Protease Activated Receptor 1 and Its Ligands as Main Regulators of the Regeneration of Peripheral Nerves

Abstract

In contrast with the brain and spinal cord, peripheral nerves possess a striking ability to regenerate after damage. This characteristic of the peripheral nervous system is mainly due to a specific population of glial cells, the Schwann cells. Schwann cells promptly activate after nerve injury, dedifferentiate assuming a repair phenotype, and assist axon regrowth. In general, tissue injury determines the release of a variety of proteases which, in parallel with the degradation of their specific targets, also activate plasma membrane receptors known as protease-activated receptors (PARs). PAR1, the prototypical member of the PAR family, is also known as thrombin receptor and is present at the Schwann cell plasma membrane. This receptor is emerging as a possible regulator of the pro-regenerative capacity of Schwann cells. Here, we summarize the most recent literature data describing the possible contribution of PAR1 and PAR1-activating proteases in regulating the regeneration of peripheral nerves.

Cardiovascular and Neurological Outcomes in Patients Treated with Edoxaban for Atrial Fibrillation and Characteristics in Patients with Cancer

“…26 AF patients exhibit elevated thrombin level which can activate PAR-1 and cause nerve fiber conduction block. 27 Moreover, PARs influence autophagy by affecting ROS production and the degradation of beta amyloid Aβ (1-42). 10 Edoxaban may ameliorate cognitive deterioration of AD 11 by reducing the expression of PARs, proinflammatory and profibrotic genes.…”

Intrinsic Expression of Coagulation Factors and Protease Activated Receptor 1 (PAR1) in Photoreceptors and Inner Retinal Layers

“…In addition, the PAR1/thrombin pathway was shown to regulate glutamate-dependent long-term potentiation (LTP) in mice hippocampal slices [37]. In the peripheral nervous system, exposing the rat sciatic nerve to high thrombin levels led to a nerve conduction block [8], and increased PAR1 activation following nerve injury was suggested to limit axonal regeneration [9]. The role of PAR1 in retinal function in vivo remains to be determined.…”

“…PAR1 and its main activator thrombin were found to play key roles in pathologies of the central and peripheral nervous systems, including in Parkinson's disease, amyotrophic lateral sclerosis (ALS), glioblastoma (GBM), diabetic neuropathy (DN), and sciatic nerve injury [3][4][5][6][7]. PAR1 is expressed in the sciatic node of Ranvier, where its activation leads to conduction block [8], and its increased activation on Schwann cells following injury was suggested to limit axonal repair [9]. Therefore, the PAR1/thrombin pathway has been marked as a potential target for the treatment of these diseases.…”

Research Progress on the Role of Microglia Membrane Proteins or Receptors in Neuroinflammation and Degeneration

“…Protease-activated receptors are considered as nonclassical pattern-recognition receptors (Friebel et al, 2021). PAR-3 and PAR-4 were initially thought to be receptors for thrombin and involved in thrombin signaling, while PAR-2 can be activated by trypsin and trypsin-like enzymes (Ocak et al, 2020;Pompili et al, 2021). PARS can effectively mediate the extracellar signal-regulated kinase (ERK1/2) signal transduction pathway to induce the nuclear reaction and activate a variety of cellular transcription factors (Yoon et al, 2017).…”