Inhibition of Matrix Metalloproteinase 9 Enhances Rod Survival in the S334ter-line3 Retinitis Pigmentosa Model

Retinitis Pigmentosa (RP) is one of the most common forms of inherited visual loss with the initial degeneration of rod photoreceptors, followed by a progressive cone photoreceptor deterioration. Coinciding with this visual loss, the extracellular matrix (ECM) is reorganized, which alters matrix met...

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Bibliographic Details
Published in:PloS one 2016-11, Vol.11 (11), p.e0167102-e0167102
Main Authors: Shin, Jung-A, Kim, Hwa Sun, Vargas, Andrew, Yu, Wan-Qing, Eom, Yun Sung, Craft, Cheryl Mae, Lee, Eun-Jin
Format: Article
Language:English
Subjects:
Analysis
Animals
Apoptosis
Biology and Life Sciences
Brain research
Cell death
Cell survival
Cells, Cultured
Clustering
Death
Degeneration
Disease Models, Animal
Excitotoxicity
Extracellular matrix
Feasibility studies
Female
Gelatinase A
Gelatinase B
Gene expression
Genetic aspects
Heterocyclic Compounds, 1-Ring - pharmacology
Laboratories
Matrix metalloproteinase
Matrix Metalloproteinase 2 - chemistry
Matrix Metalloproteinase 9 - chemistry
Medicine
Medicine and Health Sciences
Metalloproteinase
Mortality
Neurosciences
Photoreception
Photoreceptors
Preservation
Protease Inhibitors - pharmacology
Rats
Rats, Sprague-Dawley
Rats, Transgenic
Research and Analysis Methods
Retina
Retinal degeneration
Retinal Degeneration - drug therapy
Retinal Degeneration - enzymology
Retinal Rod Photoreceptor Cells - cytology
Retinal Rod Photoreceptor Cells - drug effects
Retinal Rod Photoreceptor Cells - enzymology
Retinitis
Retinitis pigmentosa
Retinitis Pigmentosa - drug therapy
Retinitis Pigmentosa - enzymology
Retinitis Pigmentosa - pathology
Rhodopsin
Rodents
Social Sciences
Sulfones - pharmacology
Survival
Traumatic brain injury
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Summary:Retinitis Pigmentosa (RP) is one of the most common forms of inherited visual loss with the initial degeneration of rod photoreceptors, followed by a progressive cone photoreceptor deterioration. Coinciding with this visual loss, the extracellular matrix (ECM) is reorganized, which alters matrix metalloproteinase (MMP) activity levels. A potential pathological role of MMPs, MMP-9 in particular, involves an excitotoxicity-mediated physiological response. In the current study, we examine the MMP-9 and MMP-2 expression levels in the rhodopsin S334ter-line3 RP rat model and investigate the impact of treatment with SB-3CT, a specific MMP-9 and MMP-2 inhibitor, on rod cell survival was tested. Retinal MMP-9 and MMP-2 expression levels were quantified by immunoblot analysis from S334ter-line3 rats compared to controls. Gelatinolytic activities of MMP-9 and MMP-2 by zymography were examined. The geometry of rod death was further evaluated using Voronoi analysis. Our results revealed that MMP-9 was elevated while MMP-2 was relatively unchanged when S334ter-line 3 retinas were compared to controls. With SB-3CT treatment, we observed gelatinolytic activity of both MMPs was decreased and diminished clustering associated with rod death, in addition to a robust preservation of rod photoreceptors. These results demonstrate that up-regulation of MMP-9 in retinas of S334ter-line3 are associated with rod death. The application of SB-3CT dramatically interferes with mechanisms leading to apoptosis in an MMP-9-dependent manner. Future studies will determine the feasibility of using SB-3CT as a potential therapeutic strategy to slow progression of vision loss in genetic inherited forms of human RP.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0167102