title: Ischemic tolerance modulates TRAIL expression and its receptors and generates a neuroprotected phenotype.
abstract: TNF-related apoptosis inducing ligand (TRAIL), a member of the TNF superfamily released by microglia, appears to be involved in the induction of apoptosis following focal brain ischemia. Indeed, brain ischemia is associated with progressive enlargement of damaged areas and prominent inflammation. As ischemic preconditioning reduces inflammatory response to brain ischemia and ameliorates brain damage, the purpose of the present study was to evaluate the role of TRAIL and its receptors in stroke and ischemic preconditioning and to propose, by modulating TRAIL pathway, a new therapeutic strategy in stroke. In order to achieve this aim a rat model of harmful focal ischemia, obtained by subjecting animals to 100 min of transient occlusion of middle cerebral artery followed by 24 h of reperfusion and a rat model of ischemic preconditioning in which the harmful ischemia was preceded by 30 mins of tMCAO, which represents the preconditioning protective stimulus, were used. Results show that the neuroprotection elicited by ischemic preconditioning occurs through both upregulation of TRAIL decoy receptors and downregulation of TRAIL itself and of its death receptors. As a counterproof, immunoneutralization of TRAIL in tMCAO animals resulted in significant restraint of tissue damage and in a marked functional recovery. Our data shed new light on the mechanisms that propagate ongoing neuronal damage after ischemia in the adult mammalian brain and provide new molecular targets for therapeutic intervention. Strategies aimed to repress the death-inducing ligands TRAIL, to antagonize the death receptors, or to activate the decoy receptors open new perspectives for the treatment of stroke.
authors.affiliation: Department of Clinical and Molecular Biomedicine, Section of Pharmacology and Biochemistry, School of Medicine, University of Catania, Viale Andrea Doria-6, Catania, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Cantarella
authors.affiliation: Department of Neuroscience, Division of Pharmacology, School of Medicine, Federico II University of Naples, Via Pansini, 5, Naples, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Pignataro
authors.affiliation: Department of Clinical and Molecular Biomedicine, Section of Pharmacology and Biochemistry, School of Medicine, University of Catania, Viale Andrea Doria-6, Catania, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Di Benedetto
authors.affiliation: Fondazione IRCCS SDN, Via Gianturco, Naples, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Anzilotti
authors.affiliation: Department of Neuroscience, Division of Pharmacology, School of Medicine, Federico II University of Naples, Via Pansini, 5, Naples, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Vinciguerra
authors.affiliation: Department of Neuroscience, Division of Pharmacology, School of Medicine, Federico II University of Naples, Via Pansini, 5, Naples, Italy.
authors.forename: O
authors.initials: O
authors.lastname: Cuomo
authors.affiliation: Department of Neuroscience, Division of Pharmacology, School of Medicine, Federico II University of Naples, Via Pansini, 5, Naples, Italy.
authors.forename: G F
authors.initials: GF
authors.lastname: Di Renzo
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Catania, Catania, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Parenti
authors.affiliation: 1] Department of Neuroscience, Division of Pharmacology, School of Medicine, Federico II University of Naples, Via Pansini, 5, Naples, Italy [2] Fondazione IRCCS SDN, Via Gianturco, Naples, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Annunziato
authors.affiliation: Department of Clinical and Molecular Biomedicine, Section of Pharmacology and Biochemistry, School of Medicine, University of Catania, Viale Andrea Doria-6, Catania, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Bernardini
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000235:genetics* / Q000378:metabolism / Q000517:prevention & control / Q000628:therapy; D005786:Gene Expression Regulation; D006801:Humans; D019194:Ischemic Preconditioning; D008297:Male; D009474:Neurons / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics* / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics* / Q000378:metabolism
chemical_list: D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand