Retinal Neuronal Death Induced by Intraocular Administration of a Nitric Oxide Donor and Its Rescue by Neurotrophic Factors in Rats

Takahata, Kazue; Katsuki, Hiroshi; Kume, Toshiaki; Nakata, Daisuke; Ito, Ken; Muraoka, Susumu; Yoneda, Fumio; Kashii, Satoshi; Honda, Yoshio; Akaike, Akinori

doi:10.1167/iovs.02-0471

Cited by 64 publications

(45 citation statements)

References 33 publications

(37 reference statements)

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“…96 NT-4 normally activates tyrosine kinase-B receptor (TrkB) present in the RGCs and therefore is considered to play a protective role against high IOP, ischemia and release of cytotoxins. [97][98][99][100][101] According to Pasutto et al 47 , mutations in the NTF4 gene resulted in the impairment of TrkB signaling, as well as neuronal growth, and therefore, the NTF4 variants may have a significant effect on neuronal survival. They postulated that agents activating TrkB could therefore be a novel glaucoma treatment.…”

Section: Wdr36 At the Glc1g Locusmentioning

confidence: 99%

Current concepts on primary open-angle glaucoma genetics: a contribution to disease pathophysiology and future treatment

Gemenetzi

Yang

Lotery

2011

Eye

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Section: Wdr36 At the Glc1g Locusmentioning

confidence: 99%

Current concepts on primary open-angle glaucoma genetics: a contribution to disease pathophysiology and future treatment

Gemenetzi

Yang

Lotery

2011

Eye

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“…Interestingly, CNTF is effective in rescuing retinal degeneration due to various causes, including mutations in genes expressed by photoreceptors or the retinal pigment epithelium (RPE), as well as those induced by strong light, neurotoxins, or antibodies. In addition, CNTF prolongs the survival of retinal ganglion cells (3)(4)(5) and promotes axonal growth in optic nerve crush or transection models (6)(7)(8). Furthermore, CNTF may affect the physiology and survival of RPE cells (9,10), which are critical in normal vision and retinal degenerative diseases.…”

mentioning

confidence: 99%

CNTF-mediated protection of photoreceptors requires initial activation of the cytokine receptor gp130 in Müller glial cells

Rhee¹,

Nusinowitz²,

Chao³

et al. 2013

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

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Ciliary neurotrophic factor (CNTF) acts as a potent neuroprotective agent in multiple retinal degeneration animal models. Recently, CNTF has been evaluated in clinical trials for the inherited degenerative disease retinitis pigmentosa (RP) and for dry agerelated macular degeneration (AMD). Despite its potential as a broad-spectrum therapeutic treatment for blinding diseases, the target cells of exogenous CNTF and its mechanism of action remain poorly understood. We have shown previously that constitutive expression of CNTF prevents photoreceptor death but alters the retinal transcriptome and suppresses visual function. Here, we use a lentivirus to deliver the same secreted human CNTF used in clinical trials to a mouse model of RP. We found that low levels of CNTF halt photoreceptor death, improve photoreceptor morphology, and correct opsin mislocalization. However, we did not detect corresponding improvement of retinal function as measured by the electroretinogram. Disruption of the cytokine receptor gp130 gene in Müller glia reduces CNTF-dependent photoreceptor survival and prevents phosphorylation of STAT3 and ERK in Müller glia and the rest of the retina. Targeted deletion of gp130 in rods also demolishes neuroprotection by CNTF and prevents further activation of Müller glia. Moreover, CNTF elevates the expression of LIF and endothelin 2, thus positively promoting Müller and photoreceptor interactions. We propose that exogenous CNTF initially targets Müller glia, and subsequently induces cytokines acting through gp130 in photoreceptors to promote neuronal survival. These results elucidate a cellular mechanism for exogenous CNTF-triggered neuroprotection and provide insight into the complex cellular responses induced by CNTF in diseased retinas.C iliary neurotrophic factor (CNTF) belongs to a small subfamily of cytokines and has long been recognized as a potent neuroprotective molecule in the vertebrate retina (1). Enhancement of photoreceptor survival by CNTF has been demonstrated in multiple animal models of retinal degeneration, ranging from zebrafish to canine (2). Interestingly, CNTF is effective in rescuing retinal degeneration due to various causes, including mutations in genes expressed by photoreceptors or the retinal pigment epithelium (RPE), as well as those induced by strong light, neurotoxins, or antibodies. In addition, CNTF prolongs the survival of retinal ganglion cells (3-5) and promotes axonal growth in optic nerve crush or transection models (6-8). Furthermore, CNTF may affect the physiology and survival of RPE cells (9, 10), which are critical in normal vision and retinal degenerative diseases. Based on its significant and broad neuroprotective effects in damaged retinas, a secreted form of human CNTF delivered from an encapsulated cell device has been tested in clinical trials and approved by the Food and Drug Administration (FDA) to treat retinitis pigmentosa (RP) and geographic atrophy (GA), a subset of age-related macular degeneration (AMD) (11-14). However, despite its clinical signifi...

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“…4 RGC loss occurs in a regional fashion, similar to that seen in NAION. 7 RGC quantitation is typically performed by either ON-axonal counts, using transmission electron microscopy (TEM), 8 or direct RGC quantitation by serial step-cut sections, 9 retrograde RGC-labeling, 10 or RGC-specific immunostaining. 7,11,12 The latter two methods can quantify RGC numbers, and regional RGC loss patterns occurring in NAION, but require additional tissue preparation and specimen manipulation.…”

mentioning

confidence: 99%

Neuron Stress and Loss Following Rodent Anterior Ischemic Optic Neuropathy in Double-Reporter Transgenic Mice

Bernstein

Guo²,

Slater³

et al. 2007

Invest. Ophthalmol. Vis. Sci.

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PURPOSE.Nonarteritic anterior ischemic optic neuropathy (NAION) is an optic nerve infarct involving axons of retinal ganglion cell (RGC) neurons. The rodent NAION model (rAION) can use transgenic mouse strains to reveal unique characteristics about the effects of sudden optic nerve ischemia on RGCs and their axons. The impact of rAION on RGC stress patterns, RGC loss, and their axons after axonal infarct were evaluated. METHODS. A double-transgenic mouse strain was used, containing a construct with cyan fluorescent protein (CFP) under Thy-1 promoter control, and a construct with ␤-galactosidase (lacZ) linked to the stress gene c-fos promoter. Thy-1 in the retina is expressed predominantly in RGCs, enabling stereologic analysis of CFP(ϩ) RGC numbers and loss post-rAIONusing confocal microscopy. RGC loss was correlated with axonal counts using transmission electron microscopy (TEM). LacZ immunohistochemistry was used to evaluate retinal cell stress after rAION. RESULTS. The 45,000 CFP(ϩ) cells in the RGC layer of control animals compared with previous RGC quantitative estimates. rAION produced RGC stress, defined as lacZ expression, in patterns corresponding with later RGC loss. rAION-associated RGC loss correlated with regional nerve fiber layer loss. Axonal loss correlates with stereologically determined RGC loss estimates in transgenic mice retinas. CONCLUSIONS. Post-ON infarct RGC stress patterns correlate with regional RGC loss. Cellular lacZ levels in most RGCs are low, suggesting rAION-affected RGCs express c-fos only transiently. CFP(ϩ) cell loss correlates closely with quantitative axonal loss, suggesting that the Thy-1 (CFP) transgenic mouse strain is appropriate for RGC stereologic analyses. (Invest Ophthalmol Vis Sci. 2007;48:2304 -2310 1 Nonarteritic anterior ischemic optic neuropathy (NAION), is the most common form of sudden ON damage in the elderly.2 NAION results from sudden anterior ON-axonal ischemia (an optic nerve infarct). 3 The resultant axonal damage selectively causes RGC loss.We recently described a rodent model of NAION (rAION) in rats 4 and mice. 5 Intravenously administered rose bengal dye circulating through the anterior ON capillaries at the optic disc is photoactivated, using laser energy directed through the transparent ocular media, resulting in the generation of superoxide radicals that damage capillary vascular endothelium, 6 producing a photoembolic blockade of anterior ON capillary blood flow and ischemic axonopathy. The lesion produces selective RGC loss, manifested by decreased RGC numbers, ON scarring, and ON-axonal dropout.4 RGC loss occurs in a regional fashion, similar to that seen in NAION. 7RGC quantitation is typically performed by either ON-axonal counts, using transmission electron microscopy (TEM), 8 or direct RGC quantitation by serial step-cut sections, 9 retrograde RGC-labeling, 10 or RGC-specific immunostaining. 7,11,12 The latter two methods can quantify RGC numbers, and regional RGC loss patterns occurring in NAION, but require additional tissue preparation a...

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Retinal Neuronal Death Induced by Intraocular Administration of a Nitric Oxide Donor and Its Rescue by Neurotrophic Factors in Rats

Abstract: Exogenous NO induces retinal neurotoxicity, suggesting that NO plays a pathogenic role in degenerative retinal diseases. BDNF and CNTF protect retinal neurons from NO-mediated neurotoxicity.

Cited by 64 publications

References 33 publications

Current concepts on primary open-angle glaucoma genetics: a contribution to disease pathophysiology and future treatment

Current concepts on primary open-angle glaucoma genetics: a contribution to disease pathophysiology and future treatment

CNTF-mediated protection of photoreceptors requires initial activation of the cytokine receptor gp130 in Müller glial cells

Neuron Stress and Loss Following Rodent Anterior Ischemic Optic Neuropathy in Double-Reporter Transgenic Mice

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