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The Journal of Neuroscience, June 20, 2007, 27(25):6633-6646; doi:10.1523/JNEUROSCI.1091-07.2007

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Development/Plasticity/Repair
FLIP_L Protects Neurons against In Vivo Ischemia and In Vitro Glucose Deprivation-Induced Cell Death

Era Taoufik,¹ Samuel Valable,^2 * Georg J. Müller,^3 * Michael L. Roberts,^4 * Didier Divoux,² Antoine Tinel,⁵ Anda Voulgari-Kokota,¹ Vivian Tseveleki,¹ Fiorella Altruda,⁶ Hans Lassmann,³ Edwige Petit,² and Lesley Probert¹

¹Laboratory of Molecular Genetics, Hellenic Pasteur Institute, 11521 Athens, Greece, ²Universite de Caen, Unité Mixte de Recherche, Centre National de la Recherche Scientifique 6185, 14074 Caen, France, ³Division of Neuroimmunology, Brain Research Institute, A-1090 Vienna, Austria, ⁴Regulon, 17455 Athens, Greece, ⁵Institute of Biochemistry, University of Lausanne, CH-1066 Epalinges, Switzerland, and ⁶Dipartimento di Genetica, Biologia e Biochimica, Universita di Torino, 10126 Torino, Italy

Correspondence should be addressed to Lesley Probert, Laboratory of Molecular Genetics, Hellenic Pasteur Institute, 127 Vassilissis Sofias Avenue, 11521 Athens, Greece. Email: lesley_probert{at}hol.gr

Knowledge of the molecular mechanisms that underlie neuron death after stroke is important to allow the development of effective neuroprotective strategies. In this study, we investigated the contribution of death receptor signaling pathways to neuronal death after ischemia using in vitro and in vivo models of ischemic injury and transgenic mice that are deficient in tumor necrosis factor receptor I (TNFRI KO) or show neuron-specific overexpression of the long isoform of cellular Fas-associated death domain-like interleukin-1-ß-converting enzyme-inhibitory protein (FLIP_L). Caspase 8 was activated in brain lesions after permanent middle cerebral artery occlusion (pMCAO) and in cortical neurons subjected to glucose deprivation (GD) and was necessary for GD-induced neuron death. Thus, neurons treated with zIETD-FMK peptide or overexpressing a dominant-negative caspase 8 mutant were fully protected against GD-induced death. The presence of the neuroprotective TNFRI was necessary for selectively sustaining p50/p65NF-B activity and the expression of the p43 cleavage form of FLIP_L, FLIP(p43), an endogenous inhibitor of caspase 8, in pMCAO lesions and GD-treated neurons. Moreover, TNF pretreatment further upregulated p50/p65NF-B activity and FLIP(p43) expression in neurons after GD. The knock-down of FLIP in wild-type (WT) neurons using a short hairpin RNA revealed that FLIP_L is essential for TNF/TNFRI-mediated neuroprotection after GD. Furthermore, the overexpression of FLIP_L was sufficient to rescue TNFRI KO neurons from GD-induced death and to enhance TNF neuroprotection in WT neurons, and neuron-specific expression of FLIP_L in transgenic mice significantly reduced lesion volume after pMCAO. Our results identify a novel role for the TNFRI–NF-B–FLIP_L pathway in neuroprotection after ischemia and identify potential new targets for stroke therapy.

Key words: ischemia; neuroprotection; apoptosis; TNF receptor I; caspase 8; FLIP

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Received Oct. 4, 2006; revised April 17, 2007; accepted May 3, 2007.

Correspondence should be addressed to Lesley Probert, Laboratory of Molecular Genetics, Hellenic Pasteur Institute, 127 Vassilissis Sofias Avenue, 11521 Athens, Greece. Email: lesley_probert{at}hol.gr

This article has been cited by other articles:

				E. Taoufik, E. Petit, D. Divoux, V. Tseveleki, M. Mengozzi, M. L. Roberts, S. Valable, P. Ghezzi, J. Quackenbush, M. Brines, et al. TNF receptor I sensitizes neurons to erythropoietin- and VEGF-mediated neuroprotection after ischemic and excitotoxic injury PNAS, April 22, 2008; 105(16): 6185 - 6190. [Abstract] [Full Text] [PDF]

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