Compound 49b prevents diabetes-induced apoptosis through increased IGFBP-3 levels.

Qiuhua Zhang, Kimberly Guy, Jayaprakash Pagadala, Youde Jiang, Robert J. Walker, Luhong Liu, Carl Soderland, Timothy S. Kern, Robert Ferry, Hui He, Charles Yates, Duane Miller, Jena J. Steinle

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Abstract

To determine whether Compound 49b, a novel PKA-activating drug, can prevent diabetic-like changes in the rat retina through increased insulin-like growth factor binding protein-3 (IGFBP-3) levels. For the cell culture studies, we used both human retinal endothelial cells (REC) and retinal Müller cells in either 5 mM (normal) or 25 mM (high) glucose. Cells were treated with 50 nM Compound 49b alone of following treatment with protein kinase A (PKA) siRNA or IGFBP-3 siRNA. Western blotting and ELISA analyses were done to verify PKA and IGFBP-3 knockdown, as well as to measure apoptotic markers. For animal studies, we used streptozotocin-treated rats after 2 and 8 months of diabetes. Some rats were treated topically with 1 mM Compound 49b. Analyses were done for retinal thickness, cell numbers in the ganglion cell layer, pericyte ghosts, and numbers of degenerate capillaries, as well as electroretinogram and heart morphology. Compound 49b requires active PKA and IGFBP-3 to prevent apoptosis of REC. Compound 49b significantly reduced the numbers of degenerate capillaries and pericyte ghosts, while preventing the decreased retinal thickness and loss of cells in the ganglion cell layer. Compound 49b maintained a normal electroretinogram, with no changes in blood pressure, intraocular pressure, or heart morphological changes. Topical Compound 49b is able to prevent diabetic-like changes in the rat retina, without producing systemic changes. Compound 49b is able to prevent REC apoptosis through increasing IGFBP-3 levels, which are reduced in response to hyperglycemia.

Original languageEnglish (US)
Pages (from-to)3004-3013
Number of pages10
JournalInvestigative ophthalmology & visual science
Volume53
Issue number6
DOIs
StatePublished - Jan 1 2012

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Insulin-Like Growth Factor Binding Protein 3
Cyclic AMP-Dependent Protein Kinases
Apoptosis
Pericytes
Endothelial Cells
Ganglia
Small Interfering RNA
Retina
Streptozocin
Intraocular Pressure
Hyperglycemia
Cell Culture Techniques
Cell Count
Western Blotting
Enzyme-Linked Immunosorbent Assay
Blood Pressure
Glucose
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

Cite this

Zhang, Q., Guy, K., Pagadala, J., Jiang, Y., Walker, R. J., Liu, L., ... Steinle, J. J. (2012). Compound 49b prevents diabetes-induced apoptosis through increased IGFBP-3 levels. Investigative ophthalmology & visual science, 53(6), 3004-3013. https://doi.org/10.1167/iovs.11-8779

Compound 49b prevents diabetes-induced apoptosis through increased IGFBP-3 levels. / Zhang, Qiuhua; Guy, Kimberly; Pagadala, Jayaprakash; Jiang, Youde; Walker, Robert J.; Liu, Luhong; Soderland, Carl; Kern, Timothy S.; Ferry, Robert; He, Hui; Yates, Charles; Miller, Duane; Steinle, Jena J.

In: Investigative ophthalmology & visual science, Vol. 53, No. 6, 01.01.2012, p. 3004-3013.

Research output: Contribution to journalArticle

Zhang, Q, Guy, K, Pagadala, J, Jiang, Y, Walker, RJ, Liu, L, Soderland, C, Kern, TS, Ferry, R, He, H, Yates, C, Miller, D & Steinle, JJ 2012, 'Compound 49b prevents diabetes-induced apoptosis through increased IGFBP-3 levels.', Investigative ophthalmology & visual science, vol. 53, no. 6, pp. 3004-3013. https://doi.org/10.1167/iovs.11-8779
Zhang, Qiuhua ; Guy, Kimberly ; Pagadala, Jayaprakash ; Jiang, Youde ; Walker, Robert J. ; Liu, Luhong ; Soderland, Carl ; Kern, Timothy S. ; Ferry, Robert ; He, Hui ; Yates, Charles ; Miller, Duane ; Steinle, Jena J. / Compound 49b prevents diabetes-induced apoptosis through increased IGFBP-3 levels. In: Investigative ophthalmology & visual science. 2012 ; Vol. 53, No. 6. pp. 3004-3013.
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