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

Cells

Silvia Fillo¹  Florigio Lista¹  Giulia Tombesi²  Marco Pirazzini³  Michela Rigoni³  Cesare Montecucco³  Aram Megighian³  Giulia Zanetti³  Samuele Negro³  Andrea Mattarei⁴  Alessandro Zugno⁴  Alice Valentini⁴  Valentina Dianin⁴ 

[1] Center of Medical and Veterinary Research of the Ministry of Defence, 00184 Rome, Italy;Department of Biology, University of Padua, 35131 Padua, Italy;Department of Biomedical Sciences, University of Padua, 35131 Padua, Italy;Department of Pharmaceutical and Pharmacological Sciences, University of Padua, 35131 Padua, Italy;

关键词: cxcr4 receptor;    neurodegeneration;    neuroregeneration;    neuromuscular junction;    motor neuron;   

DOI  :  10.3390/cells8101183

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown