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 (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.

Astroglia as a cellular target for neuroprotection and treatment of neuro‐psychiatric disorders

“…ODN is a potent protective agent that prevents oxidative stress‐induced apoptosis and attenuates H 2 O 2 ‐evoked inhibition of SOD and catalase activities in astrocytes (Hamdi et al, 2011). It has been suggested that the anti‐apoptotic activity of ODN is mediated through a putative GPCR coupled to the adenylate cyclase/protein kinase A pathway (Hamdi et al, 2012). Downstream of protein kinase A, ODN induces ERK phosphorylation which, in turn, activates the expression of the anti‐apoptotic gene Bcl‐2 and blocks the stimulation by H 2 O 2 of the proapoptotic gene Bax.…”

Protective Effect of a cAMP Analogue on Behavioral Deficits and Neuropathological Changes in Cuprizone Model of Demyelination

“…Treatment with bucladesine significantly reduced cleaved caspase-3 activity as well as TUNEL-positive cells. Elevation of intracellular cAMP modulates the Bax/Bcl-2 balance in favor of an antiapoptotic activity leading to an inhibition of H 2 O 2 -induced caspase-3 via the intrinsic apoptotic mitochondrial pathway [10]. Our results revealed that cuprizone raised the ratio of Bax/Bcl-2 and bucladesine decreased this ratio.…”

“…Caspase-3 is well known as a downstream executioner caspase of caspase-dependent apoptotic cascades. Bucladesine could decrease the caspase-3 activity induced by H 2 O 2 in the cell culture [10]. As shown in Fig.…”

“…cAMP works as a second messenger mediating signal transduction [7]. After ligand binding to G protein-coupled receptors, cAMP can activate protein kinase A (PKA) that allows phosphorylation of various downstream targets and promotes axonal regeneration [8], regulates inflammatory responses [9], and inhibits caspase-3 activity [10]. Previous studies showed that elevation of intracellular cAMP via bucladesine, a membrane-permeable cAMP analogue, improves spatial memory retention in male rats [11], enhances endogenous neural stem cell recruitment, and attenuates demyelination in experimental model of autoimmune encephalomyelitis [12].…”

Octadecaneuropeptide ODN prevents hydrogen peroxide-induced oxidative damage of biomolecules in cultured rat astrocytes

“…DBI and its processing products are collectively designated by the term endozepines [39]. ODN acts through two types of receptors, the central-type benzodiazepine receptors (CBR) associated with the GABA A receptor complex [6,18] and a metabotropic receptor positively coupled to either phospholipase C (PLC) [28] or adenylyl cyclase (AC) [24]. The primary structure of ODN has been strongly conserved during evolution [10,39], suggesting that this peptide plays important biological functions.…”