Submacular DL-α-Aminoadipic Acid Eradicates Primate Photoreceptors but Does Not Affect Luteal Pigment or the Retinal Vasculature

Shen, Weiyong; Zhang, Jun; Chung, Soo Il; Hu, Yuntao; Ma, Zhizhong; Gillies, Mark C

doi:10.1167/iovs.10-6033

Cited by 18 publications

(12 citation statements)

References 48 publications

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“…20 Higher concentrations of LAA have also been shown to be nontoxic to in vitro endothelial cells and pericytes. 27 It should be noted that, because glial cells provide structural and metabolic support for neurons, depletion of retinal glial cells may cause neuronal malfunction, which in turn affects their interaction with the vasculature. However, Song et al 20 showed that 24 hours after intravitreal injection of LAA, retinal function remained normal as examined using electroretinography.…”

Section: Discussionmentioning

confidence: 99%

Glial Cell Contribution to Basal Vessel Diameter and Pressure-Initiated Vascular Responses in Rat Retina

Bui

Cull

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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PurposeThe purpose of this study was to test the hypothesis that retinal glial cells modify basal vessel diameter and pressure-initiated vascular regulation in rat retina.MethodsIn rats, L-2-aminoadipic acid (LAA, 10 nM) was intravitreally injected to inhibit glial cell activity. Twenty-four hours following injection, retinal glial intracellular calcium (Ca2+) was labeled with the fluorescent calcium indicator Fluo-4/AM (F4, 1 mM). At 110 minutes after injection, intraocular pressure (IOP) was elevated from 20 to 50 mm Hg. Prior to and during IOP elevation, Ca2+ and retinal vessel diameter were assessed using a spectral-domain optical coherence tomography/confocal scanning laser ophthalmoscope. Dynamic changes in Ca2+ and diameter from IOP elevation were quantified. The response in LAA-treated eyes was compared with vehicle treated control eyes.ResultsL-2-Aminoadipic acid treatment significantly reduced F4-positive cells in the retina (LAA, 16 ± 20 vs. control, 55 ± 37 cells/mm2; P = 0.02). Twenty-four hours following LAA treatment, basal venous diameter was increased from 38.9 ± 3.9 to 51.8 ± 6.4 μm (P < 0.0001, n = 20), whereas arterial diameter was unchanged (from 30.3 ± 3.5 to 30.7 ± 2.8 μm; P = 0.64). In response to IOP elevation, LAA-treated eyes showed a smaller increase in glial cell Ca2+ around both arteries and veins in comparison with control (P < 0.001 for both). There was also significantly greater IOP-induced vasoconstriction in both vessel types (P = 0.05 and P = 0.02, respectively; n = 6 each).ConclusionsThe results suggest that glial cells can modulate basal retinal venous diameter and contribute to pressure-initiated vascular responses.

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Section: Discussionmentioning

confidence: 99%

Glial Cell Contribution to Basal Vessel Diameter and Pressure-Initiated Vascular Responses in Rat Retina

Bui

Cull

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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“…Macular pigment is located in Henle's layer (Snodderly et al, 1984a(Snodderly et al, , 1984bTrieschmann et al, 2008), but whether it is associated with nerve fibers of photoreceptors or Müller cell processes remains unknown. Macular pigment appeared to persist when primate photoreceptors were ablated by subretinal alpha-aminoadipic acid in a primate study, suggesting that at least some of the pigment may reside in Müller cells, which were relatively unaffected in this model (Shen et al, 2011). Analysis of the central retina from the fellow eye of this pair using proteomic techniques revealed reduced levels of Müller cellspecific proteins, including glial fibrillary acid protein, vimentin and glutamine synthetase (Len et al, 2012).…”

Section: The Role Of Müller Cellsmentioning

confidence: 85%

Macular Telangiectasia Type 2

Heeren

Holz

Issa

2013

Microperimetry and Multimodal Retinal Imaging

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Macular telangiectasia type 2 is a bilateral disease of unknown cause with characteristic alterations of the macular capillary network and neurosensory atrophy. Its prevalence may be underestimated and has recently been shown to be as high as 0.1% in persons 40 years and older. Biomicroscopy may show reduced retinal transparency, crystalline deposits, mildly ectatic capillaries, blunted venules, retinal pigment plaques, foveal atrophy, and neovascular complexes. Fluorescein angiography shows telangiectatic capillaries predominantly temporal to the foveola in the early phase and a diffuse hyperfluorescence in the late phase. High-resolution optical coherence tomography (OCT) may reveal disruption of the photoreceptor inner segment-outer segment border, hyporeflective cavities at the level of the inner or outer retina, and atrophy of the retina in later stages. Macular telangiectasia type 2 shows a unique depletion of the macular pigment in the central retina and recent therapeutic trials showed that such depleted areas cannot re-accumulate lutein and zeaxanthin after oral supplementation. There have been various therapeutic approaches with limited or no efficacy. Recent clinical trials with compounds that block vascular endothelial growth factor (VEGF) have established the role of VEGF in the pathophysiology of the disease, but have not shown significant efficacy, at least for the nonneovascular disease stages. Recent progress in structure-function correlation may help to develop surrogate outcome measures for future clinical trials.In this review article, we summarize the current knowledge on macular telangiectasia type 2, including the epidemiology, the genetics, the clinical findings, the staging and the differential diagnosis of the disease. Findings using retinal imaging are discussed, including fluorescein angiography, OCT, adaptive optics imaging, confocal scanning laser ophthalmoscopy, and fundus autofluorescence, as are the findings using visual function testing including visual acuity and fundus-controlled microperimetry. We provide an overview of the therapeutic approaches for both non-neovascular and neovascular disease stages and provide a perspective of future directions including animal models and potential therapeutic approaches.

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“…To overcome the barrier properties of RPE and the retinal inner limiting membrane, subretinal injection can be utilized. Subretinal administration of DL-AAA can alter the blood-retinal barrier in rats and eliminate photoreceptors in monkeys 33, 44 . Our results suggested that ERG a-waves and the expression of GS reduced at 7 days after subretinal injection of 70 μg/μl DL-AAA to the rats.…”

Section: Discussionmentioning

confidence: 99%

“…DL-α-aminoadipate (DL-AAA) was prepared in accordance with established procedures 32, 33, 44, 60 . Different concentrations of DL-AAA solution (7 μg/μl to 140 μg/μl) were injected into the subretinal space under dim-red light (wavelength >620 nm).…”

Section: Methodsmentioning

confidence: 99%

Improved retinal function in RCS rats after suppressing the over-activation of mGluR5

Dai

Zeng

et al. 2017

Sci Rep

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Müller cells maintain retinal synaptic homeostasis by taking up glutamate from the synaptic cleft and transporting glutamine back to the neurons. To study the interaction between Müller cells and photoreceptors, we injected either DL-α-aminoadipate or L-methionine sulfoximine–both inhibitors of glutamine synthetase–subretinally in rats. Following injection, the a-wave of the electroretinogram (ERG) was attenuated, and metabotropic glutamate receptor 5 (mGluR5) was activated. Selective antagonism of mGluR5 by 2-methyl-6-(phenylethynyl)-pyridine increased the ERG a-wave amplitude and also increased rhodopsin expression. Conversely, activation of mGluR5 by the agonist, (R,S)-2-chloro-5-hydroxyphenylglycine, decreased both the a-wave amplitude and rhodopsin expression, but upregulated expression of Gq alpha subunit and phospholipase C βIII. Overexpression of mGluR5 reduced the inward-rectifying potassium ion channel (Kir) current and decreased the expression of Kir4.1 and aquaporin-4 (AQP4). Further experiments indicated that mGluR5 formed a macromolecular complex with these two membrane channels. Lastly, increased expression of mGluR5 was found in Royal College of Surgeons rats–a model of retinitis pigmentosa (RP). Inhibition of mGluR5 in this model restored the amplitude of ERG features, and reduced the expression of glial fibrillary acidic protein. These results suggest that mGluR5 may be worth considering as a potential therapeutic target in RP.

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Submacular DL-α-Aminoadipic Acid Eradicates Primate Photoreceptors but Does Not Affect Luteal Pigment or the Retinal Vasculature

Cited by 18 publications

References 48 publications

Glial Cell Contribution to Basal Vessel Diameter and Pressure-Initiated Vascular Responses in Rat Retina

Glial Cell Contribution to Basal Vessel Diameter and Pressure-Initiated Vascular Responses in Rat Retina

Macular Telangiectasia Type 2

Improved retinal function in RCS rats after suppressing the over-activation of mGluR5

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