From Ganglion Cell to Photoreceptor Layer: Timeline of Deterioration in a Rat Ischemia/Reperfusion Model

Palmhof, Marina; Frank, Viktoria; Rappard, Pascal; Kortenhorn, Emely; Demuth, Julia; Biert, Nora; Stute, Gesa; Dick, H. Burkhard; Joachim, Stephanie C.

doi:10.3389/fncel.2019.00174

Cited by 57 publications

(70 citation statements)

References 53 publications

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“…Chronic hypoxia has been shown to cause loss of retinal neurons; including RGCs and amacrine cells [68][69][70][71] . However, in glaucoma, neurodegeneration is specific to RGCs and does not affect other retinal neurons, such as amacrine cells 72 .…”

Section: Edn1 Did Not Cause Loss Of Amacrine Cells or Müller Gliamentioning

confidence: 99%

Endothelin 1-induced retinal ganglion cell death is largely mediated by JUN activation

et al. 2020

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Glaucoma is a neurodegenerative disease characterized by loss of retinal ganglion cells (RGCs), the output neurons of the retina. Multiple lines of evidence show the endothelin (EDN, also known as ET) system is important in glaucomatous neurodegeneration. To date, the molecular mechanisms within RGCs driving EDN-induced RGC death have not been clarified. The pro-apoptotic transcription factor JUN (the canonical target of JNK signaling) and the endoplasmic reticulum stress effector and transcription factor DNA damage inducible transcript 3 (DDIT3, also known as CHOP) have been shown to act downstream of EDN receptors. Previous studies demonstrated that JUN and DDIT3 were important regulators of RGC death after glaucoma-relevant injures. Here, we characterized EDN insult in vivo and investigated the role of JUN and DDIT3 in EDN-induced RGC death. To accomplish this, EDN1 ligand was intravitreally injected into the eyes of wildtype, Six3-cre+Junfl/fl (Jun−/−), Ddit3 null (Ddit3−/−), and Ddit3−/−Jun−/− mice. Intravitreal EDN1 was sufficient to drive RGC death in vivo. EDN1 insult caused JUN activation in RGCs, and deletion of Jun from the neural retina attenuated RGC death after EDN insult. However, deletion of Ddit3 did not confer significant protection to RGCs after EDN1 insult. These results indicate that EDN caused RGC death via a JUN-dependent mechanism. In addition, EDN signaling is known to elicit potent vasoconstriction. JUN signaling was shown to drive neuronal death after ischemic insult. Therefore, the effects of intravitreal EDN1 on retinal vessel diameter and hypoxia were explored. Intravitreal EDN1 caused transient retinal vasoconstriction and regions of RGC and Müller glia hypoxia. Thus, it remains a possibility that EDN elicits a hypoxic insult to RGCs, causing apoptosis via JNK-JUN signaling. The importance of EDN-induced vasoconstriction and hypoxia in causing RGC death after EDN insult and in models of glaucoma requires further investigation.

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Section: Edn1 Did Not Cause Loss Of Amacrine Cells or Müller Gliamentioning

confidence: 99%

Endothelin 1-induced retinal ganglion cell death is largely mediated by JUN activation

et al. 2020

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“…Vascular occlusions of the retina, including arterial and venous obstructions, are among the most frequent causes of vision loss . During ischaemia of the inner retina, a large number of different cell types are affected, out of those the RGC represent the most sensitive population, usually die first . As with all neurons, regeneration is not possible.…”

Section: Introductionmentioning

confidence: 99%

iNOS‐inhibitor driven neuroprotection in a porcine retina organ culture model

Hurst

Mueller‐Buehl

Hofmann

et al. 2020

J Cellular Molecular Medi

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Since 1995, 11 million animals per year were used for research purposes in the EU, an average of 2.5 million in Germany alone, with an upward trend. 1 Ophthalmological research also frequently uses laboratory animals. An important field of research is the understanding of retinal degeneration, as its causes are not yet fully understood preventing successful treatment.In the last years, we developed retinal organ culture models, to test new therapies without euthanasia of laboratory animals. [2][3][4][5] These models are based on porcine retinae, which can be obtained as a waste product from the food industry. The morphology and AbstractNitrite oxide plays an important role in the pathogenesis of various retinal diseases, especially when hypoxic processes are involved. This degeneration can be simulated by incubating porcine retinal explants with CoCl 2 . Here, the therapeutic potential of iNOS-inhibitor 1400W was evaluated. Degeneration through CoCl 2 and treatment with the 1400W were applied simultaneously to porcine retinae explants.Three groups were compared: control, CoCl 2 , and CoCl 2 + iNOS-inhibitor (1400W).At days 4 and 8, retinal ganglion cells (RGCs), bipolar, and amacrine cells were analysed. Furthermore, the influence on the glia cells and different stress markers were evaluated. Treatment with CoCl 2 resulted in a significant loss of RGCs already after 4 days, which was counteracted by the iNOS-inhibitor. Expression of HIF-1α and its downstream targets confirmed the effective treatment with 1400W. After 8 days, the CoCl 2 group displayed a significant loss in amacrine cells and also a drastic reduction in bipolar cells was observed, which was prevented by 1400W. The decrease in microglia could not be prevented by the inhibitor. CoCl 2 induces strong degeneration in porcine retinae by mimicking hypoxia, damaging certain retinal cell types.Treatment with the iNOS-inhibitor counteracted these effects to some extent, by preventing loss of retinal ganglion and bipolar cells. Hence, this inhibitor seems to be a very promising treatment for retinal diseases. K E Y W O R D S hypoxia, iNOS-inhibitor 1400W, organ culture, retina, retinal ganglion cells | 4313 HURST eT al. How to cite this article: Hurst J, Mueller-Buehl AM, Hofmann L, et al. iNOS-inhibitor driven neuroprotection in a porcine retina organ culture model. J Cell Mol Med. 2020;24:4312-4323. https://doi.

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“…The RCGs are the first cells from the retina that suffer from hypoxia. After a very short time of arterial occlusion, there is already an irreversible loss of these cells . To this end, we want to investigate, if a rather simple approach as cooling might have neuroprotective effects on the neuro‐retina, which might delay the loss of RGCs.…”

Section: Introductionmentioning

confidence: 99%

Hypothermia protects retinal ganglion cells against hypoxia‐induced cell death in a retina organ culture model

Klemm

Hurst

Blak

et al. 2019

Clinical Exper Ophthalmology

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Background Hypoxia contributes to retinal damage in several retinal diseases, including central retinal artery occlusion, with detrimental consequences like painless, monocular loss of vision. Currently, the treatment options are severely limited due to the short therapy window, as the neuronal cells, especially the retinal ganglion cells (RGCs), are irreversibly damaged within the first few hours. Hypothermia might be a possible treatment option or at least might increase the therapy window. Methods To investigate the neuroprotective effect of hypothermia after retinal hypoxia, an easy‐to‐use ex vivo retinal hypoxia organ culture model developed in our laboratory was used that reliably induced retinal damage on a structural, molecular and functional level. The neuroprotective effect of hypothermia after retinal hypoxia was analysed using optical coherence tomography scans, histological stainings, quantitative real‐time polymerase chain reaction, western blotting and microelectrode array recordings. Results Two different hypothermic temperatures (30°C and 20°C) were evaluated, both exhibited strong neuroprotective effects. Most importantly, hypothermia increased RGC survival after retinal hypoxia. Furthermore, hypothermia counteracted the hypoxia‐induced RGC death, reduced macroglia activation, attenuated retinal thinning and protected from loss of spontaneous RGC activity. Conclusions These results indicate that already a mild reduction in temperature protects the RGCs against damage and could function as a promising therapeutic option for hypoxic diseases.

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From Ganglion Cell to Photoreceptor Layer: Timeline of Deterioration in a Rat Ischemia/Reperfusion Model

Cited by 57 publications

References 53 publications

Endothelin 1-induced retinal ganglion cell death is largely mediated by JUN activation

Endothelin 1-induced retinal ganglion cell death is largely mediated by JUN activation

iNOS‐inhibitor driven neuroprotection in a porcine retina organ culture model

Hypothermia protects retinal ganglion cells against hypoxia‐induced cell death in a retina organ culture model

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