A Nicotinic Acetylcholine Receptor Agonist Prevents Loss of Retinal Ganglion Cells in a Glaucoma Model

Iwamoto, Kazuhiro; Birkholz, Patrick J.; Schipper, Austin; Mata, David; Linn, David M.; Linn, Cindy L.

doi:10.1167/iovs.13-12688

Cited by 38 publications

(56 citation statements)

References 38 publications

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“…Previous studies from this lab have demonstrated that intravitreal injections or eye drop application of the α7 nAChR agonist, PNU-282987, in an in vivo rat model prevented the loss of RGCs normally associated with a procedure to induce glaucoma-like conditions (Iwamoto et al, 2014; Mata et al, 2015). However, these same studies also demonstrated that application of the α7 nAChR agonist significantly increased the number of RGCs in the adult retina compared to internal controls, suggesting proliferation of new RGCs.…”

Section: Introductionmentioning

confidence: 93%

Evidence of BrdU-positive retinal neurons after application of an Alpha7 nicotinic acetylcholine receptor agonist

et al. 2017

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Irreversible vision loss due to disease or age is responsible for a reduced quality of life. The experiments in this study test the hypothesis that the α7 nicotinic acetylcholine receptor agonist, PNU-282987, leads to the generation of retinal neurons in an adult mammalian retina in the absence of retinal injury or exogenous growth factors. Using antibodies against BrdU, retinal ganglion cells, progenitor cells and Müller glia, the results of this study demonstrate that multiple types of retinal cells and neurons are generated after eye drop application of PNU-282987 in adult Long Evans rats in a dose-dependent manner. The results of this study provide evidence that progenitor cells, derived from Müller glia after treatment with PNU-282987, differentiate and migrate to the photoreceptor and retinal ganglion cell layers. If retinas were treated with the alpha7 nAChR antagonist, methyllycaconitine, before agonist treatment, BrdU positive cells were significantly reduced. As adult mammalian neurons do not typically regenerate or proliferate, these results have implications for reversing vision loss due to neurodegenerative disease or the aging process to improve the quality of life for millions of patients.

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Section: Introductionmentioning

confidence: 93%

Evidence of BrdU-positive retinal neurons after application of an Alpha7 nicotinic acetylcholine receptor agonist

et al. 2017

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“…As the distribution of RGCs is uneven in different regions of the rat retina, images are obtained from four 200 µm 2 regions in each retina, 4 mm away from the center of the optic nerve head. The total number of Thy 1.1 labeled RGCs in each section are counted, averaged and compared in experimental and control retinas 31 . Using this method, RGC counts changed from an average of 225 in an image of control untreated conditions to 168 one month after the procedure to induce glaucoma-like conditions (N = 30).…”

Section: Representative Resultsmentioning

confidence: 99%

“…Only then can researchers hope to devise a way to protect retinal ganglion cells from dying. The procedure described in this paper uses an artificially induced elevation of IOP to produce a gradual, irreversible loss of retinal ganglion cells similar to that seen in glaucoma patients 31 . The procedure is minimally invasive.…”

Section: Representative Resultsmentioning

confidence: 99%

“…To support this, all future studies could modify the procedure to include routine IOP measurements to ensure that these injections lead to a measurable increase in IOP. 29,31 . Perhaps this model of RGC death will lead to the development of a more complete neuroprotective treatment that combats the devastating visual loss affecting millions of people worldwide.…”

Section: Representative Resultsmentioning

confidence: 99%

“…In this procedure, injections of 2 M hypertonic saline into the episcleral venous plexus induces glaucoma-like conditions by scarring tissue to reduce aqueous humor outflow in the trabecular meshwork leading to an increase in intraocular pressure and a significant loss of RGCs within one month of the procedure [30][31] . Glaucoma-inducing procedures, such as the one described here, may be the key to unlocking new developments in glaucoma treatments.…”

Section: Introductionmentioning

confidence: 99%

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Glaucoma-inducing Procedure in an <em>In Vivo </em>Rat Model and Whole-mount Retina Preparation

Gossman

Linn

2016

JoVE

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Glaucoma is a disease of the central nervous system affecting retinal ganglion cells (RGCs). RGC axons making up the optic nerve carry visual input to the brain for visual perception. Damage to RGCs and their axons leads to vision loss and/or blindness. Although the specific cause of glaucoma is unknown, the primary risk factor for the disease is an elevated intraocular pressure. Glaucoma-inducing procedures in animal models are a valuable tool to researchers studying the mechanism of RGC death. Such information can lead to the development of effective neuroprotective treatments that could aid in the prevention of vision loss. The protocol in this paper describes a method of inducing glaucomalike conditions in an in vivo rat model where 50 µl of 2 M hypertonic saline is injected into the episcleral venous plexus. Blanching of the vessels indicates successful injection. This procedure causes loss of RGCs to simulate glaucoma. One month following injection, animals are sacrificed and eyes are removed. Next, the cornea, lens, and vitreous are removed to make an eyecup. The retina is then peeled from the back of the eye and pinned onto sylgard dishes using cactus needles. At this point, neurons in the retina can be stained for analysis. Results from this lab show that approximately 25% of RGCs are lost within one month of the procedure when compared to internal controls. This procedure allows for quantitative analysis of retinal ganglion cell death in an in vivo rat glaucoma model. Video LinkThe video component of this article can be found at

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Amacrine cells coupled to ganglion cells via gap junctions are highly vulnerable in glaucomatous mouse retinas

Akopian

Kumar

Ramakrishnan

et al. 2016

J of Comparative Neurology

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We determined whether the structural and functional integrity of amacrine cells (ACs), the largest cohort of neurons in the mammalian retina, are affected in glaucoma. Intraocular injection of microbeads was made in mouse eyes to elevate intraocular pressure as a model of experimental glaucoma. Specific immunocytochemical markers were used to identify AC and displaced (d)ACs subpopulations in both the inner nuclear and ganglion cell layers, respectively, and to distinguish them from retinal ganglion cells (RGCs). Calretinin- and γ-aminobutyric acid (GABA)-immunoreactive (IR) cells were highly vulnerable to glaucomatous damage, whereas choline acetyltransferase (ChAT)-positive and glycinergic AC subtypes were unaffected. The AC loss began 4 weeks after initial microbead injection, corresponding to the time course of RGC loss. Recordings of electroretinogram (ERG) oscillatory potentials and scotopic threshold responses, which reflect AC and RGC activity, were significantly attenuated in glaucomatous eyes following a time course that matched that of the AC and RGC loss. Moreover, we found that it was the ACs coupled to RGCs via gap junctions that were lost in glaucoma, whereas uncoupled ACs were largely unaffected. Our results suggest that AC loss in glaucoma occurs secondary to RGC death through the gap junction-mediated bystander effect. J. Comp. Neurol., 2016. © 2016 Wiley Periodicals, Inc.

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A Nicotinic Acetylcholine Receptor Agonist Prevents Loss of Retinal Ganglion Cells in a Glaucoma Model

Abstract: The results from this study support the hypothesis that the α7 agonist, PNU-282987, has a neuroprotective effect in the rat retina. PNU-282987 may be a viable candidate for future therapeutic treatments of glaucoma.

Cited by 38 publications

References 38 publications

Evidence of BrdU-positive retinal neurons after application of an Alpha7 nicotinic acetylcholine receptor agonist

Evidence of BrdU-positive retinal neurons after application of an Alpha7 nicotinic acetylcholine receptor agonist

Glaucoma-inducing Procedure in an <em>In Vivo </em>Rat Model and Whole-mount Retina Preparation

Amacrine cells coupled to ganglion cells via gap junctions are highly vulnerable in glaucomatous mouse retinas

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