Topical Brimonidine or Intravitreal BDNF, CNTF, or bFGF Protect Cones Against Phototoxicity

Abstract

Purpose: To develop a focal photoreceptor degeneration model by blue lightemitting diode (LED)-induced phototoxicity (LIP) and investigate the protective effects of topical brimonidine (BMD) or intravitreal brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factor (CNTF), or basic fibroblast growth factor (bFGF). Methods: In anesthetized, dark-adapted, adult female Swiss mice, the left eye was dilated and exposed to blue light (10 seconds, 200 lux). After LIP, full-field electroretinograms (ERG) and spectral-domain optical coherence tomography (SD-OCT) were obtained longitudinally, and reactive-Iba-1 þ monocytic cells, TUNEL þ cells and S-opsin þ cone outer segments were examined up to 7 days. Left eyes were treated topically with BMD (1%) or vehicle, before or right after LIP, or intravitreally with BDNF (2.5 lg), CNTF (0.2 lg), bFGF (0.5 lg), or corresponding vehicle right after LIP. At 7 days, S-opsin þ cone outer segments were counted within predetermined fixed-size areas (PFA) centered on the lesion in both flattened retinas. Results: SD-OCT showed a circular region in the superior-temporal left retina with progressive thinning (207.9 6 5.6 lm to 160.7 6 6.8 lm [7 days], n ¼ 8), increasing TUNEL þ cells (peak at 3 days), decreasing S-opsin þ cone outer segments, and strong microglia activation. ERGs were normal by 3 days. Total S-opsin þ cones in the PFA for LIP-treated and fellow-retinas were 2330 6 262 and 5601 6 583 (n ¼ 8), respectively. All neuroprotectants (n ¼ 7-11), including topical BMD pre-or post-LIP, or intravitreal BDNF, CNTF, and bFGF, showed significantly greater S-opsin þ cone survival than their corresponding vehicle-treated groups. Conclusions: LIP is a reliable, quantifiable focal photoreceptor degeneration model. Topical BMD or intravitreal BDNF, CNTF, or bFGF protect against LIP-induced conephotoreceptor loss. Translational Relevance: Topical BMD or intravitreal BDNF, CNTF, or bFGF protect cones against phototoxicity. This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

Coordinated Intervention of Microglial and Müller Cells in Light-Induced Retinal Degeneration

“…19,57 In this study, we show that 1 month ALE, there are high numbers of activated microglial cells and/or macrophages in the photoreceptor layers at the center and periphery of the rings of cone degeneration, suggesting that these cells may be involved in the phagocytosis of the dead photoreceptors. Other authors have also found migration of microglia and macrophages to the outer retina in other models of light-induced retinal degeneration 59,110 and activated microglial cells at the center of the rings of photoreceptor degeneration in a rat model of inherited retinal degeneration, before the occupation of the rings by processes of Müller cells. 29 Microglial cells and Müller cells might act coordinately to phagocytose photoreceptor debris during retinal degeneration 48,49,60,111,112 ; Müller cells may release factors that induce microglial activation and migration, 96,100,103 and may also form a scaffold to guide microglial migration, 49,60 whereas activated microglia may also release factors that influence Müller cells behavior.…”

“…19,34,[50][51][52] In any case, previous works have shown that microglial cells become activated and travel through the retina in animal models of retinal degeneration, 34,35,50,[52][53][54][55][56][57][58] and are also present in the center of the rings of rod-cone degeneration. 29,59 There is also evidence that there is an interaction between microglial and Müller cells that affects trophic factor release by Müller cells 60 and therefore this interplay may also be important to regulate the responses of Müller cells in different scenarios, such as the regenerating zebrafish retina, 61 in animal models of retinal degenerations 62 and also in cocultures of activated microglia and Müller cells. 60 In this study, we have used our previously described model of light-induced retinal degeneration 2,3,13,15 and immunodetection of cones, Müller and microglial cells to investigate the role of the macro-and microglial cells in the rings of photoreceptor degeneration.…”

Pigment Epithelium-Derived Factor (PEDF) Fragments Prevent Mouse Cone Photoreceptor Cell Loss Induced by Focal Phototoxicity In Vivo

“…Therefore, taking into account this risk factor, many animal models of light-induced retinal degeneration have been developed, and serve to study the evolution of the degeneration and to test possible protective strategies [ 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 ]. Several of these studies have documented the effect of excessive exposure to short-wave visible light (blue light) on the retina [ 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 ]. Blue light, the most damaging component of sunlight, causes oxidative stress that induces the loss of retinal pigment epithelium cells and photoreceptors [ 13 , 14 , 15 , 16 , 17 , 18 ].…”

“…Several of these studies have documented the effect of excessive exposure to short-wave visible light (blue light) on the retina [ 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 ]. Blue light, the most damaging component of sunlight, causes oxidative stress that induces the loss of retinal pigment epithelium cells and photoreceptors [ 13 , 14 , 15 , 16 , 17 , 18 ]. We have recently characterized a new focal blue light emitting diode (LED) induced phototoxicity (LIP) model in albino mice that results in focal phototoxic cone degeneration in an area of the retina that coincides with the highest density of rodent photoreceptors [ 16 , 18 , 19 , 20 ].…”

“…Blue light, the most damaging component of sunlight, causes oxidative stress that induces the loss of retinal pigment epithelium cells and photoreceptors [ 13 , 14 , 15 , 16 , 17 , 18 ]. We have recently characterized a new focal blue light emitting diode (LED) induced phototoxicity (LIP) model in albino mice that results in focal phototoxic cone degeneration in an area of the retina that coincides with the highest density of rodent photoreceptors [ 16 , 18 , 19 , 20 ]. This model allows automatic quantification of S-cone outer segments (OS) that is appropriate for determining the efficacy of different neuroprotective drugs [ 16 , 18 ].…”