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Peter A Campochiaro - One of the best experts on this subject based on the ideXlab platform.

  • the mechanism of Cone Cell death in retinitis pigmentosa
    Progress in Retinal and Eye Research, 2017
    Co-Authors: Peter A Campochiaro
    Abstract:

    Abstract Retinitis Pigmentosa (RP) is a group of diseases in which one of a large number of mutations causes death of rod photoreceptors. After rods die, Cone photoreceptors slowly degenerate in a characteristic pattern. The mechanism of rod Cell death varies depending upon the gene that is mutated and the rate that rods degenerate is an important prognostic feature, because Cones do not begin to degenerate until almost all rods have been eliminated. Rod Cell death causes night blindness, but visual disability and blindness result from Cone degeneration and therefore it is critical to determine the mechanisms by which it occurs. The death of rods reduces oxygen consumption resulting in high tissue levels of oxygen in the outer retina. The excess oxygen stimulates superoxide radical production by mismatches in the electron transport chain in mitochondria and by stimulation of NADPH oxidase activity in cytoplasm. The high levels of superoxide radicals overwhelm the antioxidant defense system and generate more reactive species including peroxynitrite which is extremely damaging and difficult to detoxify. This results in progressive oxidative damage in Cones which contributes to Cone Cell death and loss of function because drugs or gene transfer that reduce oxidative stress promote Cone survival and maintenance of function. Compared with aqueous humor samples from control patients, those from patients with RP show significant elevation of carbonyl content on proteins indicating oxidative damage and a reduction in the ratio of reduced to oxidized glutathione indicating depletion of a major component of the antioxidant defense system from ongoing oxidative stress. The first step in clinical trials will be to identify doses of therapeutic agents that reverse these biomarkers of disease to assist in design of much longer trials with functional and anatomic endpoints.

  • is there excess oxidative stress and damage in eyes of patients with retinitis pigmentosa
    Antioxidants & Redox Signaling, 2015
    Co-Authors: Peter A Campochiaro, Rupert W Strauss, Gulnar Hafiz, Yulia Wolfson, Syed Mahmood Shah, Raafay Sophie, Tahreem A Mir, Hendrik P N Scholl
    Abstract:

    Abstract Retinitis pigmentosa (RP) is a group of diseases in which a mutation in one of the large variety of genes causes death of rod photoreceptors. After rods die, Cone photoreceptors gradually die resulting in constriction of visual fields and eventual blindness in many patients. Studies in animal models of RP have demonstrated that oxidative damage is a major contributor to Cone Cell death. In this study, we extended those findings to patients with RP, because compared to control patients, those with RP showed significant reduction in the reduced to oxidized glutathione (GSH/GSSG) ratio in aqueous humor and a significant increase in aqueous protein carbonyl content. In contrast, there was no significant decrease in the serum GSH/GSSG ratio or increase in carbonyl content of serum proteins. These data indicate that patients with RP have ocular oxidative stress and damage in the absence of manifestations of systemic oxidative stress and/or damage indicating that demonstrations of oxidative damage-induc...

  • nadph oxidase plays a central role in Cone Cell death in retinitis pigmentosa
    Journal of Neurochemistry, 2009
    Co-Authors: Shinichi Usui, Brian C Oveson, Sun Young Lee, Tsunehiko Yoshida, Akiko Miki, Katsuaki Miki, Takeshi Iwase, Peter A Campochiaro
    Abstract:

    Retinitis pigmentosa (RP) is a collection of diseases in which rod photoreceptors die from a variety of mutations. After rods die, the level of tissue oxygen in the outer retina becomes elevated and there is progressive oxidative damage to Cones that ultimately triggers apoptosis. In this study, we investigated the hypothesis that NADPH oxidase (Nox) and/or xanthine oxidase serve as critical intermediaries between increased tissue oxygen and the generation of excessive reactive oxygen species that cause oxidative damage to Cones. Apocynin, a blocker of Nox, but not allopurinol, a blocker of xanthine oxidase, markedly reduced the superoxide radicals visualized by hydroethidine in the outer retina in the retinal degeneration-1 (rd1(+/+)) model of RP. Compared to rd1(+/+) mice treated with vehicle, those treated with apocynin, but not those treated with allopurinol, had significantly less oxidative damage in the retina measured by ELISA for carbonyl adducts. Apocynin-treated, but not allopurinol-treated, rd1(+/+) mice had preservation of Cone Cell density, increased mRNA levels for m- and s-Cone opsin, and increased mean photopic b-wave amplitude. In Q344ter mice, a model of dominant RP in which mutant rhodopsin is expressed, apocynin treatment preserved photopic electroretinogram b-wave amplitude compared to vehicle-treated controls. These data indicate that Nox, but not xanthine oxidase, plays a critical role in generation of the oxidative stress that leads to Cone Cell death in RP and inhibition of Nox provides a new treatment strategy.

  • increased expression of glutathione peroxidase 4 strongly protects retina from oxidative damage
    Antioxidants & Redox Signaling, 2009
    Co-Authors: Brian C Oveson, Keiichi Komeima, Shinichi Usui, Thomas Lauer, Bing Xie, Peter A Campochiaro
    Abstract:

    Abstract Oxidative damage contributes to Cone Cell death in retinitis pigmentosa and death of rods, Cones, and retinal pigmented epithelial (RPE) Cells in age-related macular degeneration. In this study, we explored the strategy of overexpressing components of the endogenous antioxidant defense system to combat oxidative damage in RPE Cells and retina. In transfected cultured RPE Cells with increased expression of superoxide dismutase1 (SOD1) or SOD2, there was increased constitutive and stress-induced oxidative damage measured by the level of carbonyl adducts on proteins. In contrast, RPE Cells with increased expression of glutathione peroxidase 1 (Gpx1) or Gpx4 did not show an increase in constitutive oxidative damage. An increase in Gpx4, and to a lesser extent Gpx1, reduced oxidative stress-induced RPE Cell damage. Co-expression of Gpx4 with SOD1 or 2 partially reversed the deleterious effects of the SODs. Transgenic mice with inducible expression of Gpx4 in photoreceptors were generated, and in three...

  • blockade of neuronal nitric oxide synthase reduces Cone Cell death in a model of retinitis pigmentosa
    Free Radical Biology and Medicine, 2008
    Co-Authors: Keiichi Komeima, Brian S Rogers, Shinichi Usui, Jikui Shen, Peter A Campochiaro
    Abstract:

    Retinitis pigmentosa (RP) is a group of diseases in which many different mutations cause rod photoreceptor Cells to die and then gradually Cone photoreceptors die due to progressive oxidative damage. In this study, we have shown that peroxynitrite-induced nitrosative damage also occurs. In the rd1 mouse model of RP, there was increased staining for S-nitrosocysteine and nitrotyrosine protein adducts that are generated by peroxynitrite. Peroxynitrite is generated from nitric oxide (NO) and superoxide radicals. After degeneration of rods, injection of hydroethidine resulted in strong fluorescence in the retina of rd1 mice, indicating high levels of superoxide radicals, and this was reduced, as was nitrotyrosine staining, by apocynin, suggesting that overaction of NADP(H) oxidase is at least partially responsible. Treatment of rd1 mice with a mixture of nitric oxide synthase (NOS) inhibitors markedly reduced S-nitrosocysteine and nitrotyrosine staining and significantly increased Cone survival, indicating that NO-derived peroxynitrite contributes to Cone Cell death. Treatment with 7-nitroindazole, a relatively specific inhibitor of neuronal NOS, also significantly reduced Cone Cell death, but aminoguanidine, a relatively specific inhibitor of inducible NOS, did not. These data suggest that NO generated by neuronal NOS exacerbates oxidative damage to Cones in RP and that combined therapy to reduce NO and oxidative stress should be considered.

Serge Picaud - One of the best experts on this subject based on the ideXlab platform.

  • Functional Cone rescue by RdCVF protein in a dominant model of retinitis pigmentosa.
    Molecular Therapy, 2009
    Co-Authors: Ying Yang, Serge Picaud, Saddek Mohand-said, Thierry Léveillard, Aude Danan, Manuel Simonutti, Valérie Fontaine, Emmanuelle Clérin, José-alain Sahel
    Abstract:

    In retinitis pigmentosa (RP), a majority of causative mutations affect genes solely expressed in rods; however, Cone degeneration inevitably follows rod Cell loss. Following transplantation and in vitro studies, we demonstrated the role of photoreceptor Cell paracrine interactions and identified a Rod-derived Cone Viability Factor (RdCVF), which increases Cone survival. In order to establish the clinical relevance of such mechanism, we assessed the functional benefit afforded by the injection of this factor in a frequent type of rhodopsin mutation, the P23H rat. In this model of autosomal dominant RP, RdCVF expression decreases in parallel with primary rod degeneration, which is followed by Cone loss. RdCVF protein injections induced an increase in Cone Cell number and, more important, a further increase in the corresponding electroretinogram (ERG). These results indicate that RdCVF can not only rescue Cones but also preserve significantly their function. Interestingly, the higher amplitude of the functional versus the survival effect of RdCVF on Cones indicates that RdCVF is acting more directly on Cone function. The demonstration at the functional level of the therapeutic potential of RdCVF in the most frequent of dominant RP mutations paves the way toward the use of RdCVF for preserving central vision in many RP patients.

  • vigabatrin the gaba transaminase inhibitor damages Cone photoreceptors in rats
    American Journal of Ophthalmology, 2004
    Co-Authors: Agnes Duboc, Manuel Simonutti, Noelle Hanoteau, G Rudolf, Astrid Nehlig, Jose Sahel, Serge Picaud
    Abstract:

    In epilepsy, enhancing GABAinhibitory neurotransmission has become a major therapeutic strategy to limit the occurrence of seizures. Vigabatrin (which blocks the GABA transaminase, the GABA degrading enzyme) is a very efficient drug for the treatment of partial epilepsy, pharmacoresistant epilepsy and infantile spasms. Unfortunately, long term VGBadministration resulted in irreversible visual field constriction in approximately 40% of patients. This visual loss is associated with a dysfunction in the Cone photoreceptor pathway more than in the rod pathway. To investigate the Cellular origin of VGB toxicity, the authors treated rats daily with VGB for 45 days. Two days after arresting this treatment, rats exhibited an irreversible decrease in the photopic electroretinogram, the flicker response, and the oscillatory potentials. These functional alterations were associated with a peripheral disorganization of the outer retina. However, photoreceptor damage was not limited to these disorganized areas, but Cone inner and outer segments were severely injured in more central areas and their numbers were irreversibly decreased by 17 to 20%. Ultrastructural examination of the retina confirmed the presence of major photoreceptor damage, which were further supported by terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL) and caspase-3 activation both indicative of photoreceptor apoptosis. This study suggests that the visual field loss in vigabatrin-treated epileptic patients may result from a sequence of events starting from Cone Cell injury to a more severe disorganization of the photoreceptor layer.—Valerie Biousse

  • vigabatrin the gaba transaminase inhibitor damages Cone photoreceptors in rats
    Annals of Neurology, 2004
    Co-Authors: Agnes Duboc, Manuel Simonutti, Noelle Hanoteau, G Rudolf, Astrid Nehlig, Jose Sahel, Serge Picaud
    Abstract:

    Epileptic patients experienced an irreversible loss of their peripheral visual field upon treatment with vigabatrin (gamma-vinyl GABA), an inhibitor of the GABA degrading enzyme, GABA transaminase. Subsequently, central visual function was reported to also be irreversibly altered. This visual loss is associated with a decrease in the electroretinogram measurement localizing the deficit to the retina. To investigate its Cellular origin, we treated rats daily with vigabatrin for 45 days. Two days after arresting this treatment, rats exhibited an irreversible decrease in the photopic electroretinogram, the flicker response, and the oscillatory potentials. These functional alterations were associated with a peripheral disorganization of the outer retina. However, photoreceptor damage was not limited to these disorganized areas, but Cone inner and outer segments were severely injured in more central areas and their numbers were irreversibly decreased by 17 to 20%. Ultrastructural examination of the retina confirmed the presence of major photoreceptor damages, which were further supported by terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL) and caspase-3 activation both indicative of photoreceptor apoptosis. This study suggests that the visual field loss in vigabatrin-treated epileptic patients may result from a sequence of events starting from Cone Cell injury to a more severe disorganization of the photoreceptor layer.

Thomas G Cotter - One of the best experts on this subject based on the ideXlab platform.

  • norgestrel a progesterone analogue promotes significant long term neuroprotection of Cone photoreceptors in a mouse model of retinal disease
    Investigative Ophthalmology & Visual Science, 2019
    Co-Authors: Sarah L Roche, Nicolás Cuenca, Oksana Kutsyr, Thomas G Cotter
    Abstract:

    Purpose Retinitis pigmentosa (RP) refers to a group of inherited blinding retinal diseases, whereby the death of mutated rod photoreceptors is followed closely by the death of Cone photoreceptors. Cone Cell death can be hugely debilitating as color/daytime vision becomes impaired. Thus, treatments that are effective against Cone Cell death are urgently needed. Our research has been working toward development of a neuroprotective treatment for RP. We have previously demonstrated significant neuroprotective properties of norgestrel, a progesterone analogue, in the mouse retina. The current study further investigates the potential of norgestrel as a treatment for RP, with a focus on long-term preservation of Cone photoreceptors. Methods Using the well-established rd10 mouse model of RP, we administered a norgestrel-supplemented diet at postnatal day (P)30, following widespread loss of rod photoreceptors and at the outset of Cone degeneration. We subsequently assessed Cone Cell morphology and retinal function at P50, P60, and P80, using immunohistochemistry, electroretinograph recordings, and optomotor testing. Results While Cone Cell degeneration was widespread in the untreated rd10 retina, we observed profound preservation of Cone photoreceptor morphology in the norgestrel-treated mice for at least 50 days, out to P80. This was demonstrated by up to 28-fold more Cone arrestin-positive photoreceptors. This protection transpired to functional preservation at all ages. Conclusions This work presents norgestrel as an incredibly promising long-term neuroprotective compound for the treatment of RP. Crucially, norgestrel could be used in the mid-late stages of the disease to protect remaining Cone Cells and help preserve color/daytime vision.

Agnes Duboc - One of the best experts on this subject based on the ideXlab platform.

  • vigabatrin the gaba transaminase inhibitor damages Cone photoreceptors in rats
    American Journal of Ophthalmology, 2004
    Co-Authors: Agnes Duboc, Manuel Simonutti, Noelle Hanoteau, G Rudolf, Astrid Nehlig, Jose Sahel, Serge Picaud
    Abstract:

    In epilepsy, enhancing GABAinhibitory neurotransmission has become a major therapeutic strategy to limit the occurrence of seizures. Vigabatrin (which blocks the GABA transaminase, the GABA degrading enzyme) is a very efficient drug for the treatment of partial epilepsy, pharmacoresistant epilepsy and infantile spasms. Unfortunately, long term VGBadministration resulted in irreversible visual field constriction in approximately 40% of patients. This visual loss is associated with a dysfunction in the Cone photoreceptor pathway more than in the rod pathway. To investigate the Cellular origin of VGB toxicity, the authors treated rats daily with VGB for 45 days. Two days after arresting this treatment, rats exhibited an irreversible decrease in the photopic electroretinogram, the flicker response, and the oscillatory potentials. These functional alterations were associated with a peripheral disorganization of the outer retina. However, photoreceptor damage was not limited to these disorganized areas, but Cone inner and outer segments were severely injured in more central areas and their numbers were irreversibly decreased by 17 to 20%. Ultrastructural examination of the retina confirmed the presence of major photoreceptor damage, which were further supported by terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL) and caspase-3 activation both indicative of photoreceptor apoptosis. This study suggests that the visual field loss in vigabatrin-treated epileptic patients may result from a sequence of events starting from Cone Cell injury to a more severe disorganization of the photoreceptor layer.—Valerie Biousse

  • vigabatrin the gaba transaminase inhibitor damages Cone photoreceptors in rats
    Annals of Neurology, 2004
    Co-Authors: Agnes Duboc, Manuel Simonutti, Noelle Hanoteau, G Rudolf, Astrid Nehlig, Jose Sahel, Serge Picaud
    Abstract:

    Epileptic patients experienced an irreversible loss of their peripheral visual field upon treatment with vigabatrin (gamma-vinyl GABA), an inhibitor of the GABA degrading enzyme, GABA transaminase. Subsequently, central visual function was reported to also be irreversibly altered. This visual loss is associated with a decrease in the electroretinogram measurement localizing the deficit to the retina. To investigate its Cellular origin, we treated rats daily with vigabatrin for 45 days. Two days after arresting this treatment, rats exhibited an irreversible decrease in the photopic electroretinogram, the flicker response, and the oscillatory potentials. These functional alterations were associated with a peripheral disorganization of the outer retina. However, photoreceptor damage was not limited to these disorganized areas, but Cone inner and outer segments were severely injured in more central areas and their numbers were irreversibly decreased by 17 to 20%. Ultrastructural examination of the retina confirmed the presence of major photoreceptor damages, which were further supported by terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL) and caspase-3 activation both indicative of photoreceptor apoptosis. This study suggests that the visual field loss in vigabatrin-treated epileptic patients may result from a sequence of events starting from Cone Cell injury to a more severe disorganization of the photoreceptor layer.

Manuel Simonutti - One of the best experts on this subject based on the ideXlab platform.

  • Functional Cone rescue by RdCVF protein in a dominant model of retinitis pigmentosa.
    Molecular Therapy, 2009
    Co-Authors: Ying Yang, Serge Picaud, Saddek Mohand-said, Thierry Léveillard, Aude Danan, Manuel Simonutti, Valérie Fontaine, Emmanuelle Clérin, José-alain Sahel
    Abstract:

    In retinitis pigmentosa (RP), a majority of causative mutations affect genes solely expressed in rods; however, Cone degeneration inevitably follows rod Cell loss. Following transplantation and in vitro studies, we demonstrated the role of photoreceptor Cell paracrine interactions and identified a Rod-derived Cone Viability Factor (RdCVF), which increases Cone survival. In order to establish the clinical relevance of such mechanism, we assessed the functional benefit afforded by the injection of this factor in a frequent type of rhodopsin mutation, the P23H rat. In this model of autosomal dominant RP, RdCVF expression decreases in parallel with primary rod degeneration, which is followed by Cone loss. RdCVF protein injections induced an increase in Cone Cell number and, more important, a further increase in the corresponding electroretinogram (ERG). These results indicate that RdCVF can not only rescue Cones but also preserve significantly their function. Interestingly, the higher amplitude of the functional versus the survival effect of RdCVF on Cones indicates that RdCVF is acting more directly on Cone function. The demonstration at the functional level of the therapeutic potential of RdCVF in the most frequent of dominant RP mutations paves the way toward the use of RdCVF for preserving central vision in many RP patients.

  • vigabatrin the gaba transaminase inhibitor damages Cone photoreceptors in rats
    American Journal of Ophthalmology, 2004
    Co-Authors: Agnes Duboc, Manuel Simonutti, Noelle Hanoteau, G Rudolf, Astrid Nehlig, Jose Sahel, Serge Picaud
    Abstract:

    In epilepsy, enhancing GABAinhibitory neurotransmission has become a major therapeutic strategy to limit the occurrence of seizures. Vigabatrin (which blocks the GABA transaminase, the GABA degrading enzyme) is a very efficient drug for the treatment of partial epilepsy, pharmacoresistant epilepsy and infantile spasms. Unfortunately, long term VGBadministration resulted in irreversible visual field constriction in approximately 40% of patients. This visual loss is associated with a dysfunction in the Cone photoreceptor pathway more than in the rod pathway. To investigate the Cellular origin of VGB toxicity, the authors treated rats daily with VGB for 45 days. Two days after arresting this treatment, rats exhibited an irreversible decrease in the photopic electroretinogram, the flicker response, and the oscillatory potentials. These functional alterations were associated with a peripheral disorganization of the outer retina. However, photoreceptor damage was not limited to these disorganized areas, but Cone inner and outer segments were severely injured in more central areas and their numbers were irreversibly decreased by 17 to 20%. Ultrastructural examination of the retina confirmed the presence of major photoreceptor damage, which were further supported by terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL) and caspase-3 activation both indicative of photoreceptor apoptosis. This study suggests that the visual field loss in vigabatrin-treated epileptic patients may result from a sequence of events starting from Cone Cell injury to a more severe disorganization of the photoreceptor layer.—Valerie Biousse

  • vigabatrin the gaba transaminase inhibitor damages Cone photoreceptors in rats
    Annals of Neurology, 2004
    Co-Authors: Agnes Duboc, Manuel Simonutti, Noelle Hanoteau, G Rudolf, Astrid Nehlig, Jose Sahel, Serge Picaud
    Abstract:

    Epileptic patients experienced an irreversible loss of their peripheral visual field upon treatment with vigabatrin (gamma-vinyl GABA), an inhibitor of the GABA degrading enzyme, GABA transaminase. Subsequently, central visual function was reported to also be irreversibly altered. This visual loss is associated with a decrease in the electroretinogram measurement localizing the deficit to the retina. To investigate its Cellular origin, we treated rats daily with vigabatrin for 45 days. Two days after arresting this treatment, rats exhibited an irreversible decrease in the photopic electroretinogram, the flicker response, and the oscillatory potentials. These functional alterations were associated with a peripheral disorganization of the outer retina. However, photoreceptor damage was not limited to these disorganized areas, but Cone inner and outer segments were severely injured in more central areas and their numbers were irreversibly decreased by 17 to 20%. Ultrastructural examination of the retina confirmed the presence of major photoreceptor damages, which were further supported by terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL) and caspase-3 activation both indicative of photoreceptor apoptosis. This study suggests that the visual field loss in vigabatrin-treated epileptic patients may result from a sequence of events starting from Cone Cell injury to a more severe disorganization of the photoreceptor layer.