title: Involvement of mitochondria on neuroprotective effect of sphingosine-1-phosphate in cell death in an in vitro model of brain ischemia.
abstract: Sphingosine-1-phosphate (S1P) has been demonstrated to be an important regulator of cell death and survival. Although it has been suggested that the sphingolipid may act as a neuroprotector in the cell apoptosis induced by traumatic brain injury, the mechanisms involved in this action are unknown. In this study, the relationship between S1P and neuroprotective effect was studied in an in vitro model of ischemia, maintaining SH-SY5Y human neuroblastoma cells under oxygen-glucose deprivation (OGD). When cells were treated with 1 microM S1P simultaneously with OGD and recovery, cell viability increases in a dose-response manner. S1P treatment reduces significantly both necrosis and apoptosis cell death. On the other hand, the treatment with specific PKC epsilon (V1-2), prevents S1P protective effect of OGD/recovery-induced necrosis. Moreover, S1P treatment provokes the translocation of PKC epsilon to the mitochondria. From these results, it is reasonable to assume that S1P protection from necrosis is mediated by PKC epsilon. We also studied the action of S1P on mitochondrial inner membrane potential and mitochondrial Ca(2+) levels during ischemia. In this regard, we must point out that S1P treatment reduces the OGD-induced membrane depolarization and also reduces the increase of Ca(2+) in mitochondria during OGD. Results also indicate that mitochondria from OGD treated cells have significantly less ability to resist swelling on Ca(2+) loading than those obtained in presence of oxygen and glucose. Nevertheless, when S1P was added, this resistance increases considerably. These findings suggest that S1P may have a potential role as a neuroprotective agent in brain injury.
authors.affiliation: Departamento de Bioquímica y Biología Molecular I, Facultad de Química, Universidad Complutense de Madrid, E-28040 Madrid, Spain.
authors.forename: Alba
authors.initials: A
authors.lastname: Agudo-López
authors.forename: Begoña G
authors.initials: BG
authors.lastname: Miguel
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Fernández
authors.forename: Ana M
authors.initials: AM
authors.lastname: Martínez
mesh_terms: D001693:Biological Transport, Active / Q000502:physiology; D002545:Brain Ischemia / Q000503:physiopathology*; D002118:Calcium / Q000378:metabolism; D016923:Cell Death / Q000502:physiology; D015687:Cell Hypoxia / Q000502:physiology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology; D003600:Cytosol / Q000378:metabolism; D005947:Glucose / Q000172:deficiency / Q000378:metabolism; D006801:Humans; D008246:Lysophospholipids / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial / Q000502:physiology; D008928:Mitochondria / Q000502:physiology*; D008933:Mitochondrial Swelling / Q000502:physiology; D009336:Necrosis / Q000503:physiopathology; D010100:Oxygen / Q000378:metabolism; D051744:Protein Kinase C-epsilon / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism; D013997:Time Factors
chemical_list: D008246:Lysophospholipids; C060506:sphingosine 1-phosphate; D051744:Protein Kinase C-epsilon; D005947:Glucose; D013110:Sphingosine; D010100:Oxygen; D002118:Calcium