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

Bessero, Anne-Caroline; Chiodini, Florence; Rungger‐Brändle, Elisabeth; Bonny, Christophe; Clarke, Peter G. H.

doi:10.1111/j.1471-4159.2010.06705.x

Cited by 34 publications

(35 citation statements)

References 40 publications

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“…Several molecules, such as FADD/caspase8, MAPKs, and NF-jB have been proposed to be downstream of TNF-a in the apoptotic pathway (Andera, 2009). Studies have shown that NMDA induces phosphorylation of MAPKs (p-JNK and p-p38) and that the inhibition of its phosphorylation protects neural cells in the RGCL and the INL Bessero et al, 2010). According to these reports and the present study, there is a good possibility that thalidomide inhibits the phosphorylation of MAPKs with suppression of TNF-a as an upstream of these proteins.…”

Section: Discussionsupporting

confidence: 72%

Protective effect of thalidomide against N‐methyl‐D‐aspartate‐induced retinal neurotoxicity

Takada

Munemasa

Kuribayashi

et al. 2011

J of Neuroscience Research

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Thalidomide, an inhibitor of tumor necrosis factor-α (TNF-α) production, has been indicated to be useful for many inflammatory and oncogenic diseases. In the present study, we examined whether thalidomide (50 mg/kg/day, p.o.) has a protective effect against N-methyl-D-aspartate (NMDA)-induced retinal neurotoxicity in rats. A morphometric analysis showed that systemic administration of thalidomide protects neural cells in the ganglion cell layer (GCL) in a dose-dependent manner and significantly decreases the number of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)-positive cells in GCL and in the inner nuclear layer (INL). ELISA showed that thalidomide significantly suppressed the elevation of TNF-α 6 and 24 hr after an NMDA injection. Western blot analysis revealed a significant increase in nuclear factor-κB (NF-κB) p65 level in the retinas treated with NMDA at 24 hr after the injection, but not at 6 or 72 hr. Furthermore, an increase in p-JNK and p-p38 levels was also observed in the retina after NMDA injection. Thalidomide suppressed the increased expressions of NF-κB p65, p-JNK, and p-p38 after NMDA injection. Immunohistochemical analysis showed that thalidomide attenuated NF-κB p65 immunoreactivity in the GCL induced by NMDA treatment. In the NMDA-treated group, translocation of NF-κB p65 from the cytoplasm to the nucleus was detected in TUNEL-positive cells exposed to NMDA treatment. These results suggest new indications for thalidomide against neurodegenerative diseases.

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Section: Discussionsupporting

confidence: 72%

Protective effect of thalidomide against N‐methyl‐D‐aspartate‐induced retinal neurotoxicity

Takada

Munemasa

Kuribayashi

et al. 2011

J of Neuroscience Research

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“…S2A). Supporting the biological relevance of this finding, MKK7 and its homolog, MKK4, are the canonical activators of JNK1-3 (27), key regulators of RGC cell death (9)(10)(11)(12). As an additional validation that our siRNA finding was specifically a result of DLK pathway inhibition, RGCs were isolated from mice containing a floxed allele of Dlk (22) or wildtype controls and then transduced with adenovirus expressing the P1 bacteriophage Cre recombinase or a GFP control.…”

Section: Resultsmentioning

confidence: 54%

“…Moreover, it establishes the proof of principle for a whole-genome scan in primary RGCs to identify additional potential neuroprotective pathways and drug targets. Several previous studies have implicated the JNK pathway in both traumatic and glaucomatous models of optic neuropathy (9)(10)(11)(12). However, the mechanism by which axonal injury leads to JNK activation in RGC cell bodies has been unclear.…”

Section: Discussionmentioning

confidence: 99%

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Functional genomic screening identifies dual leucine zipper kinase as a key mediator of retinal ganglion cell death

Welsbie

Yang

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

237

307

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Glaucoma, a major cause of blindness worldwide, is a neurodegenerative optic neuropathy in which vision loss is caused by loss of retinal ganglion cells (RGCs). To better define the pathways mediating RGC death and identify targets for the development of neuroprotective drugs, we developed a high-throughput RNA interference screen with primary RGCs and used it to screen the full mouse kinome. The screen identified dual leucine zipper kinase (DLK) as a key neuroprotective target in RGCs. In cultured RGCs, DLK signaling is both necessary and sufficient for cell death. DLK undergoes robust posttranscriptional up-regulation in response to axonal injury in vitro and in vivo. Using a conditional knockout approach, we confirmed that DLK is required for RGC JNK activation and cell death in a rodent model of optic neuropathy. In addition, tozasertib, a small molecule protein kinase inhibitor with activity against DLK, protects RGCs from cell death in rodent glaucoma and traumatic optic neuropathy models. Together, our results establish a previously undescribed drug/drug target combination in glaucoma, identify an early marker of RGC injury, and provide a starting point for the development of more specific neuroprotective DLK inhibitors for the treatment of glaucoma, nonglaucomatous forms of optic neuropathy, and perhaps other CNS neurodegenerations.G laucoma is the leading cause of irreversible blindness worldwide (1). It is a neurodegenerative disease in which vision loss is caused by the axonal injury and death of retinal ganglion cells (RGCs) (2), the projection neurons that process and transmit vision from the retina to the brain. Current therapies (i.e., surgery, laser, and eye drops) all act by lowering intraocular pressure (IOP). However, pressure reduction can be difficult to achieve, and even with significant pressure lowering, RGC loss can continue. Efforts have therefore been made to develop neuroprotective agents that would complement IOP-lowering therapies by directly inhibiting the RGC cell death process (3, 4). However, no neuroprotective agent has yet been approved for clinical use.Protein kinases provide attractive targets for the development of neuroprotective agents. A number of kinases, including cyclindependent kinases, death-associated protein kinases, JNK1-3, MAPKs, and glycogen synthase kinase-3β, are involved in neuronal cell death (5-12). An additional attraction is that protein kinases are readily druggable. The pharmacology and medicinal chemistry of kinase inhibitors are well-developed, with kinases now being the most important class of drug targets after G protein-coupled receptors (13). Although the primary clinical use of kinase inhibitors continues to be as antineoplastic agents, increasing attention is being paid to their use in other areas (14,15).To identify, in a comprehensive and unbiased manner, kinases that could serve as targets for neuroprotective glaucoma therapy, we screened the entire mouse kinome for kinases whose inhibition promotes RGC survival. For this screen, we develope...

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“…In contrast to protein tyrosine kinases that promote neuronal survival, there are several pro-apoptotic protein kinases that contribute to RGC death, such as the c-Jun N-terminal kinase. 84 c-Jun, activated by c-Jun N-terminal kinase phosphorylation, mediates transcription of pro-apoptotic genes and has been shown to be upregulated in rat and monkey models of glaucoma. 85,86 siRNA-mediated gene expression knockdown of c-Jun in RGCs resulted in a threefold increase in RGC survival at 2 weeks after optic nerve lesion.…”

Section: Inhibition Of Apoptotic Pathways and Manipulation Of Mitochomentioning

confidence: 99%

Gene therapy for retinal ganglion cell neuroprotection in glaucoma

Wilson

Polo

2011

Gene Ther

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Glaucoma is the leading cause of irreversible blindness worldwide. The primary cause of glaucoma is not known, but several risk factors have been identified, including elevated intraocular pressure and age. Loss of vision in glaucoma is caused by the death of retinal ganglion cells (RGCs), the neurons that convey visual information from the retina to the brain. Therapeutic strategies aimed at delaying or halting RGC loss, known as neuroprotection, would be valuable to save vision in glaucoma. In this review, we discuss the significant progress that has been made in the use of gene therapy to understand mechanisms underlying RGC degeneration and to promote the survival of these neurons in experimental models of optic nerve injury. Gene Therapy (2012) 19, 127-136; doi:10.1038/gt.2011; published online 6 October 2011Keywords: retinal ganglion cell; neuroprotection; glaucoma NEUROPROTECTION IN GLAUCOMA: RATIONALE AND CURRENT LIMITATIONS Adult-onset glaucoma is an optic neuropathy that affects more than 50 million people around the world, with 47 million having bilateral (both eyes) blindness due to this disease. As more effective diagnostic tools become available, the number of cases is expected to rise, and a recent study predicts that there will be 70 million people with glaucoma in 2020. 1 Glaucoma is considered to be a group of diseases characterized by progressive optic nerve degeneration that results in visual field loss and irreversible blindness. The cause of glaucoma is unknown, but several risk factors have been identified, including high intraocular pressure, age and genetic predisposition. Open angle and angle-closure glaucoma, the most common forms of the disease, are often associated with high intraocular pressure. A crucial element in the pathophysiology of all forms of glaucoma is the death of retinal ganglion cells (RGCs; Figure 1) and, as these are central nervous system neurons, their loss is irreversible. At present, there is no cure for glaucoma, and the standard treatment is to lower intraocular pressure by medication or surgery. However, a significant proportion of patients continue to experience visual loss even when pharmacological treatments effectively reduce eye pressure. Therefore, novel therapeutic approaches are needed for its treatment and management.Early-onset glaucoma, comprising primary congenital glaucoma and juvenile open-angle glaucoma, has a clear genetic basis. Between 10 and 30% of individuals with juvenile open-angle glaucoma have mutations in the gene encoding myocilin, 2,3 and, on average, B40% of people with primary congenital glaucoma have mutations in the gene encoding cytochrome P450 protein. 4 Both genes are expressed in the trabecular meshwork and ciliary body, and defects in these genes may cause ocular hypertension. The elucidation of the genetic basis underlying adult-onset glaucoma is difficult because the late onset of disease limits the number of individuals available for linkage analysis. However, at least 29 genetic loci for various forms of glaucoma and 12...

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

Cited by 34 publications

References 40 publications

Protective effect of thalidomide against N‐methyl‐D‐aspartate‐induced retinal neurotoxicity

Protective effect of thalidomide against N‐methyl‐D‐aspartate‐induced retinal neurotoxicity

Functional genomic screening identifies dual leucine zipper kinase as a key mediator of retinal ganglion cell death

Gene therapy for retinal ganglion cell neuroprotection in glaucoma

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