Fig. 11

Schematic view of the potential mechanisms by which RNS60 protect motor neurons and ameliorate the neuromuscular impairment in ALS. In the motor neurons RNS60 activates the p-Akt mediated pro-survival pathway and prevents the decrease of Nrf2 mediated anti-oxidant response while reducing the mitochondrial alterations (reduced vacuoles) and oxidative stress (NT). RNS60 also enhances phosphorylation of p-Akt, and levels of Nrf2, in a subpopulation of protective astrocytes that lead to an overexpression of the IL-4. IL-4 then induces the polarization of CD68 microglia toward a prohealing M2 phenotype creating a neuroprotective environment. In the sciatic nerve RNS60 prevents demyelination by protecting Schwann cells through the p-Akt pro-survival pathway and this results in the reduced NMJ denervation. This, together with the increased of CD68 positive macrophage recruitment in the muscle and the consequent debris clearing and tissue remodeling, results in the amelioration of neuromuscular impairment. RNS60 may also exert its protective action through the activation of immunomodulatory Treg, known to be negatively correlated with the severity of ALS in patients and animal models