Excessive activation of cyclic nucleotide-gated channels contributes to neuronal degeneration of photoreceptors.
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.
Vallazza-Deschamps
Géraldine
G
Laboratoire de Physiopathologie Cellulaire et Moléculaire de la Rétine, INSERM U-592, Université Pierre et Marie Curie, Bâtiment Kourilsky 6ème étage, 75571 Paris Cedex 12, France.
Cia
David
D
Gong
Jie
J
Jellali
Abdeljelil
A
Duboc
Agnès
A
Forster
Valérie
V
Sahel
Jose A
JA
Tessier
Luc-Henri
LH
Picaud
Serge
S
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western / Q000379:methods; D019256:Cadmium Chloride / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D054815:Cyclic Nucleotide-Gated Cation Channels; D004110:Diltiazem / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D020287:In Situ Nick-End Labeling / Q000379:methods; D066298:In Vitro Techniques; D007473:Ion Channels / Q000502:physiology*; D051379:Mice; D008817:Mice, Mutant Strains; D009410:Nerve Degeneration / Q000473:pathology* / Q000503:physiopathology* / Q000517:prevention & control; D009457:Neuroglia / Q000187:drug effects / Q000502:physiology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010786:Photoreceptor Cells / Q000187:drug effects / Q000473:pathology*; D011688:Purinones / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013552:Swine; D014700:Verapamil / Q000494:pharmacology
D002121:Calcium Channel Blockers; D054815:Cyclic Nucleotide-Gated Cation Channels; D007473:Ion Channels; D010726:Phosphodiesterase Inhibitors; D011688:Purinones; D014700:Verapamil; D004110:Diltiazem; C011145:zaprinast; D019256:Cadmium Chloride; D015056:1-Methyl-3-isobutylxanthine