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Excessive activation of cyclic nucleotide‐gated channels contributes to neuronal degeneration of photoreceptors
Author(s) -
VallazzaDeschamps Géraldine,
Cia David,
Gong Jie,
Jellali Abdeljelil,
Duboc Agnès,
Forster Valérie,
Sahel Jose A.,
Tessier LucHenri,
Picaud Serge
Publication year - 2005
Publication title -
european journal of neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.346
H-Index - 206
eISSN - 1460-9568
pISSN - 0953-816X
DOI - 10.1111/j.1460-9568.2005.04306.x
Subject(s) - diltiazem , zaprinast , verapamil , retinal degeneration , phosphodiesterase , channel blocker , cyclic guanosine monophosphate , neuroprotection , pharmacology , chemistry , cyclic nucleotide gated ion channel , calcium channel , biology , retinal , endocrinology , biochemistry , calcium , cyclic nucleotide , organic chemistry , nitric oxide , gene , enzyme , nucleotide
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 µ m ). 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 µ m . 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.