IMT504 blocks allodynia in rats with spared nerve injury by promoting the migration of mesenchymal stem cells and by favoring an anti-inflammatory milieu at the injured nerve

M. CASADEI; E. FIORE; J. RUBIONE; L. DOMINGUEZ; M.F. CORONEL; C. LEIGUARDA; M. GARCÍA; G. MAZZOLINI; M.J. VILLAR; A.D. MONTANER; L. CONSTANDIL; A. ROMERO-SANDOVAL; P.R. BRUMOVSKY

PAIN

ELSEVIER SCIENCE BV

Lugar: Amsterdam; Año: 2021

0304-3959

IMT504, a non-coding, non-CpG oligodeoxynucleotide (ODN), modulates painlikebehavior in rats undergoing peripheral nerve injury, through mechanismsthat remain poorly characterized. Here, we chose the spared nerve injury modelin rats to analyze the contribution of mesenchymal stem cells (MSCs) in themechanisms of action of IMT504. We show that a single subcutaneousadministration of IMT504 reverses mechanical and cold allodynia for at least 5weeks post-treatment. This event correlated with long-lasting increases in thepercentage of MSCs in peripheral blood and injured sciatic nerves, in a processseemingly influenced by modifications in the CXCL12-CXCR4 axis. Also, injurednerves presented with reduced TNF- and IL-1 and increased TGF-1 and IL-10 protein levels. In vitro analysis of IMT504-pre-treated rat or human MSCsrevealed internalized ODN and confirmed its pro-migratory effects. Moreover,IMT504-pre-treatment induced transcript expression of Tgf-1 and Il-10 inMSCs, the increase in Il-10 becoming more robust after exposure to injurednerves. Ex vivo exposure of injured nerves to IMT504-pre-treated MSCsconfirmed the pro-to-anti-inflammatory switch observed in vivo. Interestingly, thesole exposure of injured nerves to IMT504 also resulted in downregulated Tnf-and Il-1 transcripts. Altogether, we reveal for the first time a direct associationbetween the anti-allodynic actions of IMT504, its pro-migratory and cytokinesecretion modulating effects on MSCs, and further anti-inflammatory actions atinjured nerves. The recapitulation of key outcomes in human MSCs supportsthe translational potential of IMT504 as a novel treatment for neuropathic painwith a unique mechanism of action involving the regulation of neuroimmuneinteractions.