Glutamate promotes NF-kappaB pathway in primary astrocytes: protective effects of IRFI 016, a synthetic vitamin E analogue.
Oxidative stress has been implicated in several neurodegenerative diseases affecting both neuronal and glial cells. The aim of this study was to investigate the involvement of reactive oxygen species in glutamate-evoked activation of NF-kappaB in primary astrocytes. A prolonged exposure to glutamate (24 h) caused a depletion of intracellular glutathione that, in astroglial cells, has been considered a biochemical change typical of early astrocyte dysfunction, leading to cell alterations occurring in the gliosis. These effects were initiated by AMPA/KA receptor activation and almost completely blocked by anti-oxidants. Indeed, we provide evidence that the incubation of primary astrocytes with a hydrophilic derivative of tocopherol, such as IRFI 016, was useful to reduce glutamate-induced oxidative effects. This agent also reduced in a dose-dependent manner the nuclear translocation of both p50 and p65 subunits of NF-kappaB. Altogether, these data confirm that GSH content plays a pivotal role to determine oxidative response to glutamate injury in primary astrocyte cultures and that NF-kappaB pathway is involved in this response. Furthermore, the positive effects obtained by IRFI 016 to prevent nuclear translocation of NF-kappaB may suggest new pharmacological strategies for antioxidant therapy and neuroprotection.
Caccamo
Daniela
D
Department of Biochemical, Physiological and Nutritional Sciences, University of Messina, Via Consolare Valeria, Policlinico Universitario, 98125 Messina, Italy.
Campisi
Agata
A
Marini
Herbert
H
Adamo
Elena B
EB
Li Volti
Giovanni
G
Squadrito
Francesco
F
Ientile
Riccardo
R
D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism; D001572:Benzofurans / Q000494:pharmacology*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D024202:Electrophoretic Mobility Shift Assay / Q000379:methods; D004843:Epistasis, Genetic; D016166:Free Radical Scavengers / Q000494:pharmacology; D018698:Glutamic Acid / Q000494:pharmacology*; D005978:Glutathione / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000494:pharmacology*
D001572:Benzofurans; D016166:Free Radical Scavengers; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D014810:Vitamin E; D018698:Glutamic Acid; C058293:glutathione monoisopropyl ester; D007770:L-Lactate Dehydrogenase; D005978:Glutathione; C071049:Raxofelast