Endothelin-1: a new pharmacological target for Amyotrophic Lateral Sclerosis?

Endothelin-1 (ET-1) is a vasoactive peptide produced by activated astrocytes and microglia and implicated in initiating and sustaining reactive gliosis in neurodegenerative diseases. Recent evidence shows that the peptide can play a critical role in amyotrophic lateral sclerosis (ALS). Our group has demonstrated that ET-1 is abundantly expressed in reactive astrocytes in the spinal cord of SOD-1 G93A mice and ALS patients and exerts a toxic effect on motor neurons (MNs) in an in vitro model of mixed spinal cord cultures enriched in reactive astrocytes (Ranno et al., Neurobiol Dis 2014; 65:160-71). Here, we studied the possible mechanisms involved in the selective toxicity of ET-1 on cultured MN, focusing on cell survival pathways, oxidative stress and inflammatory processes. Our data show that the toxic effect of ET-1 is not directly caused by oxidative stress or inflammatory processes, but is mediated by a reduced activation of the phosphoinositide 3-kinase (PI3K) pathway and a concomitant inhibition of nitric oxide synthase. Furthermore, we observed that ET-1 is also toxic for microglia, but its effect on MNs does not depend upon the presence of this type of glial cells. Our study confirms that ET-1 may contribute to MN death in ALS and identifies the mechanisms underlying ET-1 toxicity, suggesting that the modulation of ET-1 signaling might be a therapeutic strategy to slow down MN degeneration in ALS.