title: The octadecaneuropeptide ODN protects astrocytes against hydrogen peroxide-induced apoptosis via a PKA/MAPK-dependent mechanism.
abstract: Astrocytes synthesize and release endozepines, a family of regulatory peptides, including the octadecaneuropeptide (ODN) an endogenous ligand of both central-type benzodiazepine (CBR) and metabotropic receptors. We have recently shown that ODN exerts a protective effect against hydrogen peroxide (H(2)O(2))-induced oxidative stress in astrocytes. The purpose of the present study was to determine the type of receptor and the transduction pathways involved in the protective effect of ODN in cultured rat astrocytes. We have first observed a protective activity of ODN at very low concentrations that was abrogated by the metabotropic ODN receptor antagonist cyclo(1-8)[DLeu(5)]OP, but not by the CBR antagonist flumazenil. We have also found that the metabotropic ODN receptor is positively coupled to adenylyl cyclase in astrocytes and that the glioprotective action of ODN upon H(2)O(2)-induced astrocyte death is PKA- and MEK-dependent, but PLC/PKC-independent. Downstream of PKA, ODN induced ERK phosphorylation, which in turn activated the expression of the anti-apoptotic gene Bcl-2 and blocked the stimulation by H(2)O(2) of the pro-apoptotic gene Bax. The effect of ODN on the Bax/Bcl-2 balance contributed to abolish the deleterious action of H(2)O(2) on mitochondrial membrane integrity and caspase-3 activation. Finally, the inhibitory effect of ODN on caspase-3 activity was shown to be PKA and MEK-dependent. In conclusion, the present results demonstrate that the potent glioprotective action of ODN against oxidative stress involves the metabotropic ODN receptor coupled to the PKA/ERK-kinase pathway to inhibit caspase-3 activation.
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: Yosra
authors.initials: Y
authors.lastname: Hamdi
authors.forename: Hadhemi
authors.initials: H
authors.lastname: Kaddour
authors.forename: David
authors.initials: D
authors.lastname: Vaudry
authors.forename: Seyma
authors.initials: S
authors.lastname: Bahdoudi
authors.forename: Salma
authors.initials: S
authors.lastname: Douiri
authors.forename: Jérôme
authors.initials: J
authors.lastname: Leprince
authors.forename: Helene
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: D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001253:Astrocytes / Q000166:cytology* / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D026261:Diazepam Binding Inhibitor / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009479:Neuropeptides / Q000494:pharmacology*; D018696:Neuroprotective Agents / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D010446:Peptide Fragments / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism
chemical_list: D026261:Diazepam Binding Inhibitor; D009479:Neuropeptides; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D018094:Receptors, Metabotropic Glutamate; C067529:diazepam binding inhibitor (33-50); D006861:Hydrogen Peroxide; D017868:Cyclic AMP-Dependent Protein Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D020928:Mitogen-Activated Protein Kinases; D000262:Adenylyl Cyclases; D005978:Glutathione