title: The octadecaneuropeptide ODN prevents 6-hydroxydopamine-induced apoptosis of cerebellar granule neurons through a PKC-MAPK-dependent pathway.
abstract: Oxidative stress, induced by various neurodegenerative diseases, initiates a cascade of events leading to apoptosis, and thus plays a critical role in neuronal injury. In this study, we have investigated the potential neuroprotective effect of the octadecaneuropeptide (ODN) on 6-hydroxydopamine (6-OHDA)-induced oxidative stress and apoptosis in cerebellar granule neurons (CGN). ODN, which is produced by astrocytes, is an endogenous ligand for both central-type benzodiazepine receptors (CBR) and a metabotropic receptor. Incubation of neurons with subnanomolar concentrations of ODN (10⁻¹⁸ to 10⁻¹² M) inhibited 6-OHDA-evoked cell death in a concentration-dependent manner. The effect of ODN on neuronal survival was abrogated by the metabotropic receptor antagonist, cyclo₁₋₈ [DLeu⁵]OP, but not by a CBR antagonist. ODN stimulated polyphosphoinositide turnover and ERK phosphorylation in CGN. The protective effect of ODN against 6-OHDA toxicity involved the phospholipase C/ERK MAPK transduction cascade. 6-OHDA treatment induced an accumulation of reactive oxygen species, an increase of the expression of the pro-apoptotic gene Bax, a drop of the mitochondrial membrane potential and a stimulation of caspase-3 activity. Exposure of 6-OHDA-treated cells to ODN blocked all the deleterious effects of the toxin. Taken together, these data demonstrate for the first time that ODN is a neuroprotective agent that prevents 6-OHDA-induced oxidative stress and apoptotic cell death.
authors.affiliation: Laboratory of Functional Neurophysiology and Pathology, Research Unit, UR/11ES09, Department of Biological Sciences, Faculty of Science of Tunis, University Tunis El Manar, Tunis, Tunisia.
authors.forename: Hadhemi
authors.initials: H
authors.lastname: Kaddour
authors.forename: Yosra
authors.initials: Y
authors.lastname: Hamdi
authors.forename: David
authors.initials: D
authors.lastname: Vaudry
authors.forename: Magalie
authors.initials: M
authors.lastname: Basille
authors.forename: Laurence
authors.initials: L
authors.lastname: Desrues
authors.forename: Jérôme
authors.initials: J
authors.lastname: Leprince
authors.forename: Hélène
authors.initials: H
authors.lastname: Castel
authors.forename: Hubert
authors.initials: H
authors.lastname: Vaudry
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Tonon
authors.forename: Mohamed
authors.initials: M
authors.lastname: Amri
authors.forename: Olfa
authors.initials: O
authors.lastname: Masmoudi-Kouki
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D053148:Caspase 3 / Q000378:metabolism; D002531:Cerebellum / Q000187:drug effects* / Q000473:pathology; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D026261:Diazepam Binding Inhibitor / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000502:physiology; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D009479:Neuropeptides / Q000494:pharmacology*; D018696:Neuroprotective Agents / Q000494:pharmacology; D018384:Oxidative Stress / Q000502:physiology; D016627:Oxidopamine / Q000633:toxicity*; D010446:Peptide Fragments / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D013565:Sympatholytics / Q000633:toxicity
chemical_list: D026261:Diazepam Binding Inhibitor; D009479:Neuropeptides; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; D013565:Sympatholytics; C067529:diazepam binding inhibitor (33-50); D019938:Cyclin D1; D016627:Oxidopamine; D011493:Protein Kinase C; C505410:Casp3 protein, rat; D053148:Caspase 3; D005978:Glutathione