Caspase-3 inhibitor transiently delays inherited retinal degeneration in C3H mice carrying the rd gene

Yoshizawa, Katsuhiko; Kiuchi, Katsuji; Nambu, Hiroyuki; Yang, Jihong; Senzaki, Hideto; Kiyozuka, Yasuhiko; Shikata, Nobuaki; Tsubura, Airo

doi:10.1007/s00417-002-0427-5

Cited by 57 publications

(41 citation statements)

References 23 publications

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“…Akt signaling strongly inhibits caspase cleavage cascades (Kermer et al, 2000;Barber et al, 2001;Vincent and Feldman, 2002). Activated caspase-3 correlates with photoreceptor degeneration in various rodent models (Liu et al, 1999;Yoshizawa et al, 2002). Activated caspase-3 accumulates in the Irs2 Ϫ/Ϫ retina, which may explain the observed increase in photoreceptor cell apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Insulin Receptor Substrate 2 Is Essential for Maturation and Survival of Photoreceptor Cells

Schubert

Peachey

et al. 2005

J. Neurosci.

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Insulin receptor substrates (Irs-proteins) integrate signals from the insulin and insulin-like growth factor-1 (IGF1) receptors with other processes to control cellular growth, function, and survival. Here, we show that Irs2 promoted the maturation and survival of photoreceptors in the murine retina immediately after birth. Irs2 was mainly localized to the outer plexiform layer as well as to photoreceptor inner segments. It was also seen in ganglion cells and inner plexiform layer but in smaller amounts. Compared with control littermates, Irs2 knock-out mice lose ϳ10% of their photoreceptors 1 week after birth and up to 50% by 2 weeks of age as a result of increased apoptosis. The surviving photoreceptor cells developed short organized segments, which displayed proportionally diminished but otherwise normal electrical function. However, IGF1-stimulated Akt phosphorylation was barely detected, and cleaved/activated caspase-3 was significantly elevated in isolated retinas of Irs2 Ϫ/Ϫ mice. When diabetes was prevented, which allowed the Irs2 Ϫ/Ϫ mice to survive for 2 years, most photoreceptor cells were lost by 16 months of age. Because apoptosis is the final common pathway in photoreceptor degeneration, pharmacological strategies that increase Irs2 expression or function in photoreceptor cells could be a general treatment for blinding diseases such as retinitis pigmentosa.

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Section: Discussionmentioning

confidence: 99%

Insulin Receptor Substrate 2 Is Essential for Maturation and Survival of Photoreceptor Cells

Schubert

Peachey

et al. 2005

J. Neurosci.

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“…Whereas some studies have demonstrated caspase activation in rd1 retinae from the 2nd to 3rd postnatal week, i.e. at peak or postpeak of photoreceptor cell apoptosis (15)(16)(17), Doonan et al (18) were unable to detect increased caspase expression or activation at these and earlier time points in the same tissue, and caspase inhibition or ablation of caspase-3 failed to rescue rd1 photoreceptors from apoptosis (19,20). It has also been shown that rd1 photoreceptors degenerate irrespective of the expression of p53, a tumor suppressor gene involved in several types of apoptosis (21), or c-Fos (22), which by contrast is entirely essential for light-induced photoreceptor degeneration (23).…”

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confidence: 93%

Differential Modification of Phosducin Protein in Degenerating rd1 Retina Is Associated with Constitutively Active Ca2+/Calmodulin Kinase II in Rod Outer Segments

Hauck¹,

Ekström

Ahuja-Jensen

et al. 2006

Molecular & Cellular Proteomics

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Retinitis pigmentosa comprises a heterogeneous group of incurable progressive blinding diseases with unknown pathogenic mechanisms. The retinal degeneration 1 (rd1) mouse is a retinitis pigmentosa model that carries a mutation in a rod photoreceptor-specific phosphodiesterase gene, leading to rapid degeneration of these cells. Elucidation of the molecular differences between rd1 and healthy retinae is crucial for explaining this degeneration and could assist in suggesting novel therapies. Here we used high resolution proteomics to compare the proteomes of the rd1 mouse retina and its congenic, wildtype counterpart at postnatal day 11 when photoreceptor death is profound. Over 3000 protein spots were consistently resolved by two-dimensional gel electrophoresis and subjected to a rigorous filtering procedure involving computer-based spot analyses. Five proteins were accepted as being differentially expressed in the rd1 model and subsequently identified by mass spectrometry. The difference in one such protein, phosducin, related to an altered modification pattern in the rd1 retina rather than to changed expression levels. Additional experiments showed phosducin in healthy retinae to be highly phosphorylated in the dark-but not in the light-adapted phase. In contrast, rd1 phosducin was highly phosphorylated irrespective of light status, indicating a dysfunctional rd1 light/dark response. The increased rd1 phosducin phosphorylation coincided with increased activation of calcium/calmodulin-activated protein kinase II, which is known to utilize phosducin as a substrate. Given the increased rod calcium levels present in the rd1 mutation, calcium-evoked overactivation of this kinase may be an early and long sought for step in events leading to photoreceptor degeneration in the rd1 mouse. Molecular & Cellular Proteomics 5:324 -336, 2006.

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“…Although apoptosis often involves caspases, these play only a minor role, if any, in the rd1 degeneration. For instance, relevant caspase activation is absent during the degeneration (Kim et al, 2002;Doonan et al, 2003) and interventions of the caspase cascade fail to preserve the rd1 photoreceptors (Yoshizawa et al, 2002;Zeiss et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Excessive Activation of Poly(ADP-Ribose) Polymerase Contributes to Inherited Photoreceptor Degeneration in the Retinal Degeneration 1 Mouse

Paquet-Durand¹,

Silva²,

Talukdar³

et al. 2007

J. Neurosci.

128

135

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Retinitis pigmentosa (RP) is an inherited blinding disease for which there is no treatment available. It is characterized by a progressive and neurodegenerative loss of photoreceptors but the underlying mechanisms are poorly understood. Excessive activation of the enzyme poly(ADP-ribose) polymerase (PARP) has recently been shown to be involved in several neuropathologies. To investigate the possible role of PARP in retinal photoreceptor degeneration, we used the retinal degeneration 1 (rd1) mouse RP model to study PARP expression, PARP activity, and to test the effects of PARP inhibition on photoreceptor viability. PARP expression was found to be equal between rd1 and wild-type counterpart retinas. In contrast to this, a dramatic increase in both PARP activity per se and PARP product formation was detected by in situ assays in rd1 photoreceptors actively undergoing cell death. Furthermore, PARP activity colabeled with oxidatively damaged DNA and nuclear translocation of AIF (apoptosis-inducing factor), suggesting activation of PARP as a bridge between these events in the degenerating photoreceptors. The PARP-specific inhibitor PJ34 [N-(6-oxo-5,6-dihydrophenanthridin-2-yl)-N,Ndimethylacetamide⅐HCl] reduced the number of cells exhibiting death markers in a short-term retinal culture paradigm, a protective effect that was translated into an increased number of surviving photoreceptors when the inhibitor was used in a long-term culture setting. Our results thus demonstrate an involvement of PARP activity in rd1 photoreceptor cell death, which could have a bearing on the understanding of neurodegenerations as such. The findings also suggest that the therapeutical possibilities of PARP inhibition should include retinal diseases like RP.

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Caspase-3 inhibitor transiently delays inherited retinal degeneration in C3H mice carrying the rd gene

Abstract: The caspase-3 inhibitor was transiently effective in delaying retinal degeneration through inhibition of the apoptosis of photoreceptor cells in rd gene-carrying mice. The use of caspase-3 inhibitors may have therapeutic applications in the treatment of human retinal degeneration.

Cited by 57 publications

References 23 publications

Insulin Receptor Substrate 2 Is Essential for Maturation and Survival of Photoreceptor Cells

Insulin Receptor Substrate 2 Is Essential for Maturation and Survival of Photoreceptor Cells

Differential Modification of Phosducin Protein in Degenerating rd1 Retina Is Associated with Constitutively Active Ca2+/Calmodulin Kinase II in Rod Outer Segments

Excessive Activation of Poly(ADP-Ribose) Polymerase Contributes to Inherited Photoreceptor Degeneration in the Retinal Degeneration 1 Mouse

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