Role of the c‐Jun N‐terminal kinase pathway in retinal excitotoxicity, and neuroprotection by its inhibition

• Published in: Journal of neurochemistry 2010-06, Vol.113 (5), p.1307-1318
• Main Authors: Bessero, Anne‐Caroline, Chiodini, Florence, Rungger‐Brändle, Elisabeth, Bonny, Christophe, Clarke, Peter G. H.
• Format: Article
• Language: English
• Subjects: Adaptation, Ocular; amacrine cells; Animals; Biological and medical sciences; Blotting, Western; Calpain - physiology; Carrier Proteins - metabolism; Cell Count; Cell Death - drug effects; Cell Death - physiology; Cell physiology; d‐form of JNK‐inhibitor 1; electroretinogram; Electroretinography; Enzyme Inhibitors - pharmacology; Excitatory Amino Acid Agonists - administration & dosage; Excitatory Amino Acid Agonists - toxicity; Eye and associated structures. Visual pathways and centers. Vision; Fundamental and applied biological sciences. Psychology; Immunohistochemistry; Injections; JNK Mitogen-Activated Protein Kinases - antagonists & inhibitors; JNK Mitogen-Activated Protein Kinases - physiology; Male; Microfilament Proteins - metabolism; Molecular and cellular biology; N-Methylaspartate - administration & dosage; N-Methylaspartate - toxicity; Neurons; Neuroprotective Agents; NMDA; Rats; Rats, Sprague-Dawley; Retina; Retina - drug effects; Retina - pathology; Retina - physiology; Retinal Diseases - chemically induced; Retinal Diseases - pathology; retinal ganglion cells; Signal transduction; Signal Transduction - drug effects; Signal Transduction - physiology; Vertebrates: nervous system and sense organs; Vitreous Body
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2010.06705.x

J. Neurochem. (2010) 113, 1307–1318. Retinal excitotoxicity is associated with retinal ischemia, and with glaucomatous and traumatic optic neuropathy. The present study investigates the role of c‐Jun N‐terminal kinase (JNK) activation in NMDA‐mediated retinal excitotoxicity and determines whether neuroprotection can be obtained with the JNK pathway inhibitor, d‐form of JNK‐inhibitor 1 (d‐JNKI‐1). Young adult rats received intravitreal injections of 20 nmol NMDA, which caused extensive neuronal death in the inner nuclear and ganglion cell layers. This excitotoxicity was associated with strong activation of calpain, as revealed by fodrin cleavage, and of JNK. The cell‐permeable peptide d‐JNKI‐1 was used to inhibit JNK. Within 40 min of its intravitreal injection, FITC‐labeled d‐JNKI‐1 spread through the retinal ganglion cell layer into the inner nuclear layer and interfered with the NMDA‐induced phosphorylation of JNK. Injections of unlabeled d‐JNKI‐1 gave unprecedentedly strong neuroprotection against cell death in both layers, lasting for at least 10 days. The NMDA‐induced calpain‐specific fodrin cleavage was likewise strongly inhibited by d‐JNKI‐1. Moreover the electroretinogram was partially preserved by d‐JNKI‐1. Thus, the JNK pathway is involved in NMDA‐mediated retinal excitotoxicity and JNK inhibition by d‐JNKI‐1 provides strong neuroprotection as shown morphologically, biochemically and physiologically.