title: Endothelin-1 Induces Degeneration of Cultured Motor Neurons Through a Mechanism Mediated by Nitric Oxide and PI3K/Akt Pathway.
abstract: Endothelin-1 (ET-1) is a vasoactive peptide produced by activated astrocytes and microglia and is implicated in initiating and sustaining reactive gliosis in neurodegenerative diseases. We have previously suggested that ET-1 can play a role in the pathophysiology of amyotrophic lateral sclerosis (ALS). Indeed, we reported that this peptide is abundantly expressed in reactive astrocytes in the spinal cord of SOD1-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 with reactive astrocytes. Here, we explored the possible mechanisms underlying the toxic effect of ET-1 on cultured MNs. We show that ET-1 toxicity is not directly caused by oxidative stress or activation of cyclooxygenase-2 but requires the synthesis of nitric oxide and is mediated by a reduced activation of the phosphoinositide 3-kinase pathway. Furthermore, we observed that ET-1 is also toxic for microglia, although its effect on MNs is independent of the presence of this type of glial cells. Our study confirms that ET-1 may contribute to MN death and corroborates the view that the modulation of ET-1 signaling might be a therapeutic strategy to slow down MN degeneration in ALS.
authors.affiliation: Institute of Neurological Sciences, National Research Council (CNR), Catania, Italy.
authors.forename: S
authors.initials: S
authors.lastname: D'Antoni
authors.affiliation: Institute of Neurological Sciences, National Research Council (CNR), Catania, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Ranno
authors.affiliation: Institute of Neurological Sciences, National Research Council (CNR), Catania, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Spatuzza
authors.affiliation: Institute of Neurological Sciences, National Research Council (CNR), Catania, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Cavallaro
authors.affiliation: Institute of Neurological Sciences, National Research Council (CNR), Catania, Italy. mariavincenza.catania@cnr.it.|IRCSS Oasi Maria SS, Troina, Enna, Italy. mariavincenza.catania@cnr.it.
authors.forename: M V
authors.identifier: http://orcid.org/0000-0002-9329-8517
authors.initials: MV
authors.lastname: Catania
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use; D029681:Arabidopsis Proteins; D001205:Ascorbic Acid / Q000627:therapeutic use; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004622:Embryo, Mammalian; D019332:Endothelin-1 / Q000633:toxicity*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D047468:Immunoprecipitation; D009046:Motor Neurons / Q000187:drug effects*; D009410:Nerve Degeneration / Q000188:drug therapy / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D009687:Nuclear Proteins; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011247:Pregnancy; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects*; D013116:Spinal Cord / Q000166:cytology
chemical_list: D000975:Antioxidants; D029681:Arabidopsis Proteins; D019332:Endothelin-1; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; C523534:TIC protein, Arabidopsis; D009569:Nitric Oxide; D051546:Cyclooxygenase 2; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D001205:Ascorbic Acid
keywords: Amyotrophic lateral sclerosis; Astrocytes; Endothelin; Motor neurons; Neurodegeneration; Nitric oxide