2. Academic Validation
  3. An Agonist of the CXCR4 Receptor Strongly Promotes Regeneration of Degenerated Motor Axon Terminals

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

  • Cells. 2019 Sep 30;8(10):1183. doi: 10.3390/cells8101183.
Samuele Negro 1,  Giulia Zanetti 2,  Andrea Mattarei 3,  Alice Valentini 4,  Aram Megighian 5 6,  Giulia Tombesi 7,  Alessandro Zugno 8,  Valentina Dianin 9,  Marco Pirazzini 10,  Silvia Fillo 11,  Florigio Lista 12,  Michela Rigoni 13,  Cesare Montecucco 14 15
Affiliations

Affiliations

  • 1 Department of Biomedical Sciences, University of Padua, Padua 35131, Italy. [email protected].
  • 2 Department of Biomedical Sciences, University of Padua, Padua 35131, Italy. [email protected].
  • 3 Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padua 35131, Italy. [email protected].
  • 4 Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padua 35131, Italy. [email protected].
  • 5 Department of Biomedical Sciences, University of Padua, Padua 35131, Italy. [email protected].
  • 6 Padua Neuroscience Institute, Padua 35131, Italy. [email protected].
  • 7 Department of Biology, University of Padua, Padua 35131, Italy. [email protected].
  • 8 Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padua 35131, Italy. [email protected].
  • 9 Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padua 35131, Italy. [email protected].
  • 10 Department of Biomedical Sciences, University of Padua, Padua 35131, Italy. [email protected].
  • 11 Center of Medical and Veterinary Research of the Ministry of Defence, Rome 00184, Italy. [email protected].
  • 12 Center of Medical and Veterinary Research of the Ministry of Defence, Rome 00184, Italy. [email protected].
  • 13 Department of Biomedical Sciences, University of Padua, Padua 35131, Italy. [email protected].
  • 14 Department of Biomedical Sciences, University of Padua, Padua 35131, Italy. [email protected].
  • 15 CNR Institute of Neuroscience, Padua 35131, Italy. [email protected].
PMID: 31575088 DOI: 10.3390/cells8101183
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.

Keywords

CXCR4 receptor; motor neuron; neurodegeneration; neuromuscular junction; neuroregeneration.

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