Specific inhibition of the JNK pathway promotes locomotor recovery and neuroprotection after mouse spinal cord injury Mariaelena Repici a, b, 1 , Xiaoru Chen a, b , Marie-Pierre Morel a, b , Mohamed Doulazmi a, b , Alessandra Sclip c , Vidjeacoumary Cannaya a, b , Pietro Veglianese c , Rudolf Kraftsik d , Jean Mariani a, b, e , Tiziana Borsello c, 2 , Isabelle Dusart a, b, ⁎ , 2 a UPMC Univ Paris 06, UMR 7102, Paris, France b CNRS, UMR 7102, Paris, France c Neuronal Death and Neuroprotection Lab, Neuroscience Department, Istituto Di Ricerche Farmacologiche “Mario Negri”, Via la Masa 19, 20156 Milano, Italy d Department of Cell Biology and Morphology (DBCM), University of Lausanne, Lausanne, Switzerland e Hôpital Charles-Foix, Institut de la Longévité, Ivry, France abstract article info Article history: Received 10 August 2011 Revised 31 January 2012 Accepted 1 March 2012 Available online 9 March 2012 Keywords: JNK c-jun Caspase-3 Spinal cord injury Neuroprotection Locomotor recovery Limiting the development of secondary damage represents one of the major goals of neuroprotective thera- pies after spinal cord injury. Here, we demonstrate that specific JNK inhibition via a single intraperitoneal in- jection of the cell permeable peptide D-JNKI1 6 h after lesion improves locomotor recovery assessed by both the footprint and the BMS tests up to 4 months post-injury in mice. JNK inhibition prevents c-jun phosphor- ylation and caspase-3 cleavage, has neuroprotective effects and results in an increased sparing of white mat- ter at the lesion site. Lastly, D-JNKI1 treated animals show a lower increase of erythrocyte extravasation and blood brain barrier permeability, thus indicating protection of the vascular system. In total, these results clearly point out JNK inhibition as a promising neuroprotective strategy for preventing the evolution of sec- ondary damage after spinal cord injury. © 2012 Elsevier Inc. All rights reserved. Introduction Owing to the profound impact of spinal cord injury (SCI), exten- sive studies have been aimed at identifying therapeutic interventions following injury. Recent advances in the basic science of axonal re- generation have provided new expectancies for the prevention and cure of SCI devastating effects (Rossignol et al., 2007). Indeed, major efforts are being made to enhance spinal cord axonal regeneration through a variety of techniques including neutralization of neurite growth inhibitors, administration of neurotrophic factors, and trans- plantation of a variety of cell types (Hyun and Kim, 2010; Tator, 2006). It is also important to identify new strategies to protect neu- rons from secondary cell death, as in animal models and in human le- sions the final tissue damage after SCI is much larger than the primary lesion's size, due to a variety of processes that determine the so called secondary damage. During the hours following the first injury, cas- cades of several secondary processes such as hypoxia, ATP depletion, glutamate excitotoxicity, production of free radicals and apoptosis, take place and greatly increase the size of the primary lesion (Liu et al., 1997). The mechanisms underlying secondary damage are still poorly understood and efficient treatments dedicated to restrain it re- main to be discovered. c-Jun-N-terminal kinase (JNK) activation has been involved in many kinds of cell death and mediates stress-induced cellular events (Davis, 2000). Genomics approaches reported an up regulation of c- jun transcription at 1, 24 and 48 h following SCI (Bareyre and Schwab, 2003). An activation of JNK starting at 1 h and persisting for 3 days (Li et al., 2007) and a similar time-course of c-jun activation have also been shown in SCI (Yin et al., 2005), while JNK activity inhi- bition before the injury is able to attenuate the induction of the pro- apoptotic protein DP5 and the activation of caspase-3. Furthermore, JNK3 activation is critical for apoptosis of oligodendrocytes after spi- nal cord injury (Li et al., 2007) and a reduction of JNK activation in ol- igodendrocytes might account for the neuroprotective effect of the adenosine A2A receptor agonist in a model of T5-T8 laminectomy in mice (Genovese et al., 2009; Paterniti et al., 2011). Recently, it has also been shown that the neutralization of tumor necrosis factor re- lated apoptosis-inducing ligand (TRAIL) results in a reduction of JNK Neurobiology of Disease 46 (2012) 710–721 ⁎ Corresponding author at: Equipe Différenciation Neuronale et Gliale, NPA UMR7102, Université Pierre et Marie Curie, Bat B, 6eme, Case 12, 9 Quai Saint Bernard, 75005, Paris. Fax: +33 1 44 27 26 69. E-mail address: isabelle.dusart@upmc.fr (I. Dusart). 1 Present address: Department of Genetics, University of Leicester, Leicester, UK. 2 These authors have contributed equivalently to the work. Available online on ScienceDirect (www.sciencedirect.com). 0969-9961/$ – see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.nbd.2012.03.014 Contents lists available at SciVerse ScienceDirect Neurobiology of Disease journal homepage: www.elsevier.com/locate/ynbdi