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Publication Detail
Excessive activation of cyclic nucleotide-gated channels contributes to neuronal degeneration of photoreceptors
  • Publication Type:
    Journal article
  • Publication Sub Type:
  • Authors:
    Vallazza-Deschamps G, Cia D, Gong J, Jellali A, Duboc A, Forster V, Sahel JA, Tessier LH, Picaud S
  • Publication date:
  • Pagination:
    1013, 1022
  • Journal:
  • Volume:
  • Issue:
  • Print ISSN:
  • Keywords:
    1-Methyl-3-isobutylxanthine, Adult, Animals, Animals, Newborn, Apoptosis, Blotting, Western, Cadmium Chloride, Calcium, Calcium Channel Blockers, Cell Death, Cells, Cultured, Comparative Study, Diltiazem, Disease Models, Animal, Dose-Response Relationship, Drug, drug effects, Drug Interactions, In Situ Nick-End Labeling, In Vitro, Ion Channels, methods, Mice, Mice, Mutant Strains, MOUSE, MOUSE RETINA, Nerve Degeneration, Neuroglia, pathology, pharmacology, Phosphodiesterase Inhibitors, photoreceptor, Photoreceptors, physiology, physiopathology, prevention & control, Purinones, RAT, Rats, Rats, Wistar, Research Support, Non-U.S.Gov't, Retina, rod, Swine, toxicity, Verapamil
  • Addresses:
    Laboratoire de Physiopathologie Cellulaire et Moleculaire de la Retine, INSERM U-592, Universite Pierre et Marie Curie, Batiment Kourilsky 6eme etage, 75571 Paris Cedex 12, France
  • Notes:
    DA - 20050922IS - 0953-816X (Print)LA - engPT - Journal ArticleRN - 0 (Calcium Channel Blockers)RN - 0 (Ion Channels)RN - 0 (Phosphodiesterase Inhibitors)RN - 0 (Purinones)RN - 0 (cyclic-nucleotide gated ion channels)RN - 10108-64-2 (Cadmium Chloride)RN - 28822-58-4 (1-Methyl-3-isobutylxanthine)RN - 37762-06-4 (zaprinast)RN - 42399-41-7 (Diltiazem)RN - 52-53-9 (Verapamil)SB - IM
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 Ca(2+) 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 Ca(2+) 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 Ca(2+) channel blockers suppressed rod Ca(2+) channel currents similarly. This suppression of the currents by the diltiazem isomers was very weak (16.5%) at the neuroprotective concentration (10 microm). 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 microm. 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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