In vivo evaluation of outer retinal function and structure after retrobulbar optic nerve crush by lateral orbitotomy in goats

Traumatic nerve injury activates cell stress pathways, resulting in neuronal death and loss of vital neural functions. To date, there are no available neuroprotectants for the treatment of traumatic neural injuries. Here, we studied three important flavanones of citrus components, in vitro and in vivo, to reveal their roles in inhibiting the JNK (c-Jun N-terminal kinase)-JUN pathway and their neuroprotective effects in the optic nerve crush injury model, a kind of traumatic nerve injury in the central nervous system. Results showed that both neural injury in vivo and cell stress in vitro activated the JNK-JUN pathway and increased JUN phosphorylation. We also demonstrated that naringenin treatment completely inhibited stress-induced JUN phosphorylation in cultured cells, whereas nobiletin and hesperidin only partially inhibited JUN phosphorylation. Neuroprotection studies in optic nerve crush injury mouse models revealed that naringenin treatment increased the survival of retinal ganglion cells after traumatic optic nerve injury, while the other two components had no neuroprotective effect. The neuroprotection effect of naringenin was due to the inhibition of JUN phosphorylation in crush-injured retinal ganglion cells. Therefore, the citrus component naringenin provides neuroprotection through the inhibition of the JNK-JUN pathway by inhibiting JUN phosphorylation, indicating the potential application of citrus chemical components in the clinical therapy of traumatic optic nerve injuries.

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Differential Effects of Immunophilin-Ligands (FK506 and V-10,367) on Survival and Regeneration of Rat Retinal Ganglion Cells In Vitro and after Optic Nerve Crush In Vivo

Journal of Neurotrauma ◽

10.1089/089771503321532888 ◽

2003 ◽

Vol 20 (3) ◽

pp. 297-307 ◽

Cited By ~ 20

Author(s):

Philip Rosenstiel ◽

Peter Schramm ◽

Stefan Isenmann ◽

Stefan Brecht ◽

Christian Eickmeier ◽

...

Keyword(s):

Optic Nerve ◽

Retinal Ganglion Cells ◽

Ganglion Cells ◽

Optic Nerve Crush ◽

Retinal Ganglion ◽

Nerve Crush ◽

Differential Effects

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Up-regulation of SKIP relates to retinal ganglion cells apoptosis after optic nerve crush in vivo

Journal of Molecular Histology ◽

10.1007/s10735-014-9589-9 ◽

2014 ◽

Vol 45 (6) ◽

pp. 715-721 ◽

Cited By ~ 6

Author(s):

Yu Wu ◽

Fan Xu ◽

Hui Huang ◽

Lifei Chen ◽

Meidan Wen ◽

...

Keyword(s):

Optic Nerve ◽

Retinal Ganglion Cells ◽

Ganglion Cells ◽

Optic Nerve Crush ◽

Retinal Ganglion ◽

Nerve Crush

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MEF2 transcription factors differentially contribute to retinal ganglion cell loss after optic nerve injury

PLoS ONE ◽

10.1371/journal.pone.0242884 ◽

2020 ◽

Vol 15 (12) ◽

pp. e0242884

Author(s):

Xin Xia ◽

Caroline Y. Yu ◽

Minjuan Bian ◽

Catalina B. Sun ◽

Bogdan Tanasa ◽

...

Keyword(s):

Transcription Factors ◽

Optic Nerve ◽

Nerve Injury ◽

Neuroprotective Effect ◽

Optic Nerve Crush ◽

Retinal Ganglion ◽

Post Translational Modification ◽

Optic Nerve Injury ◽

Nerve Crush

Loss of retinal ganglion cells (RGCs) in optic neuropathies results in permanent partial or complete blindness. Myocyte enhancer factor 2 (MEF2) transcription factors have been shown to play a pivotal role in neuronal systems, and in particular MEF2A knockout was shown to enhance RGC survival after optic nerve crush injury. Here we expanded these prior data to study bi-allelic, tri-allelic and heterozygous allele deletion. We observed that deletion of all MEF2A, MEF2C, and MEF2D alleles had no effect on RGC survival during development. Our extended experiments suggest that the majority of the neuroprotective effect was conferred by complete deletion of MEF2A but that MEF2D knockout, although not sufficient to increase RGC survival on its own, increased the positive effect of MEF2A knockout. Conversely, MEF2A over-expression in wildtype mice worsened RGC survival after optic nerve crush. Interestingly, MEF2 transcription factors are regulated by post-translational modification, including by calcineurin-catalyzed dephosphorylation of MEF2A Ser-408 known to increase MEF2A-dependent transactivation in neurons. However, neither phospho-mimetic nor phospho-ablative mutation of MEF2A Ser-408 affected the ability of MEF2A to promote RGC death in vivo after optic nerve injury. Together these findings demonstrate that MEF2 gene expression opposes RGC survival following axon injury in a complex hierarchy, and further support the hypothesis that loss of or interference with MEF2A expression might be beneficial for RGC neuroprotection in diseases such as glaucoma and other optic neuropathies.

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Effect of Brimonidine on Retinal Ganglion Cell Survival in an Optic Nerve Crush Model

Yearbook of Neurology and Neurosurgery ◽

10.1016/s0513-5117(09)79071-4 ◽

2009 ◽

Vol 2009 ◽

pp. 74-75

Author(s):

J. Leavitt

Keyword(s):

Optic Nerve ◽

Ganglion Cell ◽

Cell Survival ◽

Retinal Ganglion Cell ◽

Optic Nerve Crush ◽

Retinal Ganglion ◽

Nerve Crush ◽

Retinal Ganglion Cell Survival

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Blocking LINGO-1 in vivo reduces degeneration and enhances regeneration of the optic nerve

Multiple Sclerosis Journal - Experimental Translational and Clinical ◽

10.1177/2055217316641704 ◽

2016 ◽

Vol 2 ◽

pp. 205521731664170 ◽

Cited By ~ 1

Author(s):

Melissa M Gresle ◽

Yaou Liu ◽

Trevor J Kilpatrick ◽

Dennis Kemper ◽

Qi-Zhu Wu ◽

...

Keyword(s):

Optic Nerve ◽

Axonal Regeneration ◽

Antibody Therapy ◽

Experimental Models ◽

Therapeutic Effects ◽

Axonal Loss ◽

Nerve Crush ◽

Acute Optic Neuritis ◽

Injury Models

Background Two ongoing phase II clinical trials (RENEW and SYNERGY) have been developed to test the efficacy of anti-LINGO-1 antibodies in acute optic neuritis and relapsing forms of multiple sclerosis, respectively. Across a range of experimental models, LINGO-1 has been found to inhibit neuron and oligodendrocyte survival, axon regeneration, and (re)myelination. The therapeutic effects of anti-LINGO-1 antibodies on optic nerve axonal loss and regeneration have not yet been investigated. Objective In this series of studies we investigate if LINGO-1 antibodies can prevent acute inflammatory axonal loss, and promote axonal regeneration after injury in rodent optic nerves. Methods The effects of anti-LINGO-1 antibody on optic nerve axonal damage were assessed using rodent myelin oligodendrocyte glycoprotein experimental autoimmune encephalomyelitis (EAE), and its effects on axonal regeneration were assessed in optic nerve crush injury models. Results In the optic nerve, anti-LINGO-1 antibody therapy was associated with improved optic nerve parallel diffusivity measures on MRI in mice with EAE and reduced axonal loss in rat EAE. Both anti-LINGO-1 antibody therapy and the genetic deletion of LINGO-1 reduced nerve crush-induced axonal degeneration and enhanced axonal regeneration. Conclusion These data demonstrate that LINGO-1 blockade is associated with axonal protection and regeneration in the injured optic nerve.

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