Abstract
Neuronal damage and impaired vision in different retinal disorders are induced, among other factors, by ischemia/reperfusion (I/R). Since the mechanisms and the progression of ischemic injury are still not completely clarified, a timeline of this retinal degeneration is needed. In this study, we investigated protein and mRNA alterations at 2, 6, 12, and 24 h as well as 3 and 7 days after ischemia to determine the course of an ischemic insult through the whole retina. Moreover, functional analyses were performed at later stages. We detected a significant functional loss of cells in the inner nuclear layer and photoreceptors at 3 and 7 days. Additionally, the thickness of the whole retina was decreased at these points in time, indicating a severe degradation of all retinal layers. Immunohistological and qRT-PCR analyses of retinal ganglion cells (RGCs), glial cells, AII amacrine, cone and rod bipolar as well as cone and rod photoreceptor cells confirmed this first assumption. Our results show that all investigated cell types were damaged by ischemia induction. Especially RGCs, cone bipolar cells, and photoreceptor cones are very sensitive to I/R. These cells were lost shortly after ischemia induction with a progressive course up to 7 days. In addition, Müller cell gliosis was observed over the entire period of time. These results provide evidence, that I/R induces damage of the whole retina at early stages and increases over time. In conclusion, our study could demonstrate the intense impact of an ischemic injury. The ischemic defect spreads across the whole retina right up to the outer layers in the long-term and thus seems to impair the visual perception already during the stimulus processing. In addition, our findings indicate that the cone pathway seems to be particularly affected by this damage.
Highlights
Retinal neurodegenerative diseases, including age-related macular degeneration (AMD), diabetic retinopathy, glaucoma, and retinal vein occlusion, are multi factorial and so far insufficiently investigated
Our results show that all investigated cell types were damaged by ischemia induction
We demonstrated an impaired functionality of the inner nuclear layer (INL) and photoreceptors, via ERG measurements, as well as a progressive loss of amacrine, cone bipolar and cone photoreceptor cells, via immunohistology and quantitative real-time PCR (qRT-PCR)
Summary
Retinal neurodegenerative diseases, including AMD, diabetic retinopathy, glaucoma, and retinal vein occlusion, are multi factorial and so far insufficiently investigated. The consequence for the several retinal cell types is a lower oxygenation capacity and supply of nutrients followed by the formation of oxidative stress during the recurring blood flow (Kaur et al, 2008; Minhas et al, 2012; Kim et al, 2013) These conditions result in a loss of retinal functionality, inflammation, and retinal tissue damage, including neuronal cell death (Szabo et al, 1991; Dijk et al, 2004a; Kaur et al, 2008; Belforte et al, 2011; Joachim et al, 2012; Minhas et al, 2012; Andreeva et al, 2014; Schmid et al, 2014; Nakahara et al, 2015). It is known that RGCs and other inner retinal cells, like amacrine cells, are mainly affected by I/R (Lam et al, 1999; Goldblum and Mittag, 2002; Zheng et al, 2004; Bek, 2009; Nakano et al, 2011; Schmid et al, 2014)
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