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Excessive activation of cyclic nucleotide-gated channels contributes to neuronal degeneration of photoreceptors

Authors

  • Géraldine Vallazza-Deschamps,

    1. Laboratoire de Physiopathologie Cellulaire et Moléculaire de la Rétine, INSERM U-592, Université Pierre et Marie Curie, Bâtiment Kourilsky 6ème étage, 184 rue du Faubourg Saint-Antoine, 75571 Paris Cedex 12, France
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  • David Cia,

    1. Laboratoire de Physiopathologie Cellulaire et Moléculaire de la Rétine, INSERM U-592, Université Pierre et Marie Curie, Bâtiment Kourilsky 6ème étage, 184 rue du Faubourg Saint-Antoine, 75571 Paris Cedex 12, France
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  • Jie Gong,

    1. Laboratoire de Physiopathologie Cellulaire et Moléculaire de la Rétine, INSERM U-592, Université Pierre et Marie Curie, Bâtiment Kourilsky 6ème étage, 184 rue du Faubourg Saint-Antoine, 75571 Paris Cedex 12, France
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  • Abdeljelil Jellali,

    1. Laboratoire de Physiopathologie Cellulaire et Moléculaire de la Rétine, INSERM U-592, Université Pierre et Marie Curie, Bâtiment Kourilsky 6ème étage, 184 rue du Faubourg Saint-Antoine, 75571 Paris Cedex 12, France
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  • Agnès Duboc,

    1. Laboratoire de Physiopathologie Cellulaire et Moléculaire de la Rétine, INSERM U-592, Université Pierre et Marie Curie, Bâtiment Kourilsky 6ème étage, 184 rue du Faubourg Saint-Antoine, 75571 Paris Cedex 12, France
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  • Valérie Forster,

    1. Laboratoire de Physiopathologie Cellulaire et Moléculaire de la Rétine, INSERM U-592, Université Pierre et Marie Curie, Bâtiment Kourilsky 6ème étage, 184 rue du Faubourg Saint-Antoine, 75571 Paris Cedex 12, France
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  • Jose A. Sahel,

    1. Laboratoire de Physiopathologie Cellulaire et Moléculaire de la Rétine, INSERM U-592, Université Pierre et Marie Curie, Bâtiment Kourilsky 6ème étage, 184 rue du Faubourg Saint-Antoine, 75571 Paris Cedex 12, France
    2. Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts, Paris, France
    3. Fondation Ophtalmologique Adolphe de Rothschild, Paris, France
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  • Luc-Henri Tessier,

    1. Laboratoire de Physiopathologie Cellulaire et Moléculaire de la Rétine, INSERM U-592, Université Pierre et Marie Curie, Bâtiment Kourilsky 6ème étage, 184 rue du Faubourg Saint-Antoine, 75571 Paris Cedex 12, France
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  • Serge Picaud

    1. Laboratoire de Physiopathologie Cellulaire et Moléculaire de la Rétine, INSERM U-592, Université Pierre et Marie Curie, Bâtiment Kourilsky 6ème étage, 184 rue du Faubourg Saint-Antoine, 75571 Paris Cedex 12, France
    2. Fondation Ophtalmologique Adolphe de Rothschild, Paris, France
    3. AP-HP, Paris, France
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Dr Serge Picaud, 1Laboratoire de Physiopathologie Cellulaire et Moléculaire de la Rétine, as above.
E-mail: picaud@st-antoine.inserm.fr

Abstract

In different animal models, photoreceptor degeneration was correlated to an abnormal increase in cGMP concentration. The cGMP-induced photoreceptor toxicity was demonstrated by applying the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine on retinal explants. To assess the role of cGMP-gated channels in this cGMP toxicity, the Ca2+ channel blockers verapamil and l- and d-diltiazem, which block cGMP-gated channels with different efficacies, were applied to in vitro animal models of photoreceptor degeneration. These models included: (i) adult rat retinal explants incubated with zaprinast, a more specific inhibitor of the rod phosphodiesterase than 3-isobutyl-1-methylxanthine and (ii) rd mouse retinal explants. Photoreceptor apoptosis was assessed by terminal dUTP nick end labelling and caspase 3 activation. Effects of the blockers on the synaptic rod Ca2+ channels were measured by patch-clamp recording. In the zaprinast-induced photoreceptor degeneration model, both diltiazem isomers rescued photoreceptors whereas verapamil had no influence. Their neuroprotective efficacy was correlated to their inhibition of cGMP-gated channels (l-diltiazem > d-diltiazem > verapamil = 0). In contrast, all three Ca2+ channel blockers suppressed rod Ca2+ channel currents similarly. This suppression of the currents by the diltiazem isomers was very weak (16.5%) at the neuroprotective concentration (10 µm). In rd retinal explants, both diltiazem isomers also slowed down rod degeneration in contrast to verapamil. l-diltiazem exhibited this effect at concentrations ranging from 1 to 20 µm. This study further supports the photoreceptor neuroprotection by diltiazem particularly in the rd mouse retina, whereas the absence of neuroprotection by verapamil further suggests the role of cGMP-gated channel activation in the induction of photoreceptor degeneration.

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