title: Involvement of endogenous antioxidant systems in the protective activity of pituitary adenylate cyclase-activating polypeptide against hydrogen peroxide-induced oxidative damages in cultured rat astrocytes.
abstract: Astroglial cells possess an array of cellular defense mechanisms, including superoxide dismutase (SOD) and catalase antioxidant enzymes, to prevent damages caused by oxidative stress. Nevertheless, astroglial cell viability and functionality can be affected by significant oxidative stress. We have previously shown that pituitary adenylate cyclase-activating polypeptide (PACAP) is a potent glioprotective agent that prevents hydrogen peroxide (H2 O2 )-induced apoptosis in cultured astrocytes. The purpose of this study was to investigate the potential protective effect of PACAP against oxidative-generated alteration of astrocytic antioxidant systems. Incubation of cells with subnanomolar concentrations of PACAP inhibited H2 O2 -evoked reactive oxygen species accumulation, mitochondrial respiratory burst, and caspase-3 mRNA level increase. PACAP also stimulated SOD and catalase activities in a concentration-dependent manner, and counteracted the inhibitory effect of H2 O2 on the activity of these two antioxidant enzymes. The protective action of PACAP against H2 O2 -evoked inhibition of antioxidant systems in astrocytes was protein kinase A, PKC, and MAP-kinase dependent. In the presence of H2 O2 , the SOD blocker NaCN and the catalase inhibitor 3-aminotriazole, both suppressed the protective effects of PACAP on SOD and catalase activities, mitochondrial function, and cell survival. Taken together, these results indicate that the anti-apoptotic effect of PACAP on astroglial cells can account for the activation of endogenous antioxidant enzymes and reduction in respiration rate, thus preserving mitochondrial integrity and preventing caspase-3 expression provoked by oxidative stress. Considering its powerful anti-apoptotic and anti-oxidative properties, the PACAPergic signaling system should thus be considered for the development of new therapeutical approaches to cure various pathologies involving oxidative neurodegeneration. We propose the following cascade for the glioprotective action of Pituitary adenylate cyclase-activating polypeptide (PACAP) against H2 O2 -induced astrocyte damages and cell apoptosis in cultured rat astrocytes. PACAP, through activation of its receptor, PAC1-R, and the protein kinase A (PKA), protein kinase C (PKC), and MAP-kinases signaling pathways, prevents accumulation of ROS and inhibition of SOD and catalase activities. This allows the preservation of mitochondrial membrane integrity and the reduction in caspase-3 activation induced by H2 O2 . These data may lead to the development of new strategies for cerebral injury treatment. Cat, catalase; Cyt. C, cytochrome C; SOD, superoxide dismutase.
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: Salma
authors.initials: S
authors.lastname: Douiri
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.|Inserm U982, Laboratory of Neuronal and Neuroendocrine Communication and Differentiation, University of Rouen, Mont-Saint-Aignan, France.
authors.forename: Seyma
authors.initials: S
authors.lastname: Bahdoudi
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.affiliation: Inserm U982, Laboratory of Neuronal and Neuroendocrine Communication and Differentiation, University of Rouen, Mont-Saint-Aignan, France.
authors.forename: Roger
authors.initials: R
authors.lastname: Cubì
authors.affiliation: Inserm U982, Laboratory of Neuronal and Neuroendocrine Communication and Differentiation, University of Rouen, Mont-Saint-Aignan, France.|Regional Platform for Cell Imaging of Normandie (PRIMACEN), Institute for Biomedical Research and Innovation, University of Rouen, Mont-Saint-Aignan, France.
authors.forename: Magali
authors.initials: M
authors.lastname: Basille
authors.affiliation: INRS - Institut Armand-Frappier, Laval, Quebec, Canada.|Laboratoire International Associé Samuel de Champlain, Institut Armand-Frappier, Laval, Quebec, Canada.|International Associated Laboratory Samuel de Champlain, University of Rouen, Mont-Saint-Aignan, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Fournier
authors.affiliation: Inserm U982, Laboratory of Neuronal and Neuroendocrine Communication and Differentiation, University of Rouen, Mont-Saint-Aignan, France.|Regional Platform for Cell Imaging of Normandie (PRIMACEN), Institute for Biomedical Research and Innovation, University of Rouen, Mont-Saint-Aignan, France.|International Associated Laboratory Samuel de Champlain, University of Rouen, Mont-Saint-Aignan, France.
authors.forename: Hubert
authors.initials: H
authors.lastname: Vaudry
authors.affiliation: Inserm U982, Laboratory of Neuronal and Neuroendocrine Communication and Differentiation, University of Rouen, Mont-Saint-Aignan, France.|Regional Platform for Cell Imaging of Normandie (PRIMACEN), Institute for Biomedical Research and Innovation, University of Rouen, Mont-Saint-Aignan, France.
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Tonon
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: Mohamed
authors.initials: M
authors.lastname: Amri
authors.affiliation: Inserm U982, Laboratory of Neuronal and Neuroendocrine Communication and Differentiation, University of Rouen, Mont-Saint-Aignan, France.|Regional Platform for Cell Imaging of Normandie (PRIMACEN), Institute for Biomedical Research and Innovation, University of Rouen, Mont-Saint-Aignan, France.|International Associated Laboratory Samuel de Champlain, University of Rouen, Mont-Saint-Aignan, France.
authors.forename: David
authors.initials: D
authors.lastname: Vaudry
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: Olfa
authors.initials: O
authors.lastname: Masmoudi-Kouki
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D000975:Antioxidants / Q000378:metabolism / Q000494:pharmacology*; D001253:Astrocytes / Q000187:drug effects*; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D002374:Catalase / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000633:toxicity*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000378:metabolism; D000076104:Oligodendrocyte Transcription Factor 2; D016877:Oxidants / Q000633:toxicity*; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D013482:Superoxide Dismutase / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D013997:Time Factors; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D000975:Antioxidants; D051792:Basic Helix-Loop-Helix Proteins; D002374:Catalase; D005904:Glial Fibrillary Acidic Protein; D006861:Hydrogen Peroxide; D007770:L-Lactate Dehydrogenase; D009419:Nerve Tissue Proteins; D000076104:Oligodendrocyte Transcription Factor 2; D016877:Oxidants; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D013482:Superoxide Dismutase; D013481:Superoxides; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C522729:Olig2 protein, rat
keywords: PACAP; apoptosis; astroglial cells; catalase; oxidative stress; superoxide dismutase