Caspase-3 Inhibitor Rescues N -Methyl- N -nitrosourea-induced Retinal Degeneration in Sprague–Dawley Rats

Yoshizawa, Katsuhiko; Yang, Jihong; Senzaki, Hideto; Uemura, Yoshiko; Kiyozuka, Yasuhiko; Shikata, Nobuaki; Oishi, Yuji; Miki, H; Tsubura, Airo

doi:10.1006/exer.2000.0921

Cited by 66 publications

(66 citation statements)

References 29 publications

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“…These are the RCS rat, 30 rhodopsin S334ter rats 34 and in apoptosis induced by N-methyl-Nnitrosourea in Sprague ± Dawley rats. 35 The apparent differences between these studies and this present study may be explained by the use of two different animal models i.e. rats and mice.…”

Section: Em Of Three Independent Experimentsmentioning

confidence: 57%

“…Untreated than the effective dose of caspase inhibitors shown to have protective effects in photoreceptors in previous studies. 34,35 Cytochrome-c is not released from the mitochondria following light-exposure Release of cytochrome c from the mitochondrial intermembrane space is a fundamental event in apoptosis as it sets in motion the assembly of the apoptosome, resulting in activation of caspase-9, the downstream effector caspases-7 and -3 and ultimately cell death. 8 We therefore investigated the cellular distribution of cytochrome c during light-induced photoreceptor apoptosis using subcellular fractionation studies.…”

Section: Resultsmentioning

confidence: 99%

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Caspase-independent photoreceptor apoptosis in vivo and differential expression of apoptotic protease activating factor-1 and caspase-3 during retinal development

2002

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Apoptosis is the mode of photoreceptor cell death in many retinal dystrophies. Exposure of Balb/c mice to excessive levels of light induces photoreceptor apoptosis and represents an animal model for the study of retinal degenerations. Caspases have emerged as central regulators of apoptosis, executing this tightly controlled death pathway in many cells. Previously we have reported that light-induced photoreceptor apoptosis occurs independently of one the key executioners of apoptosis, caspase-3. This present study extends these results reporting on the lack of activation of other caspases in this model including caspases-8, -9, -7, and -1. Furthermore, photoreceptor apoptosis cannot be inhibited with the broad range caspase inhibitor zVAD-fmk indicating that lightinduced retinal degeneration is caspase-independent. We demonstrate that cytochrome c does not translocate from mitochondria to the cytosol during photoreceptor apoptosis. We also show that during retinal development apoptotic protease activating factor (Apaf-1) protein levels are markedly decreased and this is associated with the inability to activate the mitochondrial caspase cascade in the mature retina. In addition, there is also a significant reduction in expression of caspases-3 and -9 during retinal maturation and these levels do not increase following light exposure. Finally, we show that the calcium-dependent proteases calpains are active during light-induced retinal degeneration and establish that the calcium channel blocker D-cis-diltiazem completely inhibits photoreceptor apoptosis.

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Section: Em Of Three Independent Experimentsmentioning

confidence: 57%

Section: Resultsmentioning

confidence: 99%

Caspase-independent photoreceptor apoptosis in vivo and differential expression of apoptotic protease activating factor-1 and caspase-3 during retinal development

2002

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“…An extensive investigation in animals has revealed that MNU-induced photoreceptor cell loss is due to apoptosis with a decrease in Bcl-2 protein, increase in Bax protein, and nuclear factor κB and activation of caspases (1,5). Previous studies have evaluated a caspase-3 inhibitor (1), nicotinamide (25), X-linked inhibitor of apoptosis protein (26), poly(ADP-ribose) polymerase inhibitor (27), and mutant of acidic fibroblast growth factor (28) as possible therapies for MNU-induced cell loss because they were found to prevent MNU-induced retinal damage and counteract photoreceptor cell loss.…”

Section: Discussionmentioning

confidence: 99%

“…No therapeutic drugs have yet been discovered for retinitis pigmentosa; therefore, the development of new drugs for therapeutic intervention is of paramount importance. NMethyl-N-nitrosourea (MNU) is a direct-acting alkylating agent that induces retinal photoreceptor cell death by an apoptotic mechanism (1). In a range of animals including adult mice and rats, MNU has been reported to induce photoreceptor cell death at approximately 7 days after a single systemic administration (2 -4).…”

Section: Introductionmentioning

confidence: 99%

Role of Oxidative Stress in Retinal Photoreceptor Cell Death in N-Methyl-N-nitrosourea–Treated Mice

et al. 2012

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Abstract. This study aimed to investigate whether oxidative stress contributes to retinal cell death in a mouse model of photoreceptor degeneration induced by N-methyl-N-nitrosourea (MNU). We measured in vitro MNU-induced radical production in retinal cell cultures of murine 661W photoreceptor-derived cells; RGC-5, a mouse ganglion cell line; and primary retinal cells. The addition of MNU induced oxidative radical generation in 661W and primary retinal cells, but not in RGC-5 cells. Edaravone, a free radical scavenger, at 1 μM reduced MNU-induced radical production in 661W and primary retinal cells. To induce in vivo retinal photoreceptor degeneration in mice, we administered 60 mg/kg MNU by intraperitoneal injection. We intravenously administered 1 mg/kg edaravone immediately and at 6 h after the MNU injection. Retinal photoreceptor degeneration was evaluated by measuring the thickness of the outer nuclear layer (ONL) by terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining and by oxidative stress markers. MNU caused photoreceptor cell loss at 7 days after administration. Edaravone inhibited ONL thinning and reduced TUNEL-positive cells and the oxidative stress markers. These findings indicate that MNU leads to selective photoreceptor degradation via oxidative stress in vitro and in vivo and may help to understand the pathogenic mechanism of retinitis pigmentosa.

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“…MNU-induced photoreceptor cell apoptosis involves Bcl-2 family proteins and activation of caspase-3, -6 and -8 [57]. In our study, Ac-DEVD-CHO, a caspase-3 inhibitor, was injected intravitreally at a dose of 4000 ng, twice at 0 and 10 hr after 60 mg/kg MNU was administered to 50-day-old rats [58]. This Ac-DEVD-CHO injection significantly reduced the TUNEL index 24 hr post-MNU in the central retina (83.7% vs. 71.8%) and peripheral retina (79.5% vs. 59.7%), and selectively rescued photoreceptor cell loss 7 days after MNU administration.…”

Section: Disease Control Of Mnu-induced Retinal Degenerationmentioning

confidence: 99%

N-Methyl-N-nitrosourea-induced Retinal Degeneration in Animals

Tsubura

Yoshizawa

Kiuchi

et al. 2003

Acta Histochem. Cytochem

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Retinitis pigmentosa (RP) is a human disease characterized by loss of photoreceptor cells leading to visual disturbance and eventually to blindness. Establishment of reliable animal models is essential for better understanding of this disease and approaches to therapeutic intervention. N-Methyl-N-nitrosourea (MNU)-induced retinal degeneration is highly reproducible, and involves photoreceptor cell loss that ends approximately 7 days after a single systemic administration of MNU. Although the triggering mechanisms of pathogenesis are different and the apoptosis cascade may differ from human RP, MNU-induced photoreceptor cell loss is due to apoptosis. Here, we describe disease progression and therapeutic trials of MNU-induced retinal degeneration in animals.

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Caspase-3 Inhibitor Rescues N -Methyl- N -nitrosourea-induced Retinal Degeneration in Sprague–Dawley Rats

Cited by 66 publications

References 29 publications

Caspase-independent photoreceptor apoptosis in vivo and differential expression of apoptotic protease activating factor-1 and caspase-3 during retinal development

Caspase-independent photoreceptor apoptosis in vivo and differential expression of apoptotic protease activating factor-1 and caspase-3 during retinal development

Role of Oxidative Stress in Retinal Photoreceptor Cell Death in N-Methyl-N-nitrosourea–Treated Mice

N-Methyl-N-nitrosourea-induced Retinal Degeneration in Animals

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