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 (H2O2)-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 cyclo1–8[DLeu5]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 H2O2-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 H2O2 of the pro-apoptotic gene Bax. The effect of ODN on the Bax/Bcl-2 balance contributed to abolish the deleterious action of H2O2 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.
Highlights
Diazepam-binding inhibitor (DBI) is an 86-amino acid polypeptide that has been originally isolated from rat brain extracts as an endogenous ligand of benzodiazepine receptors [1]
We have previously shown that ODN, at a concentration of 0.1 nM, is able to reverse the effect of 300 mM H2O2-induced astrocyte cell death [34]
We have recently found that the endozepine ODN protects astrocytes upon H2O2 injury [34]
Summary
Diazepam-binding inhibitor (DBI) is an 86-amino acid polypeptide that has been originally isolated from rat brain extracts as an endogenous ligand of benzodiazepine receptors [1]. DBI and its derived peptides, including the octadecaneuropeptide ODN, are collectively termed endozepines [2,3]. It was initially reported that the endozepines ODN and DBI act as inverse agonists of centraltype benzodiazepine receptors DBI was found to interact with peripheral-type benzodiazepine receptors, called translocator protein [6]. It has been shown that DBI-derived peptides can activate a metabotropic receptor coupled either to adenylyl cyclase (AC) or to phospholipase C (PLC) [7,8,9,10]. The sequence of ODN has been well conserved during evolution [11], and data suggest that this peptide is involved in the regulation of important biological functions such as the control of food intake, sleep, aggressiveness and anxiety [12,13,14,15,16,17]
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