Caspase-Dependent Apoptosis in Light-Induced Retinal Degeneration

Perche, Olivier; Doly, M.; Ranchon-Cole, Isabelle

doi:10.1167/iovs.06-1258

Cited by 52 publications

(39 citation statements)

References 38 publications

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“…In both inherited retinal degeneration and light-induced retinal degeneration, caspase-3 inhibitors showed a protective effect, suggesting that photoreceptor degeneration is related to caspase-3 activation (Perche et al, 2007(Perche et al, , 2008. For these reasons, we confirmed that caspase-3/7 was activated by light injury, being significant at 48 h after light exposure.…”

Section: Discussionsupporting

confidence: 73%

Calpain Inhibitor Protects Cells against Light-Induced Retinal Degeneration

Imai¹,

Shimazawa²,

Nakanishi³

et al. 2010

J Pharmacol Exp Ther

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Calpains are activated by excessive light exposure and related to retinal degeneration. We investigated the protective effects of ((1S)-1-((((1S)-1-benzyl-3-cyclopropylamino-2,3-di-oxopropyl)amino)carbonyl)-3-methylbutyl)carbamic acid 5-methoxy-3-oxapentyl ester (SNJ-1945), a calpain inhibitor, against lightinduced retinal degeneration in mice. SNJ-1945 was orally administrated at doses of 100 and 200 mg/kg at 30 min before and just after light exposure. Light-induced calpain activation was evaluated by using proteolysis of ␣-spectrin and p35 (a neuron-specific activator for cyclin-dependent kinase 5). The effects of SNJ-1945 against light-induced retinal damage were examined by the thickness of the outer nuclear layer (ONL). Photoreceptor apoptosis was assessed by counting terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL)-positive cells in ONL. Retinal functions were measured in terms of a-and b-wave amplitudes by using an electroretinogram. As the mechanism of SNJ-1945, caspase-3/7 measurement was carried out. SNJ-1945 inhibited the proteolysis of ␣-spectrin and p35 by light exposure and presented a decrease in the numbers of TUNEL-positive cells and ONL atrophy. Furthermore, SNJ-1945 presented a decrease in a-and b-wave amplitude and caspase-3/7 activation induced by light exposure. These findings suggest that the activation of calpain plays a pivotal role in photoreceptor degeneration by light exposure, and SNJ-1945 may be a candidate for effectively treating diseases related to photoreceptor degeneration.

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Section: Discussionsupporting

confidence: 73%

Calpain Inhibitor Protects Cells against Light-Induced Retinal Degeneration

Imai¹,

Shimazawa²,

Nakanishi³

et al. 2010

J Pharmacol Exp Ther

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“…These inhibitors have been used and tested extensively to study the apoptotic pathways in retinal degeneration models (44,45). In separate experiments (n ϭ 6 retinas each; 3 independent experiments), 2 L of 12.5 mM NMDA plus 2 L of 2 mM of caspase-1 or caspase-3 inhibitor were injected into the vitreous, followed by TcapQ as described.…”

Section: Procedures Of In Vivo Intravitreal Injectionmentioning

confidence: 99%

Single-cell imaging of retinal ganglion cell apoptosis with a cell-penetrating, activatable peptide probe in an in vivo glaucoma model

Barnett

Zhang

Maxwell

et al. 2009

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

125

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Molecular imaging probes have potential for in vivo identification of apoptosis and other intracellular processes. TcapQ, a cell-penetrating, near-infrared fluorescent peptide probe designed to be optically silent through intramolecular fluorescence quenching and activated by effector caspases, has been previously described and validated in vitro. Herein, using NMDA-induced apoptosis of retinal ganglion cells (RGCs), representing an in vivo rat model of glaucoma, we assessed the ability of TcapQ to image single-cell apoptosis through effector caspase activity. Following intravitreal injection, intracellular TcapQ activation occurred specifically in RGCs, identified individual apoptotic cells, showed a clear dose-response relationship with NMDA, and colocalized with TUNEL labeling in the retina. There was a significant diminution of probe activation following pretreatment with a specific inhibitor of caspase-3. Stereospecificity was also exhibited by the lack of intracellular fluorescence upon administration of the noncleavable isomer, d TcapQ. TcapQ has potential utility in detecting and monitoring single-cell apoptosis in glaucoma in vivo.

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“…Conventional cultured retinas exhibited similar expression pattern of cleaved caspase-3, indicating that this apoptotic pathway does not contribute to photoreceptor apoptosis in the porcine retina following culture and low-intensity illumination. Even though only periodic low-intensity illumination was tested in the current study, it is known that different apoptotic pathways can be induced depending on light intensity and duration in rodent models (Contin et al, 2013;Hao et al, 2002;Perche et al, 2007).…”

Section: Opsin Accumulation and Cyclic Illumination Promote Er-stressmentioning

confidence: 99%

Autophagy and ER-stress contribute to photoreceptor degeneration in cultured adult porcine retina

et al. 2014

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Abbreviations: AMD, age-related macular degeneration; BSA, bovine serum albumin; CHOP, C/EBP homology protein; CtBP2, C-terminal binding protein 2; ER, endoplasmic reticulum; GRP78/BiP, glucoseregulated protein 78kDa/Binding immunoglobulin protein, INL, inner nuclear layer; IPL, inner plexiform layer; LC3B, microtubule-associated protein light chain 3B; mTOR, mammalian target of rapamycin; ONL, outer nuclear layer; OPL, outer nuclear layer; PBS, phosphate buffered saline; PNA, peanut agglutinin; p62/SQSTM1; nucleoporin p62/sequestosom 1; PSD-95, postsynaptic density protein 95; rd1, retinal degeneration 1; RPE, retinal pigment epithelium; UPS, ubiquitin-proteasome system; 2 AbstractThe aim of this study was to investigate rod and cone photoreceptor degeneration in organotypic cultures of adult porcine retina. Our hypothesis was that the photoreceptors accumulate opsins, which, together with exposure to cyclic dim light illumination, induce autophagy and endoplasmic reticulum stress (ER-stress) to overcome damaging protein overload. For this purpose, retinas were cultured for 48 h and 72 h during which they were illuminated with dim light for 8 h/day; specimens were analyzed by means of immunohistochemistry, western blot and transmission electron microscopy. ER-stress and photoreceptor degeneration was observed in conventionally cultured retinas. The additional stress in the form of dim light illumination for 8 h/day resulted in increased levels of the ER-stress markers GRP78/BiP and CHOP, as well as increased level of active caspase-12. Increased autophagic processes in cone and rod photoreceptors were detected by LC3B-II increases and occurrence of autophagosomes at the ultrastructural level. Illumination also resulted in altered protein expression for autophagy inducers such as p62 and Beclin-1. Moreover, there was a decrease in phosphorylated mammalian target of rapamycin (mTOR), which further indicate an increase of autophagy. Rod and cone photoreceptors in retinas from a diurnal animal that were exposed to dim light illumination in vitro displayed autophagy and ER-stress processes. In particular, these processes resulted in decreased protein levels for rhodopsin.3

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Caspase-Dependent Apoptosis in Light-Induced Retinal Degeneration

Abstract: In the authors' model of retinal degeneration, photoreceptor cells die through a caspase-dependent mechanism. However, the molecular events involved during and after light exposure seemed to implicate different proteases.

Cited by 52 publications

References 38 publications

Calpain Inhibitor Protects Cells against Light-Induced Retinal Degeneration

Calpain Inhibitor Protects Cells against Light-Induced Retinal Degeneration

Single-cell imaging of retinal ganglion cell apoptosis with a cell-penetrating, activatable peptide probe in an in vivo glaucoma model

Autophagy and ER-stress contribute to photoreceptor degeneration in cultured adult porcine retina

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