Blockade of Rho-associated kinase prevents inhibition of axon regeneration induced by anti-ganglioside antibodies

ANDRES BERARDO; BACAGLIO, CRISTIAN ROMAN; BAEZ, BARBARA; SAMBUELLI, RUBÉN; SHEIKH, K. A.; LOPEZ, PABLO HECTOR HORACIO

NEURAL REGENERATION RESEARCH

SHENYANG EDITORIAL DEPT NEURAL REGENERATION RES

Año: 2023

1673-5374

Anti-ganglioside antibodies (anti-Gg Abs) are associated with delayed/poor clinical recovery in axonal and demyelinating forms of Guillain Barrè Syndrome (GBS). In most cases, incomplete recovery involves failure of the peripheral nervous system to regenerate. Cross-linking of cell surface gangliosides by anti-Gg Abs trigger inhibition of nerve repair in in vitro and in vivo paradigms of axon regeneration by a mechanism that involves the activation of the small GTPase RhoA, which negatively modulates growth cone cytoskeleton. Similar to anti-ganglioside Abs, the vast majority of inhibitors of axon regeneration described, so far, halt neurite outgrowth via activation of the small GTPase RhoA/ROCK signaling pathways, therefore it is not surprising that its pharmacological modulation has consolidated as a potential therapeutic target over the past years. The aim of this work was to perform a proof of concept study to demonstrate the effectiveness of Y-27632, a selective pharmacological inhibitor of ROCK, in an animal model of axon regeneration of peripheral nerves, where the passive immunization with a mAb targeting gangliosides GD1a and GT1b was previously reported to exert a potent inhibitory effect on regeneration of both myelinated and unmyelinated fibers. Our results demonstrate a differential sensitivity of myelinated and unmyelinated axons to the pro-regenerative effect of Y-27632. Treatment with a total dosage of 9 mg/kg of Y-27632 resulted in a complete prevention of anti-GD1a/GT1b mAb-mediated inhibition of axon regeneration of unmyelinated fibers to skin and the functional recovery of mechanical cutaneous sensitivity. In contrast, the same dose showed toxic effects on the regeneration of myelinated fibers. Interestingly, scale down of the dosage of Y-27632 to 5 mg/kg resulted in a significant although not complete recovery of regenerated myelinated axons exposed to anti-GD1a/GT1b mAb in the absence of toxicity in animals exposed to only Y-27632. Overall, these findings confirm the participation in vivo of RhoA/ROCK signaling pathways in the molecular mechanisms associated with the in vivo inhibition of axon regeneration induced by anti-GD1a/GT1b mAb. Our findings open the possibility of therapeutic pharmacological intervention targeting RhoA/Rock pathway in immune neuropathies associated with the presence of anti-Gg Abs and delayed or incomplete clinical recovery.