May 2003
Volume 44, Issue 13
Free
ARVO Annual Meeting Abstract  |   May 2003
Cellular and Molecular Pathways underlying Photoreceptor Rescue by CNTF+BDNF Treatment in Mouse Retinal Explants
Author Affiliations & Notes
  • A.R. Caffe
    Wallenberg Retina Ctr, Univ of Lund- Dept. Ophthalmology, Lund, Sweden
  • S. Azadi
    Wallenberg Retina Ctr, Univ of Lund- Dept. Ophthalmology, Lund, Sweden
  • Y. Zhang
    Wallenberg Retina Ctr, Univ of Lund- Dept. Ophthalmology, Lund, Sweden
  • M.T. Perez
    Wallenberg Retina Ctr, Univ of Lund- Dept. Ophthalmology, Lund, Sweden
  • T. van Veen
    Wallenberg Retina Ctr, Univ of Lund- Dept. Ophthalmology, Lund, Sweden
  • Footnotes
    Commercial Relationships  A.R. Caffe, None; S. Azadi, None; Y. Zhang, None; M.T. Perez, None; T. van Veen, None.
  • Footnotes
    Support  FFB, Wallenberg Foundation, KMA, SSMF, Crafoord Foundation, Dutch Retina Foundation,
Investigative Ophthalmology & Visual Science May 2003, Vol.44, 2826. doi:
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      A.R. Caffe, S. Azadi, Y. Zhang, M.T. Perez, T. van Veen; Cellular and Molecular Pathways underlying Photoreceptor Rescue by CNTF+BDNF Treatment in Mouse Retinal Explants . Invest. Ophthalmol. Vis. Sci. 2003;44(13):2826.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Abstract: : Purpose: Various individual or combined survival factors have been tested for their capacity to rescue rd photoreceptors. The conclusion is that currently the cocktail CNTF+BDNF provides the best pharmacological protection in mouse retinal explants (RE). In order to develop this cocktail for pharmaceutical application the molecular and cellular pathways that mediate its effect must be determined. When treated with CNTF+BDNF, rd RE upregulate GDNF and NGF mRNAs, whereas FGF2 transcript is not further upregulated. These proteins might function either intra- or extracellularly. The purpose here is to distinguish between these possibilities as well as to determine the involved intracellular signaling pathways. Methods: C3H +/+ and rd mice were used to generate RE according to an established procedure. RE were cultured with or without 10 ng/ml CNTF+BDNF supplemented with neutralizing antibody against either GFR-α1, ß-NGF or FGF2 (dilution 1:1000). The ligands activate intracellular pathways including the PI3K and ERK1/2 cascades. To test participation of these signaling pathways in CNTF+BDNF photoreceptor rescue, rd and +/+ RE were cultured with LY294002 (inhibits PI3K) or U0126 (inhibits ERK) or the combination of these chemicals. The culture medium was replaced trice a week. In all cases the rows of photoreceptors in the ONL were counted and the data analyzed statistically. Results: None of the antibodies had a significant effect on the normal genotypic development of either +/+ or rd RE. However, cultivation of rd RE with CNTF+BDNF supplemented with antibodies against GFR-α1 markedly reduced rescue of photoreceptor cells. Addition of ß-NGF or FGF2 neutralizing antibodies had modest consequences. Supplementation of 10 µM LY294002 or 10 µM U0126 individually to the +/+ and rd control or CNTF+BDNF-treated rd RE had minor effects, but the combined treatment completely prevented rescue in rd RE by CNTF+BDNF treatment. Conclusions: Whereas the +/+ mouse retina can generate a competent injury response on its own in culture, in similar conditions the rd retina lacks this ability. Treatment of the rd RE with CNTF+BDNF restores this tissue’s capacity to manifest this healing response. We assume that this phenomenon is implicated in the photoreceptor rescue. It appears that the GDNF and NGF neurotrophic factors play a substantial role in this rescue, initially via an extracellular pathway. After secretion, likely by Muller cells, these factors bind to photoreceptor cell surface receptors and activate multiple intracellular signaling pathways.

Keywords: neuroprotection • retinal culture • growth factors/growth factor receptors 
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