retraction, synapse retraction, or elimination, would likely involve components of fibrinolytic pathways. Those early studies led to several discoveries: plasminogen activators (PAs), primarily urokinase, were developmentally regulated at neonatal mouse neuromuscular junction (NMJ) [2]; the principal tissue inhibitor of thrombin, protease nexin I (PNI; serine protease inhibitor E2—serpinE2) was developmentally localized at NMJs [3]; thrombin activity correlated with postnatal-activitydependent synapse elimination in a Hebbian manner at the NMJ [4,5]
Anti-inflammatory, and profibrinolytic molecule, and some evidence has suggested that one mechanism for its efficacy was via endothelial cells (ECs) cytoprotection related to the endothelial protein receptor (EPCR)–activated protein C (APC)-protease-activated receptor 1 (PAR1) signaling pathway
Summary
Our initial concept began with visualizing synapse formation, such as the formation of blood clots, which involved thrombin-mediated coagulation. Perhaps inspired in part by the Maratea meeting, much progress has been made related to coagulation-related enzymes, receptors, and inhibitors in the nervous system, with additional groups making important contributions This has culminated in recent designations for the “coag-inflamm nexus” [24], with terms such as “coag-neurology”, the “neuro-glial coagulonome”, and neuro-thromboinflammation used to describe this emerging field. These all point to the critical roles that coagulation and inflammation play in neural development and the pathogenesis of neurologic diseases. This article and others in this issue are a testament to the novel work of those endeavoring to understand this field and to translate findings to the clinic
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