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.

TNF-related apoptosis inducing ligand (TRAIL), a member of the TNF superfamily released by microglia, appears to be involved inthe induction of apoptosis following focal brain ischemia. Indeed, brain ischemia is associated with progressive enlargement ofdamaged areas and prominent inflammation. As ischemic preconditioning reduces inflammatory response to brain ischemia andameliorates brain damage, the purpose of the present study was to evaluate the role of TRAIL and its receptors in stroke andischemic preconditioning and to propose, by modulating TRAIL pathway, a new therapeutic strategy in stroke. In order to achievethis aim a rat model of harmful focal ischemia, obtained by subjecting animals to 100 min of transient occlusion of middlecerebral artery followed by 24 h of reperfusion and a rat model of ischemic preconditioning in which the harmful ischemia waspreceded by 30 mins of tMCAO, which represents the preconditioning protective stimulus, were used. Results show that theneuroprotection elicited by ischemic preconditioning occurs through both upregulation of TRAIL decoy receptors anddownregulation of TRAIL itself and of its death receptors. As a counterproof, immunoneutralization of TRAIL in tMCAO animalsresulted in significant restraint of tissue damage and in a marked functional recovery. Our data shed new light on themechanisms that propagate ongoing neuronal damage after ischemia in the adult mammalian brain and provide new moleculartargets for therapeutic intervention. Strategies aimed to repress the death-inducing ligands TRAIL, to antagonize the deathreceptors, or to activate the decoy receptors open new perspectives for the treatment of stroke.

Ischemic tolerance modulates TRAIL expression and its receptors and generates a neuroprotected phenotype

CANTARELLA, GIUSEPPINA;Di Benedetto G;PARENTI, Carmela;BERNARDINI, Renato
2014-01-01

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.
2014
TNF-related apoptosis inducing ligand (TRAIL), a member of the TNF superfamily released by microglia, appears to be involved inthe induction of apoptosis following focal brain ischemia. Indeed, brain ischemia is associated with progressive enlargement ofdamaged areas and prominent inflammation. As ischemic preconditioning reduces inflammatory response to brain ischemia andameliorates brain damage, the purpose of the present study was to evaluate the role of TRAIL and its receptors in stroke andischemic preconditioning and to propose, by modulating TRAIL pathway, a new therapeutic strategy in stroke. In order to achievethis aim a rat model of harmful focal ischemia, obtained by subjecting animals to 100 min of transient occlusion of middlecerebral artery followed by 24 h of reperfusion and a rat model of ischemic preconditioning in which the harmful ischemia waspreceded by 30 mins of tMCAO, which represents the preconditioning protective stimulus, were used. Results show that theneuroprotection elicited by ischemic preconditioning occurs through both upregulation of TRAIL decoy receptors anddownregulation of TRAIL itself and of its death receptors. As a counterproof, immunoneutralization of TRAIL in tMCAO animalsresulted in significant restraint of tissue damage and in a marked functional recovery. Our data shed new light on themechanisms that propagate ongoing neuronal damage after ischemia in the adult mammalian brain and provide new moleculartargets for therapeutic intervention. Strategies aimed to repress the death-inducing ligands TRAIL, to antagonize the deathreceptors, or to activate the decoy receptors open new perspectives for the treatment of stroke.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.11769/55304
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