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

被引：36

作者：

Bessero, Anne-Caroline ^{[1
,2
]}

Chiodini, Florence ^{[3
]}

Rungger-Braendle, Elisabeth ^{[3
]}

Bonny, Christophe ^{[4
]}

Clarke, Peter G. H. ^{[1
]}

机构：

[1] Univ Lausanne, DBCM, Lausanne, Switzerland

[2] Univ Lausanne, Jules Gonin Eye Hosp, Lausanne, Switzerland

[3] Univ Eye Clin, Cell Biol Lab, Geneva, Switzerland

[4] CHUV Univ Hosp, Div Med Genet, Lausanne, Switzerland

来源：

JOURNAL OF NEUROCHEMISTRY | 2010年 / 113卷 / 05期

基金：

瑞士国家科学基金会;

关键词：

amacrine cells; d-form of JNK-inhibitor 1; electroretinogram; neurons; NMDA; retinal ganglion cells; ADULT-RAT RETINA; ASPARTATE-INDUCED EXCITOTOXICITY; NMDA-INDUCED NEUROTOXICITY; ACTIVATED PROTEIN-KINASES; GANGLION-CELLS; IN-VIVO; PEPTIDE INHIBITOR; CEREBRAL-ISCHEMIA; B-WAVE; ELECTRORETINOGRAM;

D O I：

10.1111/j.1471-4159.2010.06705.x

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

P>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.

引用

页码：1307 / 1318

页数：12