1. ¹Département de Biologie cellulaire et de Morphologie, Université de Lausanne, CH-1005 Lausanne, Switzerland
2. ²Département de Physiologie, Université de Lausanne, CH-1005 Lausanne, Switzerland
3. ³Centre des Neurosciences Psychiatriques, Hôpital Psychiatrique, CERY, CH-1008 Prilly, Switzerland
4. ⁴Service of Medical Genetics, Centre Hospitalier Universitaire Vaudois, CH- 1011 Lausanne, Switzerland
5. ⁵Department of Internal Medicine, Centre Hospitalier Universitaire Vaudois, CH-1011 Lausanne, Switzerland
6. ⁶The Ben May Institute for Cancer Research, The University of Chicago, 924 East 57th Street, Chicago, IL 60637, USA
7. ⁷Istituto di ricerche Farmacologiche 'Mario Negri', Via Eritrea 62, Milano 20157, Italy

Correspondence: T Borsello, Départment de Biologie Cellulaire et de Morphologie, Université de Lausanne, CH-1005 Lausanne, Switzerland. Tel: +41-21-692-5277; Fax: +41-21-692-5105; E-mail: Tiziana.Borsello@unil.ch or Biol. Neurodeg. Disorders Laboratory, Istituto di ricerche Farmacologiche 'Mario Negri', Via Eritrea 62, Milano 20157, Italy. Tel: +39-02-39014469/39014592; Fax: +39-02-3546277; E-mail: borsello@marionegri.it

⁸These authors contributed equally to this work

Received 4 April 2006; Revised 8 May 2006; Accepted 9 May 2006; Published online 23 June 2006.

Abstract

Excitotoxic insults induce c-Jun N-terminal kinase (JNK) activation, which leads to neuronal death and contributes to many neurological conditions such as cerebral ischemia and neurodegenerative disorders. The action of JNK can be inhibited by the D-retro-inverso form of JNK inhibitor peptide (D-JNKI1), which totally prevents death induced by N-methyl-D-aspartate (NMDA) in vitro and strongly protects against different in vivo paradigms of excitotoxicity. To obtain optimal neuroprotection, it is imperative to elucidate the prosurvival action of D-JNKI1 and the death pathways that it inhibits. In cortical neuronal cultures, we first investigate the pathways by which NMDA induces JNK activation and show a rapid and selective phosphorylation of mitogen-activated protein kinase kinase 7 (MKK7), whereas the only other known JNK activator, mitogen-activated protein kinase kinase 4 (MKK4), was unaffected. We then analyze the action of D-JNKI1 on four JNK targets containing a JNK-binding domain: MAPK-activating death domain-containing protein/differentially expressed in normal and neoplastic cells (MADD/DENN), MKK7, MKK4 and JNK-interacting protein-1 (IB1/JIP-1).