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Protection of retinal ganglion cells by caspase substrate-binding peptide IQACRG from N-methyl-D-aspartate receptor-mediated excitotoxicity.
Invest Ophthalmol Vis Sci. 2010 Feb; 51(2):1198-207.IO

Abstract

PURPOSE

This study investigated whether the enzymatically inactive caspase mimetic IQACRG protects rat retinal ganglion cells (RGCs) from excitotoxic insults. Minimally invasive delivery of the peptide to the retina was explored, and the mechanisms of neuroprotection were elucidated.

METHODS

IQACRG was linked to penetratin (P-IQACRG) to facilitate cellular uptake. RGC labeling by biotinylated-P-IQACRG delivered via intravitreal or subconjunctival injection was demonstrated by avidin-biotin chemistry. The authors used histologic and electrophysiological measures to evaluate the neuroprotective potential of P-IQACRG against RGC death induced by N-methyl-D-aspartate (NMDA) in vitro and in vivo. In addition, they monitored activity of an enzyme that is downstream of caspase-1, matrix metalloproteinase-9 (MMP-9), and protein levels of the caspase-3/7 substrate, myocyte enhancer factor 2C (MEF2C), to determine the effectiveness of IQACRG in blocking excessive caspase activity.

RESULTS

IQACRG significantly reduced NMDA-induced RGC death in culture and in vivo. Ex vivo electrophysiological recording of the retina on multielectrode arrays demonstrated functional rescue of RGCs by IQACRG. The authors also found that delivery of IQACRG to the retina inhibited NMDA-triggered MMP-9 activity and prevented cleavage of MEF2C protein that would otherwise have been engendered by caspase activation preceding RGC death. Strikingly, subconjunctival injection of P-IQACRG was very effective in preventing NMDA-induced RGC death in vivo.

CONCLUSIONS

These data demonstrate that IQACRG protects RGCs from excitotoxicity in vitro and in vivo. The positive results with subconjunctival administration of P-IQACRG suggest that in the future this treatment may be useful clinically in diseases such as glaucoma and retinal ischemia.

Authors+Show Affiliations

Del E. Webb Center for Neuroscience, Aging, and Stem Cell Research, Burnham Institute for Medical Research, La Jolla, California 92037, USA.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19815732

Citation

Seki, Masaaki, et al. "Protection of Retinal Ganglion Cells By Caspase Substrate-binding Peptide IQACRG From N-methyl-D-aspartate Receptor-mediated Excitotoxicity." Investigative Ophthalmology & Visual Science, vol. 51, no. 2, 2010, pp. 1198-207.
Seki M, Soussou W, Manabe S, et al. Protection of retinal ganglion cells by caspase substrate-binding peptide IQACRG from N-methyl-D-aspartate receptor-mediated excitotoxicity. Invest Ophthalmol Vis Sci. 2010;51(2):1198-207.
Seki, M., Soussou, W., Manabe, S., & Lipton, S. A. (2010). Protection of retinal ganglion cells by caspase substrate-binding peptide IQACRG from N-methyl-D-aspartate receptor-mediated excitotoxicity. Investigative Ophthalmology & Visual Science, 51(2), 1198-207. https://doi.org/10.1167/iovs.09-4102
Seki M, et al. Protection of Retinal Ganglion Cells By Caspase Substrate-binding Peptide IQACRG From N-methyl-D-aspartate Receptor-mediated Excitotoxicity. Invest Ophthalmol Vis Sci. 2010;51(2):1198-207. PubMed PMID: 19815732.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Protection of retinal ganglion cells by caspase substrate-binding peptide IQACRG from N-methyl-D-aspartate receptor-mediated excitotoxicity. AU - Seki,Masaaki, AU - Soussou,Walid, AU - Manabe,Shin-ichi, AU - Lipton,Stuart A, Y1 - 2009/10/08/ PY - 2009/10/10/entrez PY - 2009/10/10/pubmed PY - 2010/2/18/medline SP - 1198 EP - 207 JF - Investigative ophthalmology & visual science JO - Invest Ophthalmol Vis Sci VL - 51 IS - 2 N2 - PURPOSE: This study investigated whether the enzymatically inactive caspase mimetic IQACRG protects rat retinal ganglion cells (RGCs) from excitotoxic insults. Minimally invasive delivery of the peptide to the retina was explored, and the mechanisms of neuroprotection were elucidated. METHODS: IQACRG was linked to penetratin (P-IQACRG) to facilitate cellular uptake. RGC labeling by biotinylated-P-IQACRG delivered via intravitreal or subconjunctival injection was demonstrated by avidin-biotin chemistry. The authors used histologic and electrophysiological measures to evaluate the neuroprotective potential of P-IQACRG against RGC death induced by N-methyl-D-aspartate (NMDA) in vitro and in vivo. In addition, they monitored activity of an enzyme that is downstream of caspase-1, matrix metalloproteinase-9 (MMP-9), and protein levels of the caspase-3/7 substrate, myocyte enhancer factor 2C (MEF2C), to determine the effectiveness of IQACRG in blocking excessive caspase activity. RESULTS: IQACRG significantly reduced NMDA-induced RGC death in culture and in vivo. Ex vivo electrophysiological recording of the retina on multielectrode arrays demonstrated functional rescue of RGCs by IQACRG. The authors also found that delivery of IQACRG to the retina inhibited NMDA-triggered MMP-9 activity and prevented cleavage of MEF2C protein that would otherwise have been engendered by caspase activation preceding RGC death. Strikingly, subconjunctival injection of P-IQACRG was very effective in preventing NMDA-induced RGC death in vivo. CONCLUSIONS: These data demonstrate that IQACRG protects RGCs from excitotoxicity in vitro and in vivo. The positive results with subconjunctival administration of P-IQACRG suggest that in the future this treatment may be useful clinically in diseases such as glaucoma and retinal ischemia. SN - 1552-5783 UR - https://www.unboundmedicine.com/medline/citation/19815732/Protection_of_retinal_ganglion_cells_by_caspase_substrate_binding_peptide_IQACRG_from_N_methyl_D_aspartate_receptor_mediated_excitotoxicity_ L2 - https://iovs.arvojournals.org/article.aspx?doi=10.1167/iovs.09-4102 DB - PRIME DP - Unbound Medicine ER -