NEUTRALIZATION OF TUMOR NECROSIS FACTOR RELATED APOPTOSIS INDUCING LIGAND (TRAIL) REDUCES SPINAL CORD INJURY DAMAGE IN MICE

Giuseppina Cantarella (1) , Giulia Di Benedetto (1) , Mimmo Scollo (1) , Irene Paterniti (1) , Salvatore Cuzzocrea (1) , Paolo Bosco (1) , Giuseppe Nocentini (1) , Carlo Riccardi (1) , Renato Bernardini (1)

1 Experimental and Clinical Pharmacology

Spinal cord injury (SCI) is a major cause of disability, its clinical outcome depending mostly upon the extent of damage where proapoptotic cytokines play a crucial role. In particular, the inducers of apoptosis belonging to TNF receptor superfamily and their respective ligands are upregulated after SCI. In this study, the role of the proapoptotic cytokine TRAIL in SCI-induced damage was investigated in the mouse. SCI resulted in severe trauma, characterized by prominent inflammation-related damage and apoptosis. Both inflammatory and Schwann's cells displayed immunostaining for TRAIL and its receptor DR5, in the white and grey matter of the peri-lesional area, as also confirmed by Western blotting experiments Immunoneutralization of TRAIL resulted in improved functional recovery, reduced apoptotic cell number, modulation of molecules involved in the inflammatory response (FasL, TNF-, IL-1 and MPO) and the corresponding signaling (caspase-8 and -3 activation, JNK phosphorylation, Bax and Bcl-2 expression). Since Glucocorticoid-Induced TNF receptor superfamily-related protein (GITR) activated by its ligand (GITRL) contributes to SCI-related inflammation, interactions between TRAIL and GITRL were investigated. SCI was associated with up-regulated GITR and GITRL expression, a phenomenon prevented by anti-TRAIL treatment. Moreover, the expression of both TRAIL and DR5 was reduced in tissues from mice lacking the GITR gene (GITR-/-) in comparison with wild type (WT) mice suggesting that TRAIL and GITRL activated pathways synergise in the development of SCI-related inflammatory damage. Characterization of new targets within such molecular systems may constitute a platform for innovative treatment of SCI.

Mots clés: Neurodegeneration/Neuroprotection; Animal models; Molecular & Cellular Neurobiology; Neuropharmacology; neuronal death; neuroinflammation; cytokines; immunoneutralization; GITR/GITRL

Giuseppina Cantarella, Giulia Di Benedetto, Mimmo Scollo, Irene Paterniti, Salvatore Cuzzocrea, et al.. NEUTRALIZATION OF TUMOR NECROSIS FACTOR RELATED APOPTOSIS INDUCING LIGAND (TRAIL) REDUCES SPINAL CORD INJURY DAMAGE IN MICE. Neuropsychopharmacology, 2010, n/a (n/a), pp.n/a-n/a. ⟨10.1038/npp.2009.234⟩. ⟨hal-00506038⟩