An Agonist of the CXCR4 Receptor Strongly Promotes Regeneration of Degenerated Motor Axon Terminals.

Negro Negro,Tombesi Tombesi,Zanetti Zanetti,Valentini Valentini,Pirazzini Pirazzini,Mattarei Mattarei,Dianin Dianin,Rigoni Rigoni,Fillo Fillo,Montecucco Montecucco,Lista Lista,Megighian Megighian,Zugno Zugno

doi:10.3390/cells8101183

Negro Negro, Tombesi Tombesi + Show 11 more

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https://doi.org/10.3390/cells8101183

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Abstract

The activation of the G-protein coupled receptor CXCR4 by its ligand CXCL12α is involved in a large variety of physiological and pathological processes, including the growth of B cells precursors and of motor axons, autoimmune diseases, stem cell migration, inflammation, and several neurodegenerative conditions. Recently, we demonstrated that CXCL12α potently stimulates the functional recovery of damaged neuromuscular junctions via interaction with CXCR4. This result prompted us to test the neuroregeneration activity of small molecules acting as CXCR4 agonists, endowed with better pharmacokinetics with respect to the natural ligand. We focused on NUCC-390, recently shown to activate CXCR4 in a cellular system. We designed a novel and convenient chemical synthesis of NUCC-390, which is reported here. NUCC-390 was tested for its capability to induce the regeneration of motor axon terminals completely degenerated by the presynaptic neurotoxin α-Latrotoxin. NUCC-390 was found to strongly promote the functional recovery of the neuromuscular junction, as assayed by electrophysiology and imaging. This action is CXCR4 dependent, as it is completely prevented by AMD3100, a well-characterized CXCR4 antagonist. These data make NUCC-390 a strong candidate to be tested in human therapy to promote nerve recovery of function after different forms of neurodegeneration.

Highlights

A variety of damages, such as mechanical traumas and autoimmune or neurotoxic attacks, can affect peripheral neurons, owing to their anatomical exposure
The main result reported here is that the small molecule NUCC-390 promotes the recovery of the physiological function of the murine neuromuscular junction (NMJ) after complete degeneration of its motor axon terminal
These results indicate that NUCC-390 acts in an opposite way of AMD3100, the bicyclam antagonist of CXCR4 and HIV entry inhibitor, which has been approved for clinical use with the names

Summary

Introduction

A variety of damages, such as mechanical traumas and autoimmune or neurotoxic attacks, can affect peripheral neurons, owing to their anatomical exposure. Together with its essential physiological role, this explains why the peripheral nervous system (PNS) has retained the capability to regenerate its neurons through evolution, at variance from the central one [1,2,3,4,5]. Cells 2019, 8, 1183 of and players in the regeneration process is of crucial importance, as it will lead to the discovery of novel drugs to support current protocols of rehabilitation after accidents or other damage to PNS neurons. We recently reported that a signaling axis composed of a member of this family, CXCR4, and its natural ligand, CXCL12α, contributes to the functional and anatomical recovery of the neuromuscular junction (NMJ) following an acute nerve terminal damage [8]. In response to a motor axon terminal injury perisynaptic Schwann cells (PSCs) synthetize and release the chemokine

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