Retinal safety of intravitreal rtPA in healthy rats and under excitotoxic conditions.

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Version: Final published version
Serval ID
serval:BIB_9384107D032F
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Retinal safety of intravitreal rtPA in healthy rats and under excitotoxic conditions.
Journal
Molecular vision
Author(s)
Daruich A., Parcq J., Delaunay K., Naud M.C., Le Rouzic Q., Picard E., Crisanti P., Vivien D., Berdugo M., Behar-Cohen F.
ISSN
1090-0535 (Electronic)
ISSN-L
1090-0535
Publication state
Published
Issued date
2016
Peer-reviewed
Oui
Volume
22
Pages
1332-1341
Language
english
Notes
Publication types: Journal Article
Publication Status: epublish
Abstract
Intravitreal recombinant tissue plasminogen activator (rtPA) is used off-label for the surgical management of submacular hemorrhage, a severe complication of neovascular age-related macular degeneration. rtPA is approved for coronary and cerebral thrombolysis. However, in ischemic stroke rtPA is known to increase excitotoxic neural cell death by interacting with the N-methyl-D-aspartate (NMDA) receptor. We therefore investigated the retinal toxicity of rtPA in healthy rats and in a model of NMDA-induced retinal excitotoxicity.
First, rtPA at three different doses (2.16 µg/5 µl, 0.54 µg/5 µl, and 0.27 µg/5 µl) or vehicle (NaCl 0.9%) was injected intravitreally in healthy rat eyes. Electroretinograms (ERGs) were performed at 24 h or 7 days. Annexin V-fluorescein isothiocyanate (FITC)-labeled apoptotic retinal ganglion cells (RGCs) were counted on flatmounted retinas at 24 h or 7 days. Next, NMDA + vehicle or NMDA + rtPA (0.27 µg/5 µl) was injected intravitreally to generate excitotoxic conditions. Apoptotic annexin V-FITC-labeled RGCs and surviving Brn3a-labeled RGCs were quantified on flatmounted retinas and radial sections, 18 h after treatment.
In healthy rat eyes, the number of apoptotic RGCs was statistically significantly increased 24 h after the administration of rtPA at the highest dose (2.16 µg/5 µl; p = 0.0250) but not at the lower doses of 0.54 and 0.27 µg/5 µl (p = 0.36 and p = 0.20), compared to vehicle. At day 7, there was no difference in the apoptotic RGC count between the rtPA- and vehicle-injected eyes (p = 0.70, p = 0.52, p = 0.11). ERG amplitudes and implicit times were not modified at 24 h or 7 days after injection of any tested rtPA doses, compared to the baseline. Intravitreal administration of NMDA induced RGC death, but under these excitotoxic conditions, coadministration of rtPA did not increase the number of dead RGCs (p = 0.70). Similarly, the number of surviving RGCs on the flatmounted retinas and retinal sections did not differ between the eyes injected with NMDA + vehicle and NMDA + rtPA (p = 0.59 and p = 0.67).
At low clinical equivalent doses corresponding to 25 µg/0.1 ml in humans, intravitreal rtPA is not toxic for healthy rat retinas and does not enhance NMDA-induced excitotoxicity. Vitreal equivalent doses ≥200 µg/0.1 ml should be avoided in patients, due to potential RGC toxicity.

Keywords
Animals, Apoptosis/drug effects, Electroretinography, Intravitreal Injections, Male, Neurotoxins/toxicity, Rats, Long-Evans, Recombinant Proteins/administration & dosage, Recombinant Proteins/adverse effects, Recombinant Proteins/pharmacology, Retina, Retinal Ganglion Cells/drug effects, Retinal Ganglion Cells/metabolism, Tissue Plasminogen Activator/administration & dosage, Tissue Plasminogen Activator/adverse effects, Tissue Plasminogen Activator/pharmacology
Pubmed
Web of science
Create date
06/12/2016 20:25
Last modification date
20/08/2019 14:56
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